Original Research

Colorectal cancer (CRC) is the third leading cause of cancer-related death in veterans, despite significant advances in treatment options.^1,2 Over the past 20 years, the median survival of patients with metastatic CRC (mCRC), has improved with the most recent clinical trials demonstrating a median overall survival (OS) of up to 29 months.³

In addition to standard chemotherapeutic regimens using 5-fluorouracil, oxaliplatin, and irinotecan, biologic therapies have resulted in improved OS for patients with mCRC. These therapies include the human vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab and the epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab. Additional agents, including aflibercept, ramucirumab, regorafenib, and TAS-102, also have been FDA approved for mCRC, though the OS benefit for these agents as part of the series of standard-of-care treatments is less clear.

Investigators continue to determine subtypes of CRC to further advance treatment options. The histologic classification of colon cancers is actually a collection of multiple cancer subtypes. Each subtype possesses a unique biology largely dependent on the mutations present within the cancer. Recent data, reviewed below, indicate predictive and prognostic benefits to understanding the unique mutational profile of mCRC. Here, the authors present a brief updated summary of these biomarkers and a discussion of treatment strategies.

Resistance to Anti-EGFR Therapies

KRAS and NRAS are members of the RAS family of oncogenes. Activating mutations in these genes results in the propagation of growth factor signals independent of EGFR. The most common KRAS mutations are found in exon 2 (codon 12 or 13). Numerous studies over the past 10 years have confirmed that KRAS mutations at exon 2 predict resistance to cetuximab and panitumumab.^4-11 Since at least 2009, restricting use of cetuximab and panitumumab has been the standard of care for patients with KRAS exon 2 wild-type cancers.¹²

Recent investigations have indicated a predictive role for extended-spectrum KRAS and NRAS mutations (KRAS mutations at exons 2, 3, and 4 and NRAS mutations at exons 2, 3, and 4). In the OPUS clinical trial, patients whose cancers possessed extended-spectrum RAS mutations received no benefit with the addition of cetuximab to standard chemotherapy in response rate (RR), progression-free survival (PFS), or OS compared with standard chemotherapy alone.¹³ Interestingly, median OS was shorter for those treated with cetuximab when a RAS mutation was present, though the difference was not statistically significant. Additional studies also have confirmed similar benefits in different settings.^8,14-18

The CALGB/SWOG 80405 phase 3 clinical trial investigated the first-line use of biologic therapies in combination with standard chemotherapy. The extendedspectrum RAS testing from this study now has been presented.^3,19 In the RAS wild-type population, the median OS was 31.2 months in the chemotherapy plus bevacizumab arm and 32.0 months in the chemotherapy plus cetuximab arm (no significant difference). No difference in PFS was observed. A significant improvement in the RR was seen in the cetuximab arm for the RAS wild-type population.

Predictive Biomarkers

BRAF is an oncogene in the RAF gene family that encodes a serine-threonine protein kinase found in the Ras-Raf-MAPK cascade. About 10% of CRC harbor a BRAF mutation.^20,21 The most significant and prevalent mutation occurs at the kinase domain from the single substitution V600E. Numerous clinical studies have suggested the presence of this mutation as a predictor of resistance to anti-EGFR therapies and a marker of poor prognosis.^6,17,22-25 In a retrospective analysis of RAS and BRAF mutation status of PRIME study data, patients without RAS and BRAF mutations showed significantly better OS and PFS when treated with FOLFOX4 (5-fluorouracil, oxaliplatin, and leucovorin) plus panitumumab, compared with FOLFOX4 alone.⁸ The presence of BRAF mutations in RAS wild-type patients resulted in a worse outcome. Treatment with anti-EGFR therapy did not significantly improve median PFS or OS.

PIK3CA mutations. Phosphoinositide 3-kinase (PI3K) is a lipid kinase important for multiple cellular processes including cell growth, proliferation, survival, and apoptosis. PIK3CA encodes the catalytic subunit and is mutant in about 20% of mCRC.²⁶ The PI3K is downstream of EGFR signaling; activation of this pathway in the setting of an oncogenic mutation might lead to resistance to anti-EGFR therapies. Sartore-Bianchi and colleagues examined 110 patients with mCRC treated with either panitumumab or cetuximab.²⁷ Of these, 15 patient cancers featured PIK3CA mutations, and none of these responded to anti-EGFR therapies. In addition, preclinical studies have demonstrated that targeting CRC downstream of PI3K might result in significant treatment benefit.^28,29

Human epidermal growth factor receptor 2 (HER2) amplification. A subpopulation of CRC with amplification of HER2, a growth factor receptor commonly used in selecting treatment options in breast cancer, has recently been described. The HERACLES phase 2 study evaluated dual HER2 targeting with lapatinib and trastuzumab in therapy-refractory mCRC with HER2 amplification.³⁰ A RR of 35% was observed in this treatment-refractory population.

BRAF mutations. In addition to predicting a poor prognosis and resistance to EGFR-directed therapies, BRAF mutations might be predictive of treatment response using combination regimens containing RAF inhibitors. A recent phase 1B study of a combination therapy using the BRAF inhibitor vemurafenib with irinotecan and cetuximab observed a partial RR of 35%.³¹ This is being investigated further in the Southwest Oncology Group 1406 phase 2 trial.

Mismatch repair deficiency. Detection of microsatellite instability or the presence of mismatch repair deficiency has become standard-of-care testing for CRC. This is important for the detection of Lynch syndrome and predicting potential resistance to adjuvant 5-fluorouracil in the adjuvant setting.^32,33 A recent clinical trial has demonstrated benefits for the use of programmed death 1 (PD-1) inhibitors in the setting of mismatch repair deficiency, including a RR of 40% and PFS of 5.4 months.³⁴

Discussion

Metastatic CRC is now better understood as a collection of multiple cancer subtypes based on mutational profile. This improved understanding of the biology of CRC is altering treatment strategies to a precision medicine-based approach. It is now the standard of care for all patients with mCRC to have the cancers assayed for mutations in KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF. Anti-EGFR therapies should not be used for patients with RAS or BRAF mutations outside of a clinical trial because of a demonstrated lack of benefit in all lines of therapy. Currently, there is no evidence that these mutations significantly alter the response to the approved anti-angiogenic agents bevacizumab, aflibercept, ramucirumab, and regorafenib.

The timing of EGFR-directed therapies for patients with wild-type KRAS, NRAS, and BRAF is still being debated. According to the available data, first-line treatment with anti-EGFR agents in combination with FOLFOX or FOLFIRI (5-fluorouracil, irinotecan, and leucovorin) should be considered for all patients with KRAS, NRAS, and BRAF wild-type mCRCs. The toxicities of anti-EGFR therapies also should be considered for this setting, as some patients find that the acneiform rash, fatigue, nausea, and diarrhea that occur with these agents can have a negative impact on quality of life. As there is no improvement in OS with first-line anti-EGFR therapies for these patients, the increased toxicity from these agents limits their use. In addition, patients with mCRC with known PIK3CA mutation should consider use of EGFR-directed therapies only in the later line setting.

Research is focused on how to best use the mutational profile of the tumor to tailor therapies for mCRC. High-quality, large-volume data sets will become more important as molecular subtypes of cancer become more narrowly defined and less common. Further investigations are needed to look for other markers of resistance and to identify biomarkers predictive of treatment sensitivity.

This is an exciting time in the treatment of many cancers, especially mCRC, which significantly impacts the veteran population, because routine DNA sequencing of patient samples has allowed for rapid advances in the realization of precision medicine. This allows for improved patient selection to reduce costs and toxicities while increasing the benefit for veterans.

Acknowledgments
This work was supported by the National Institutes of Health (P30 CA014520, Core Grant, University of Wisconsin Carbone Cancer Center).

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.

Click here to read the digital edition.

Colorectal cancer (CRC) is the third leading cause of cancer-related death in veterans, despite significant advances in treatment options.^1,2 Over the past 20 years, the median survival of patients with metastatic CRC (mCRC), has improved with the most recent clinical trials demonstrating a median overall survival (OS) of up to 29 months.³

In addition to standard chemotherapeutic regimens using 5-fluorouracil, oxaliplatin, and irinotecan, biologic therapies have resulted in improved OS for patients with mCRC. These therapies include the human vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab and the epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab. Additional agents, including aflibercept, ramucirumab, regorafenib, and TAS-102, also have been FDA approved for mCRC, though the OS benefit for these agents as part of the series of standard-of-care treatments is less clear.

Investigators continue to determine subtypes of CRC to further advance treatment options. The histologic classification of colon cancers is actually a collection of multiple cancer subtypes. Each subtype possesses a unique biology largely dependent on the mutations present within the cancer. Recent data, reviewed below, indicate predictive and prognostic benefits to understanding the unique mutational profile of mCRC. Here, the authors present a brief updated summary of these biomarkers and a discussion of treatment strategies.

Resistance to Anti-EGFR Therapies

KRAS and NRAS are members of the RAS family of oncogenes. Activating mutations in these genes results in the propagation of growth factor signals independent of EGFR. The most common KRAS mutations are found in exon 2 (codon 12 or 13). Numerous studies over the past 10 years have confirmed that KRAS mutations at exon 2 predict resistance to cetuximab and panitumumab.^4-11 Since at least 2009, restricting use of cetuximab and panitumumab has been the standard of care for patients with KRAS exon 2 wild-type cancers.¹²

Recent investigations have indicated a predictive role for extended-spectrum KRAS and NRAS mutations (KRAS mutations at exons 2, 3, and 4 and NRAS mutations at exons 2, 3, and 4). In the OPUS clinical trial, patients whose cancers possessed extended-spectrum RAS mutations received no benefit with the addition of cetuximab to standard chemotherapy in response rate (RR), progression-free survival (PFS), or OS compared with standard chemotherapy alone.¹³ Interestingly, median OS was shorter for those treated with cetuximab when a RAS mutation was present, though the difference was not statistically significant. Additional studies also have confirmed similar benefits in different settings.^8,14-18

The CALGB/SWOG 80405 phase 3 clinical trial investigated the first-line use of biologic therapies in combination with standard chemotherapy. The extendedspectrum RAS testing from this study now has been presented.^3,19 In the RAS wild-type population, the median OS was 31.2 months in the chemotherapy plus bevacizumab arm and 32.0 months in the chemotherapy plus cetuximab arm (no significant difference). No difference in PFS was observed. A significant improvement in the RR was seen in the cetuximab arm for the RAS wild-type population.

Predictive Biomarkers

BRAF is an oncogene in the RAF gene family that encodes a serine-threonine protein kinase found in the Ras-Raf-MAPK cascade. About 10% of CRC harbor a BRAF mutation.^20,21 The most significant and prevalent mutation occurs at the kinase domain from the single substitution V600E. Numerous clinical studies have suggested the presence of this mutation as a predictor of resistance to anti-EGFR therapies and a marker of poor prognosis.^6,17,22-25 In a retrospective analysis of RAS and BRAF mutation status of PRIME study data, patients without RAS and BRAF mutations showed significantly better OS and PFS when treated with FOLFOX4 (5-fluorouracil, oxaliplatin, and leucovorin) plus panitumumab, compared with FOLFOX4 alone.⁸ The presence of BRAF mutations in RAS wild-type patients resulted in a worse outcome. Treatment with anti-EGFR therapy did not significantly improve median PFS or OS.

PIK3CA mutations. Phosphoinositide 3-kinase (PI3K) is a lipid kinase important for multiple cellular processes including cell growth, proliferation, survival, and apoptosis. PIK3CA encodes the catalytic subunit and is mutant in about 20% of mCRC.²⁶ The PI3K is downstream of EGFR signaling; activation of this pathway in the setting of an oncogenic mutation might lead to resistance to anti-EGFR therapies. Sartore-Bianchi and colleagues examined 110 patients with mCRC treated with either panitumumab or cetuximab.²⁷ Of these, 15 patient cancers featured PIK3CA mutations, and none of these responded to anti-EGFR therapies. In addition, preclinical studies have demonstrated that targeting CRC downstream of PI3K might result in significant treatment benefit.^28,29

Human epidermal growth factor receptor 2 (HER2) amplification. A subpopulation of CRC with amplification of HER2, a growth factor receptor commonly used in selecting treatment options in breast cancer, has recently been described. The HERACLES phase 2 study evaluated dual HER2 targeting with lapatinib and trastuzumab in therapy-refractory mCRC with HER2 amplification.³⁰ A RR of 35% was observed in this treatment-refractory population.

BRAF mutations. In addition to predicting a poor prognosis and resistance to EGFR-directed therapies, BRAF mutations might be predictive of treatment response using combination regimens containing RAF inhibitors. A recent phase 1B study of a combination therapy using the BRAF inhibitor vemurafenib with irinotecan and cetuximab observed a partial RR of 35%.³¹ This is being investigated further in the Southwest Oncology Group 1406 phase 2 trial.

Mismatch repair deficiency. Detection of microsatellite instability or the presence of mismatch repair deficiency has become standard-of-care testing for CRC. This is important for the detection of Lynch syndrome and predicting potential resistance to adjuvant 5-fluorouracil in the adjuvant setting.^32,33 A recent clinical trial has demonstrated benefits for the use of programmed death 1 (PD-1) inhibitors in the setting of mismatch repair deficiency, including a RR of 40% and PFS of 5.4 months.³⁴

Discussion

Metastatic CRC is now better understood as a collection of multiple cancer subtypes based on mutational profile. This improved understanding of the biology of CRC is altering treatment strategies to a precision medicine-based approach. It is now the standard of care for all patients with mCRC to have the cancers assayed for mutations in KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF. Anti-EGFR therapies should not be used for patients with RAS or BRAF mutations outside of a clinical trial because of a demonstrated lack of benefit in all lines of therapy. Currently, there is no evidence that these mutations significantly alter the response to the approved anti-angiogenic agents bevacizumab, aflibercept, ramucirumab, and regorafenib.

The timing of EGFR-directed therapies for patients with wild-type KRAS, NRAS, and BRAF is still being debated. According to the available data, first-line treatment with anti-EGFR agents in combination with FOLFOX or FOLFIRI (5-fluorouracil, irinotecan, and leucovorin) should be considered for all patients with KRAS, NRAS, and BRAF wild-type mCRCs. The toxicities of anti-EGFR therapies also should be considered for this setting, as some patients find that the acneiform rash, fatigue, nausea, and diarrhea that occur with these agents can have a negative impact on quality of life. As there is no improvement in OS with first-line anti-EGFR therapies for these patients, the increased toxicity from these agents limits their use. In addition, patients with mCRC with known PIK3CA mutation should consider use of EGFR-directed therapies only in the later line setting.

Research is focused on how to best use the mutational profile of the tumor to tailor therapies for mCRC. High-quality, large-volume data sets will become more important as molecular subtypes of cancer become more narrowly defined and less common. Further investigations are needed to look for other markers of resistance and to identify biomarkers predictive of treatment sensitivity.

This is an exciting time in the treatment of many cancers, especially mCRC, which significantly impacts the veteran population, because routine DNA sequencing of patient samples has allowed for rapid advances in the realization of precision medicine. This allows for improved patient selection to reduce costs and toxicities while increasing the benefit for veterans.

Acknowledgments
This work was supported by the National Institutes of Health (P30 CA014520, Core Grant, University of Wisconsin Carbone Cancer Center).

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.

Click here to read the digital edition.

Colorectal cancer (CRC) is the third leading cause of cancer-related death in veterans, despite significant advances in treatment options.^1,2 Over the past 20 years, the median survival of patients with metastatic CRC (mCRC), has improved with the most recent clinical trials demonstrating a median overall survival (OS) of up to 29 months.³

In addition to standard chemotherapeutic regimens using 5-fluorouracil, oxaliplatin, and irinotecan, biologic therapies have resulted in improved OS for patients with mCRC. These therapies include the human vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab and the epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab. Additional agents, including aflibercept, ramucirumab, regorafenib, and TAS-102, also have been FDA approved for mCRC, though the OS benefit for these agents as part of the series of standard-of-care treatments is less clear.

Investigators continue to determine subtypes of CRC to further advance treatment options. The histologic classification of colon cancers is actually a collection of multiple cancer subtypes. Each subtype possesses a unique biology largely dependent on the mutations present within the cancer. Recent data, reviewed below, indicate predictive and prognostic benefits to understanding the unique mutational profile of mCRC. Here, the authors present a brief updated summary of these biomarkers and a discussion of treatment strategies.

Resistance to Anti-EGFR Therapies

KRAS and NRAS are members of the RAS family of oncogenes. Activating mutations in these genes results in the propagation of growth factor signals independent of EGFR. The most common KRAS mutations are found in exon 2 (codon 12 or 13). Numerous studies over the past 10 years have confirmed that KRAS mutations at exon 2 predict resistance to cetuximab and panitumumab.^4-11 Since at least 2009, restricting use of cetuximab and panitumumab has been the standard of care for patients with KRAS exon 2 wild-type cancers.¹²

Recent investigations have indicated a predictive role for extended-spectrum KRAS and NRAS mutations (KRAS mutations at exons 2, 3, and 4 and NRAS mutations at exons 2, 3, and 4). In the OPUS clinical trial, patients whose cancers possessed extended-spectrum RAS mutations received no benefit with the addition of cetuximab to standard chemotherapy in response rate (RR), progression-free survival (PFS), or OS compared with standard chemotherapy alone.¹³ Interestingly, median OS was shorter for those treated with cetuximab when a RAS mutation was present, though the difference was not statistically significant. Additional studies also have confirmed similar benefits in different settings.^8,14-18

The CALGB/SWOG 80405 phase 3 clinical trial investigated the first-line use of biologic therapies in combination with standard chemotherapy. The extendedspectrum RAS testing from this study now has been presented.^3,19 In the RAS wild-type population, the median OS was 31.2 months in the chemotherapy plus bevacizumab arm and 32.0 months in the chemotherapy plus cetuximab arm (no significant difference). No difference in PFS was observed. A significant improvement in the RR was seen in the cetuximab arm for the RAS wild-type population.

Predictive Biomarkers

BRAF is an oncogene in the RAF gene family that encodes a serine-threonine protein kinase found in the Ras-Raf-MAPK cascade. About 10% of CRC harbor a BRAF mutation.^20,21 The most significant and prevalent mutation occurs at the kinase domain from the single substitution V600E. Numerous clinical studies have suggested the presence of this mutation as a predictor of resistance to anti-EGFR therapies and a marker of poor prognosis.^6,17,22-25 In a retrospective analysis of RAS and BRAF mutation status of PRIME study data, patients without RAS and BRAF mutations showed significantly better OS and PFS when treated with FOLFOX4 (5-fluorouracil, oxaliplatin, and leucovorin) plus panitumumab, compared with FOLFOX4 alone.⁸ The presence of BRAF mutations in RAS wild-type patients resulted in a worse outcome. Treatment with anti-EGFR therapy did not significantly improve median PFS or OS.

PIK3CA mutations. Phosphoinositide 3-kinase (PI3K) is a lipid kinase important for multiple cellular processes including cell growth, proliferation, survival, and apoptosis. PIK3CA encodes the catalytic subunit and is mutant in about 20% of mCRC.²⁶ The PI3K is downstream of EGFR signaling; activation of this pathway in the setting of an oncogenic mutation might lead to resistance to anti-EGFR therapies. Sartore-Bianchi and colleagues examined 110 patients with mCRC treated with either panitumumab or cetuximab.²⁷ Of these, 15 patient cancers featured PIK3CA mutations, and none of these responded to anti-EGFR therapies. In addition, preclinical studies have demonstrated that targeting CRC downstream of PI3K might result in significant treatment benefit.^28,29

Human epidermal growth factor receptor 2 (HER2) amplification. A subpopulation of CRC with amplification of HER2, a growth factor receptor commonly used in selecting treatment options in breast cancer, has recently been described. The HERACLES phase 2 study evaluated dual HER2 targeting with lapatinib and trastuzumab in therapy-refractory mCRC with HER2 amplification.³⁰ A RR of 35% was observed in this treatment-refractory population.

BRAF mutations. In addition to predicting a poor prognosis and resistance to EGFR-directed therapies, BRAF mutations might be predictive of treatment response using combination regimens containing RAF inhibitors. A recent phase 1B study of a combination therapy using the BRAF inhibitor vemurafenib with irinotecan and cetuximab observed a partial RR of 35%.³¹ This is being investigated further in the Southwest Oncology Group 1406 phase 2 trial.

Mismatch repair deficiency. Detection of microsatellite instability or the presence of mismatch repair deficiency has become standard-of-care testing for CRC. This is important for the detection of Lynch syndrome and predicting potential resistance to adjuvant 5-fluorouracil in the adjuvant setting.^32,33 A recent clinical trial has demonstrated benefits for the use of programmed death 1 (PD-1) inhibitors in the setting of mismatch repair deficiency, including a RR of 40% and PFS of 5.4 months.³⁴

Discussion

Metastatic CRC is now better understood as a collection of multiple cancer subtypes based on mutational profile. This improved understanding of the biology of CRC is altering treatment strategies to a precision medicine-based approach. It is now the standard of care for all patients with mCRC to have the cancers assayed for mutations in KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF. Anti-EGFR therapies should not be used for patients with RAS or BRAF mutations outside of a clinical trial because of a demonstrated lack of benefit in all lines of therapy. Currently, there is no evidence that these mutations significantly alter the response to the approved anti-angiogenic agents bevacizumab, aflibercept, ramucirumab, and regorafenib.

The timing of EGFR-directed therapies for patients with wild-type KRAS, NRAS, and BRAF is still being debated. According to the available data, first-line treatment with anti-EGFR agents in combination with FOLFOX or FOLFIRI (5-fluorouracil, irinotecan, and leucovorin) should be considered for all patients with KRAS, NRAS, and BRAF wild-type mCRCs. The toxicities of anti-EGFR therapies also should be considered for this setting, as some patients find that the acneiform rash, fatigue, nausea, and diarrhea that occur with these agents can have a negative impact on quality of life. As there is no improvement in OS with first-line anti-EGFR therapies for these patients, the increased toxicity from these agents limits their use. In addition, patients with mCRC with known PIK3CA mutation should consider use of EGFR-directed therapies only in the later line setting.

Research is focused on how to best use the mutational profile of the tumor to tailor therapies for mCRC. High-quality, large-volume data sets will become more important as molecular subtypes of cancer become more narrowly defined and less common. Further investigations are needed to look for other markers of resistance and to identify biomarkers predictive of treatment sensitivity.

This is an exciting time in the treatment of many cancers, especially mCRC, which significantly impacts the veteran population, because routine DNA sequencing of patient samples has allowed for rapid advances in the realization of precision medicine. This allows for improved patient selection to reduce costs and toxicities while increasing the benefit for veterans.

Acknowledgments
This work was supported by the National Institutes of Health (P30 CA014520, Core Grant, University of Wisconsin Carbone Cancer Center).

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.

Click here to read the digital edition.

Hypogonadism is characterized by low testosterone levels that can result in symptoms such as reduced libido, erectile dysfunction (ED), fatigue, anemia, decreased bone density, decreased lean body mass, and increased body fat.^1,2 The Endocrine Society defines male hypogonadism as serum total testosterone level (T) < 300 ng/dL, a threshold at which the likelihood of most symptoms associated with hypogonadism increases.¹

Testosterone replacement therapy (TRT) is recommended for treatment of androgen deficiency in symptomatic men with unequivocally low serum T levels. Although current guidelines recommend against using TRT in men with a history of prostate cancer (PCa),^1,3 and the FDA has a black box warning against prescribing TRT for these men, little evidence suggests that TRT stimulates tumor growth in patients treated for low-risk PCa.^4-6 Retrospective studies and case series suggest that TRT can be safe in patients with low-risk PCa treated with radical prostatectomy, brachytherapy, or external beam radiation.^7,8 Despite observed increases in prostate specific antigen (PSA), TRT does not seem to increase PCa recurrence rates when used cautiously, even in men with high-risk disease.⁹

Almost 3 million men living in the U.S. have been diagnosed with PCa. While 1 in 7 men will be diagnosed with PCa during their lifetime, most men diagnosed with PCa do not die of it.¹⁰ More than 90% of patients with PCa have localized or low-grade disease that does not result in PCa-related mortality.¹¹ Active surveillance, brachytherapy, external beam radiation, and radical prostatectomy are considered appropriate monotherapy modalities for low-risk PCa.¹² With successful treatment of early PCa, primary care providers may increasingly encounter PCa survivors with or without symptomatic hypogonadism. Surprisingly, the prevalence of hypogonadism in men with low-risk PCa has not been reported.

The primary objective of this study was to estimate the prevalence of hypogonadism in low-risk PCa survivors who received curative treatment. A second objective was to examine the presence of hypogonadism among subgroups of patients. The authors hypothesized that the prevalence in this population may be high enough to support prospective trials designed to determine the safety of TRT in selected hypogonadal men with a history of PCa.

Methods

This is a cross-sectional study conducted at the Edward Hines, Jr. VA Hospital (EHJVA) that included a convenience sample of 52 veterans aged 25 to 100 years who had been treated for low-risk PCa more than 12 months previously and were currently receiving medical care at EHJVA. Low-risk PCa was defined as tumors with a Gleason score ≤ 6 and PSA at diagnosis < 10 or a (clinical or pathologic) American Joint Committee on Cancer (AJCC) stage I or II. Patients were excluded if they had any of the following: Gleason score > 7, PSA at diagnosis > 10, prior TRT or androgen deprivation therapy, recurrent or active PCa, incomplete treatment of PCa, or history of breast cancer. The study was approved by the institutional review board at EHJVA.

Participant Identification and Recruitment

The EHJVA cancer registry provided a roster of about 600 patients who were diagnosed with AJCC stage I or II PCa after 2002 and had completed treatment by 2011. About 50% of the patients were excluded because they no longer were receiving care at EHJVA. More than 150 patients were excluded because they did not have upcoming appointments at EHJVA, they followed up at community-based outpatient clinics, or they did not meet the remaining parameters of the inclusion criteria.

Between April 2013 and August 2014, the authors approached 75 potentially eligible patients who had upcoming outpatient care appointments at EHJVA and invited them to participate in the study. After explaining the risks and benefits, 15 patients declined to participate. Although 60 eligible patients signed an informed consent, 6 later refused to consent to the medical record review. After the medical record review, 2 patients were excluded because their eligibility could not be confirmed (eg, missing tumor stage or PSA information). A total of 52 men were included in this study.

Data Collection

The study participants were asked to complete a brief validated Androgen Deficiency in the Aging Male (ADAM) questionnaire and provide a blood sample. The standard ADAM questionnaire consists of 10 yes/no questions concerning symptoms of androgen deficiency. A positive questionnaire was defined as a “yes” to any 3 questions.¹³ A blood sample was obtained between 7AM and 9AM for total and free testosterone level, follicle stimulating hormone, and luteinizing hormone (LH) to determine whether the hypogonadism was primary or secondary to a hypothalamicpituitary process. Additional data were collected, including age, height, weight, race, presence of diabetes mellitus (DM), tumor characteristics at diagnosis (ie, PSA, Gleason score, AJCC stage), and first course of cancer treatment.

Main Outcomes and Measures

The primary outcome was hypogonadism. Patients with serum T < 250 ng/dL were identified as having hypogonadism (the lower limit of the reference range in the EHJVA laboratory assay 250-1,100 ng/dL). The type of hypogonadism was further categorized as primary (LH > 10.6 IU/L) or secondary (LH < 10.6 IU/L). Patients with a body mass index (BMI) > 30 kg/m2 were considered obese.

The prevalence of hypogonadism was assessed overall and for subgroups of patients. The 95% confidence interval (CI) was calculated for each estimate. The correlation between BMI and serum T was also determined. Analyses were carried out using SAS 9.2 (SAS Institute Inc., Cary, North Carolina).

Results

The mean age was 69.1 years and patients were primarily white (Table 1). Half the patients were obese, and 40% had DM. The majority of patients had been diagnosed with stage I PCa, had received radiation as their primary treatment, and had completed the PCa treatment more than 5 years ago.

The prevalence of hypogonadism did not differ by race, DM, or tumor stage (Table 3). The oldest age group had the highest prevalence, but it was not statistically significant. However, obese patients were significantly more likely to have hypogonadism than were nonobese patients (57.6% vs 7.6%, P < .001). The negative association between BMI and serum T was more apparent when the correlation (r = -0.37, P < .01) between these 2 factors were examined (Figure). Patients with a higher ADAM score (> 3) were more likely to have hypogonadism than patients with a lower score (40.6% vs 20.0%, P = .14; Table 3). The prevalence of hypogonadism was higher in patients who were treated with radiation compared with patients who had surgery (41.6% vs 13.3%, P = .05). However, obese patients were more likely to have been treated with radiation (Table 4). After stratifying by obesity status, there was no difference in hypogonadism by treatment type.

Discussion

To the authors’ knowledge, this is the first study to assess the prevalence of hypogonadism in treated low-risk PCa survivors. In this sample of 52 men in an outpatient setting, about 1 in 3 had low testosterone levels. Three patients had primary hypogonadism, and 14 had secondary
(hypogonadotrophic) hypogonadism. Obese patients were significantly more likely to have hypogonadism than were nonobese patients. There was no evidence of an associationbetween PCa treatment and hypogonadism.

Estimates of prevalence of hypogonadism in the general population vary in the literature based on different patient demographics, study designs, and geography. A recent review found that the prevalence of hypogonadism in adult men ≥ 18 years had a range of 2.1% to 31.2% since the authors included studies that were population-based, community-based, and primary care or screening-based.¹⁴ The prevalence of hypogonadism was 15.0% to 78.8% in obese people and 21.4% to 33% in men with newly diagnosed PCa.¹⁴

Mulligan and colleagues estimated that 38.7% of men aged ≥ 45 years who visited primary care clinics in the U.S. had hypogonadism.¹⁵ They also found that the prevalence of hypogonadism, defined as serum T < 300 ng/dL, was significantly higher in men with obesity, DM, hypertension, hyperlipidemia, asthma or chronic obstructive pulmonary disease, and prostate disease. The prevalence of hypogonadism in this study was slightly lower (32.6%), but the authors used a different serum T level (< 250 ng/dL).15 Using the Mulligan and colleagues’ definition of serum T level, there was a prevalence of 40.3% in this study’s population of men with treated low-risk PCa.

Other patient characteristics were examined to determine whether the prevalence of hypogonadism differed by age, tumor stage, or mode of treatment. Testosterone levels drop in all men, 1% per year on average after age 30 years.¹⁵ Hypogonadism has been consistently found to increase with age and certain comorbidities. Zarotsky and colleagues found a 17% increase in the risk for hypogonadism with every 10-year increase in age.¹⁴ In this study, the authors did not find a significant difference in the prevalence of hypogonadism in this group by age or DM.

In the Prostate Cancer Outcomes Study (PCOS), the prevalence of erectile dysfunction was almost 90% in the prostatectomy and radiotherapy group after 15 years. It was unclear whether this was due to PCa and its treatment, the normal aging process, or a combination of factors, but no significant differences were observed between the treatment groups. However, it is unclear whether the PCOS men had hypogonadism, because testosterone levels were not reported.¹⁶

In the current study, the association between obesity and hypogonadism is consistent with epidemiologic evidence that suggests complex multidirectional interactions between testosterone, sex hormone-binding globulin, obesity, metabolic syndrome, and type 2 DM (T2DM), mediated by cytokines and adipokines. Several studies show that obesity adversely affects testicular function and is associated with a reduction in sex hormone-binding globulin, serum T, and free testosterone levels.^17,18 In addition, secondary hypogonadism has been shown to be higher in men who are overweight (25-29 kg/m2 BMI) and obese (≥ 30 kg/ m2 BMI) compared with normal weight men.^19,20 Hypogonadism has also been shown to increase insulin resistance, thereby increasing the risk for developing metabolic syndrome, which is a precursor for cardiovascular disease (CVD) and T2DM.²¹ Furthermore, low testosterone concentration may be associated with increased insulin resistance, incidence of CVD events, anemia, and low bone density.^19,22,23

The relationship between obesity, metabolic syndrome, and androgen deficiency remains unclear because of the complex mechanisms involved in this association. Impairment of hypothalamic-pituitary function by decreased LH pulse amplitude, inhibitory effects of estrogen at the
hypothalamus and pituitary, and the effects of leptin, ghrelin, and resistin, both centrally and on testicular Leydig cells, may explain lower testosterone level in obese males.^24,25 Recent studies have suggested a possible increased risk of  CV events among groups of men prescribed TRT.^26,27 However, other studies demonstrate beneficial effects of TRT on CVD risk factors, and research over several decades suggests a strong beneficial relationship between normal T and CV health.26 The evidence to suggest that TRT increases CV morbidity and mortality risks is poor,²⁸ but FDA is investigating the link between TRT and adverse CV outcomes.²⁹

Testosterone replacement therapy is recommended for symptomatic men with androgen deficiency to induce or maintain secondary sex characteristics and improve their sexual function, sense of well-being, muscle mass, strength, and bone mineral density. In a recent study supported by the National Institutes of Health (NIH) in men aged 65 years, increasing serum testosterone levels to mid-normal range for 1 year was associated with a moderate benefit in sexual function and improved mood, but there was no significant benefit in vitality (as measured by a fatigue scale) or walking distance.²⁸ In the NIH study, 4 men in the testosterone group and 1 in the placebo group received a diagnosis of PCa during or within the subsequent year of treatment, but the sample size was inadequate to reliably assess the effect of testosterone
on the risk of PCa.²⁸

With increasing direct-to-consumer marketing of branded pharmaceutical products in the U.S., there is widening interest in testosterone levels and hypogonadism symptoms in middle-aged and older men. Indeed, 2.3 million patients received a prescription for testosterone in 2013, up from 1.3 million in 2010.^29,30 This change has become important because whereas TRT is standard therapy in symptomatic hypogonadal men, it has long been considered taboo for men with a history of PCa, regardless of disease status. Transdermal testosterone is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate, according to the package insert.³¹ Androgens are contraindicated in men with known or suspected carcinoma of the prostate or breast, according to the testosterone cypionate injection package insert.³² Although TRT may increase serum PSA levels in some men, it often remains within clinically acceptable ranges and has not been shown to increase the risk for PCa. A recent observation from 3 registries of more than 1,000 hypogonadal men receiving TRT for up to 17 years concluded that TRT does not increase the risk for PCa.³³

Prostate cancer encompasses a heterogeneous collection of androgen-dependent and independent cells. Androgens have been known to play an important role in PCa biology, but this relationship is more complex than the traditional view that androgens stimulate PCa growth. More than 7 decades ago, Huggins and colleagues showed that disseminated PCa was inhibited by eliminating androgens by castration and activated by androgen injections.³⁴ Recently, the androgen hypothesis and the relationship of testosterone to PCa has been more clearly defined. Although it has been established that effective suppression of serum T levels with surgical or chemical castration remains an essential strategy in the management of advanced PCa, the assertion that testosterone causes growth of PCa has been challenged.^35,36

Recent studies have shown that there may be a more complex relationship between serum T and PCa risk than was previously established.³⁷ Although PCa cells have been shown to become androgen-independent as they progress into the castrate-resistant phase,⁹ several studies have indicated that low-serum T is associated with greater PCa risk and more worrisome features of PCa.^38,39 Hence, a saturation model has been proposed: Changes in serum T concentrations below the point of maximal androgen-androgen receptor (AR) binding will elicit substantial changes in PCa growth, as seen with castration or with serum T administration to castrated men.⁴⁰ However, once maximal androgen-AR binding is reached, the presence of additional androgen produces little further effect, suggesting that there is a limit to the ability of androgens to stimulate growth of PCa.⁴⁰

A meta-analysis of 45 articles studying the relationship between serum T and PCa risk has reported conflicting results.⁴ Eugonadal testosterone levels, whether physiologically or pharmacologically replaced, do not seem to promote PCa growth. It is unclear whether the timing of sex hormone exposure affects PCa or whether the cancer may influence blood levels of sex hormones. Since 2004, there have been case series totaling almost 150 men treated with prostatectomy, brachytherapy, or external beam radiation who have been safely treated with TRT.^6-9 These case studies suggest that after a thorough discussion of risks and benefits, TRT may be safer than previously thought for men who have been successfully treated for PCa, are deemed low risk for recurrence, and are monitored closely. However, no randomized controlled trials are available, and published guidelines recommend against starting TRT in patients with a history of breast or PCa.¹

Limitations

This study has limitations. The sample size is small and, therefore, it may not have had enough power to show differences in prevalence by subgroups. In addition, the population may not be representative of all male veterans who seek care in the VA or of men in other health care settings, because this was a convenience sample of VA patients who received most of their care in the VA. However, the prevalence of hypogonadism, in this outpatient population is very similar to that found among men seen in primary care clinics.¹⁴ Finally, because pretreatment serum T levels were lacking, the authors were unable to assess whether hypogonadism was present before surgery or radiation therapy, and unable to determine whether treatment had any effect on serum T levels.

The study has several strengths. First, to the authors’ knowledge, this is the first study to assess the prevalence of hypogonadism after patients with low-risk PCa have received treatment with curative intent. Second, the authors assessed hypogonadism in every patient by measuring serum T levels in the early morning when levels are known to be at their highest. Third, differentiating primary and secondary hypogonadism helped provide insight into the possible etiology of the low serum T levels. Fourth, this study was performed at a single institution that uses electronic medical records, with almost complete data on patient demographics, PCa treatment, and receipt of TRT or androgen deprivation therapy. Fifth, because this study had the participation of endocrinologists and urologists, the study design helped answer questions pertinent to both medical and surgical specialties.

Conclusion

As life expectancy increases, many survivors of treated PCa present with symptoms of hypogonadism associated with low serum T levels and request TRT. The prevalence of hypogonadism before or after treatment for PCa in this population is not known. This study suggests that many low-risk PCa survivors have hypogonadism. Because hypogonadism negatively impacts quality of life by increasing the risk for sexual dysfunction, mood disturbances, bone fracture, development of metabolic syndrome, frailty, and decline in the feeling of general well-being and may have significant deleterious effects on other body systems, consideration for treatment is warranted.

Patients with PCa may be untreated because the safety of TRT in this population is unknown. Clinical practice guidelines caution against using TRT in this population, and recent literature questions the benefits and risks associated with the long-term safety of TRT, particularly in older men.^28,41 Although further studies are necessary before definitive conclusions can be drawn, increasing evidence, albeit small, suggests that TRT can be cautiously considered in selected hypogonadal men treated with curative intent for PCa and without evidence of active disease. However, because obese patients are at higher risk for aggressive PCa and mortality, it is unclear whether obese PCa survivors have an additional risk in regard to TRT.^42,43 To help clinicians provide information and care for their patients, appropriately designed prospective randomized studies using a collaborative approach and long-term follow-up are urgently needed to determine the safety of TRT in hypogonadal men with a history of low-risk PCa.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the Edward Hines Jr. VA Hospital. Dr. Silva’s work was carried out while she was a postdoctoral fellow supported by the VA Office of Academic Affiliations (TPP 42-013). The authors thank Ahmer V. Farooq, DO, Department of Surgery, Division of Urology, for his help in planning the design of the study. Dr. Agrawal affirms that all coauthors contributed significantly to the work and had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Hypogonadism is characterized by low testosterone levels that can result in symptoms such as reduced libido, erectile dysfunction (ED), fatigue, anemia, decreased bone density, decreased lean body mass, and increased body fat.^1,2 The Endocrine Society defines male hypogonadism as serum total testosterone level (T) < 300 ng/dL, a threshold at which the likelihood of most symptoms associated with hypogonadism increases.¹

Testosterone replacement therapy (TRT) is recommended for treatment of androgen deficiency in symptomatic men with unequivocally low serum T levels. Although current guidelines recommend against using TRT in men with a history of prostate cancer (PCa),^1,3 and the FDA has a black box warning against prescribing TRT for these men, little evidence suggests that TRT stimulates tumor growth in patients treated for low-risk PCa.^4-6 Retrospective studies and case series suggest that TRT can be safe in patients with low-risk PCa treated with radical prostatectomy, brachytherapy, or external beam radiation.^7,8 Despite observed increases in prostate specific antigen (PSA), TRT does not seem to increase PCa recurrence rates when used cautiously, even in men with high-risk disease.⁹

Almost 3 million men living in the U.S. have been diagnosed with PCa. While 1 in 7 men will be diagnosed with PCa during their lifetime, most men diagnosed with PCa do not die of it.¹⁰ More than 90% of patients with PCa have localized or low-grade disease that does not result in PCa-related mortality.¹¹ Active surveillance, brachytherapy, external beam radiation, and radical prostatectomy are considered appropriate monotherapy modalities for low-risk PCa.¹² With successful treatment of early PCa, primary care providers may increasingly encounter PCa survivors with or without symptomatic hypogonadism. Surprisingly, the prevalence of hypogonadism in men with low-risk PCa has not been reported.

The primary objective of this study was to estimate the prevalence of hypogonadism in low-risk PCa survivors who received curative treatment. A second objective was to examine the presence of hypogonadism among subgroups of patients. The authors hypothesized that the prevalence in this population may be high enough to support prospective trials designed to determine the safety of TRT in selected hypogonadal men with a history of PCa.

Methods

This is a cross-sectional study conducted at the Edward Hines, Jr. VA Hospital (EHJVA) that included a convenience sample of 52 veterans aged 25 to 100 years who had been treated for low-risk PCa more than 12 months previously and were currently receiving medical care at EHJVA. Low-risk PCa was defined as tumors with a Gleason score ≤ 6 and PSA at diagnosis < 10 or a (clinical or pathologic) American Joint Committee on Cancer (AJCC) stage I or II. Patients were excluded if they had any of the following: Gleason score > 7, PSA at diagnosis > 10, prior TRT or androgen deprivation therapy, recurrent or active PCa, incomplete treatment of PCa, or history of breast cancer. The study was approved by the institutional review board at EHJVA.

Participant Identification and Recruitment

The EHJVA cancer registry provided a roster of about 600 patients who were diagnosed with AJCC stage I or II PCa after 2002 and had completed treatment by 2011. About 50% of the patients were excluded because they no longer were receiving care at EHJVA. More than 150 patients were excluded because they did not have upcoming appointments at EHJVA, they followed up at community-based outpatient clinics, or they did not meet the remaining parameters of the inclusion criteria.

Between April 2013 and August 2014, the authors approached 75 potentially eligible patients who had upcoming outpatient care appointments at EHJVA and invited them to participate in the study. After explaining the risks and benefits, 15 patients declined to participate. Although 60 eligible patients signed an informed consent, 6 later refused to consent to the medical record review. After the medical record review, 2 patients were excluded because their eligibility could not be confirmed (eg, missing tumor stage or PSA information). A total of 52 men were included in this study.

Data Collection

The study participants were asked to complete a brief validated Androgen Deficiency in the Aging Male (ADAM) questionnaire and provide a blood sample. The standard ADAM questionnaire consists of 10 yes/no questions concerning symptoms of androgen deficiency. A positive questionnaire was defined as a “yes” to any 3 questions.¹³ A blood sample was obtained between 7AM and 9AM for total and free testosterone level, follicle stimulating hormone, and luteinizing hormone (LH) to determine whether the hypogonadism was primary or secondary to a hypothalamicpituitary process. Additional data were collected, including age, height, weight, race, presence of diabetes mellitus (DM), tumor characteristics at diagnosis (ie, PSA, Gleason score, AJCC stage), and first course of cancer treatment.

Main Outcomes and Measures

The primary outcome was hypogonadism. Patients with serum T < 250 ng/dL were identified as having hypogonadism (the lower limit of the reference range in the EHJVA laboratory assay 250-1,100 ng/dL). The type of hypogonadism was further categorized as primary (LH > 10.6 IU/L) or secondary (LH < 10.6 IU/L). Patients with a body mass index (BMI) > 30 kg/m2 were considered obese.

The prevalence of hypogonadism was assessed overall and for subgroups of patients. The 95% confidence interval (CI) was calculated for each estimate. The correlation between BMI and serum T was also determined. Analyses were carried out using SAS 9.2 (SAS Institute Inc., Cary, North Carolina).

Results

The mean age was 69.1 years and patients were primarily white (Table 1). Half the patients were obese, and 40% had DM. The majority of patients had been diagnosed with stage I PCa, had received radiation as their primary treatment, and had completed the PCa treatment more than 5 years ago.

The prevalence of hypogonadism did not differ by race, DM, or tumor stage (Table 3). The oldest age group had the highest prevalence, but it was not statistically significant. However, obese patients were significantly more likely to have hypogonadism than were nonobese patients (57.6% vs 7.6%, P < .001). The negative association between BMI and serum T was more apparent when the correlation (r = -0.37, P < .01) between these 2 factors were examined (Figure). Patients with a higher ADAM score (> 3) were more likely to have hypogonadism than patients with a lower score (40.6% vs 20.0%, P = .14; Table 3). The prevalence of hypogonadism was higher in patients who were treated with radiation compared with patients who had surgery (41.6% vs 13.3%, P = .05). However, obese patients were more likely to have been treated with radiation (Table 4). After stratifying by obesity status, there was no difference in hypogonadism by treatment type.

Discussion

To the authors’ knowledge, this is the first study to assess the prevalence of hypogonadism in treated low-risk PCa survivors. In this sample of 52 men in an outpatient setting, about 1 in 3 had low testosterone levels. Three patients had primary hypogonadism, and 14 had secondary
(hypogonadotrophic) hypogonadism. Obese patients were significantly more likely to have hypogonadism than were nonobese patients. There was no evidence of an associationbetween PCa treatment and hypogonadism.

Estimates of prevalence of hypogonadism in the general population vary in the literature based on different patient demographics, study designs, and geography. A recent review found that the prevalence of hypogonadism in adult men ≥ 18 years had a range of 2.1% to 31.2% since the authors included studies that were population-based, community-based, and primary care or screening-based.¹⁴ The prevalence of hypogonadism was 15.0% to 78.8% in obese people and 21.4% to 33% in men with newly diagnosed PCa.¹⁴

Mulligan and colleagues estimated that 38.7% of men aged ≥ 45 years who visited primary care clinics in the U.S. had hypogonadism.¹⁵ They also found that the prevalence of hypogonadism, defined as serum T < 300 ng/dL, was significantly higher in men with obesity, DM, hypertension, hyperlipidemia, asthma or chronic obstructive pulmonary disease, and prostate disease. The prevalence of hypogonadism in this study was slightly lower (32.6%), but the authors used a different serum T level (< 250 ng/dL).15 Using the Mulligan and colleagues’ definition of serum T level, there was a prevalence of 40.3% in this study’s population of men with treated low-risk PCa.

Other patient characteristics were examined to determine whether the prevalence of hypogonadism differed by age, tumor stage, or mode of treatment. Testosterone levels drop in all men, 1% per year on average after age 30 years.¹⁵ Hypogonadism has been consistently found to increase with age and certain comorbidities. Zarotsky and colleagues found a 17% increase in the risk for hypogonadism with every 10-year increase in age.¹⁴ In this study, the authors did not find a significant difference in the prevalence of hypogonadism in this group by age or DM.

In the Prostate Cancer Outcomes Study (PCOS), the prevalence of erectile dysfunction was almost 90% in the prostatectomy and radiotherapy group after 15 years. It was unclear whether this was due to PCa and its treatment, the normal aging process, or a combination of factors, but no significant differences were observed between the treatment groups. However, it is unclear whether the PCOS men had hypogonadism, because testosterone levels were not reported.¹⁶

In the current study, the association between obesity and hypogonadism is consistent with epidemiologic evidence that suggests complex multidirectional interactions between testosterone, sex hormone-binding globulin, obesity, metabolic syndrome, and type 2 DM (T2DM), mediated by cytokines and adipokines. Several studies show that obesity adversely affects testicular function and is associated with a reduction in sex hormone-binding globulin, serum T, and free testosterone levels.^17,18 In addition, secondary hypogonadism has been shown to be higher in men who are overweight (25-29 kg/m2 BMI) and obese (≥ 30 kg/ m2 BMI) compared with normal weight men.^19,20 Hypogonadism has also been shown to increase insulin resistance, thereby increasing the risk for developing metabolic syndrome, which is a precursor for cardiovascular disease (CVD) and T2DM.²¹ Furthermore, low testosterone concentration may be associated with increased insulin resistance, incidence of CVD events, anemia, and low bone density.^19,22,23

The relationship between obesity, metabolic syndrome, and androgen deficiency remains unclear because of the complex mechanisms involved in this association. Impairment of hypothalamic-pituitary function by decreased LH pulse amplitude, inhibitory effects of estrogen at the
hypothalamus and pituitary, and the effects of leptin, ghrelin, and resistin, both centrally and on testicular Leydig cells, may explain lower testosterone level in obese males.^24,25 Recent studies have suggested a possible increased risk of  CV events among groups of men prescribed TRT.^26,27 However, other studies demonstrate beneficial effects of TRT on CVD risk factors, and research over several decades suggests a strong beneficial relationship between normal T and CV health.26 The evidence to suggest that TRT increases CV morbidity and mortality risks is poor,²⁸ but FDA is investigating the link between TRT and adverse CV outcomes.²⁹

Testosterone replacement therapy is recommended for symptomatic men with androgen deficiency to induce or maintain secondary sex characteristics and improve their sexual function, sense of well-being, muscle mass, strength, and bone mineral density. In a recent study supported by the National Institutes of Health (NIH) in men aged 65 years, increasing serum testosterone levels to mid-normal range for 1 year was associated with a moderate benefit in sexual function and improved mood, but there was no significant benefit in vitality (as measured by a fatigue scale) or walking distance.²⁸ In the NIH study, 4 men in the testosterone group and 1 in the placebo group received a diagnosis of PCa during or within the subsequent year of treatment, but the sample size was inadequate to reliably assess the effect of testosterone
on the risk of PCa.²⁸

With increasing direct-to-consumer marketing of branded pharmaceutical products in the U.S., there is widening interest in testosterone levels and hypogonadism symptoms in middle-aged and older men. Indeed, 2.3 million patients received a prescription for testosterone in 2013, up from 1.3 million in 2010.^29,30 This change has become important because whereas TRT is standard therapy in symptomatic hypogonadal men, it has long been considered taboo for men with a history of PCa, regardless of disease status. Transdermal testosterone is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate, according to the package insert.³¹ Androgens are contraindicated in men with known or suspected carcinoma of the prostate or breast, according to the testosterone cypionate injection package insert.³² Although TRT may increase serum PSA levels in some men, it often remains within clinically acceptable ranges and has not been shown to increase the risk for PCa. A recent observation from 3 registries of more than 1,000 hypogonadal men receiving TRT for up to 17 years concluded that TRT does not increase the risk for PCa.³³

Prostate cancer encompasses a heterogeneous collection of androgen-dependent and independent cells. Androgens have been known to play an important role in PCa biology, but this relationship is more complex than the traditional view that androgens stimulate PCa growth. More than 7 decades ago, Huggins and colleagues showed that disseminated PCa was inhibited by eliminating androgens by castration and activated by androgen injections.³⁴ Recently, the androgen hypothesis and the relationship of testosterone to PCa has been more clearly defined. Although it has been established that effective suppression of serum T levels with surgical or chemical castration remains an essential strategy in the management of advanced PCa, the assertion that testosterone causes growth of PCa has been challenged.^35,36

Recent studies have shown that there may be a more complex relationship between serum T and PCa risk than was previously established.³⁷ Although PCa cells have been shown to become androgen-independent as they progress into the castrate-resistant phase,⁹ several studies have indicated that low-serum T is associated with greater PCa risk and more worrisome features of PCa.^38,39 Hence, a saturation model has been proposed: Changes in serum T concentrations below the point of maximal androgen-androgen receptor (AR) binding will elicit substantial changes in PCa growth, as seen with castration or with serum T administration to castrated men.⁴⁰ However, once maximal androgen-AR binding is reached, the presence of additional androgen produces little further effect, suggesting that there is a limit to the ability of androgens to stimulate growth of PCa.⁴⁰

A meta-analysis of 45 articles studying the relationship between serum T and PCa risk has reported conflicting results.⁴ Eugonadal testosterone levels, whether physiologically or pharmacologically replaced, do not seem to promote PCa growth. It is unclear whether the timing of sex hormone exposure affects PCa or whether the cancer may influence blood levels of sex hormones. Since 2004, there have been case series totaling almost 150 men treated with prostatectomy, brachytherapy, or external beam radiation who have been safely treated with TRT.^6-9 These case studies suggest that after a thorough discussion of risks and benefits, TRT may be safer than previously thought for men who have been successfully treated for PCa, are deemed low risk for recurrence, and are monitored closely. However, no randomized controlled trials are available, and published guidelines recommend against starting TRT in patients with a history of breast or PCa.¹

Limitations

This study has limitations. The sample size is small and, therefore, it may not have had enough power to show differences in prevalence by subgroups. In addition, the population may not be representative of all male veterans who seek care in the VA or of men in other health care settings, because this was a convenience sample of VA patients who received most of their care in the VA. However, the prevalence of hypogonadism, in this outpatient population is very similar to that found among men seen in primary care clinics.¹⁴ Finally, because pretreatment serum T levels were lacking, the authors were unable to assess whether hypogonadism was present before surgery or radiation therapy, and unable to determine whether treatment had any effect on serum T levels.

The study has several strengths. First, to the authors’ knowledge, this is the first study to assess the prevalence of hypogonadism after patients with low-risk PCa have received treatment with curative intent. Second, the authors assessed hypogonadism in every patient by measuring serum T levels in the early morning when levels are known to be at their highest. Third, differentiating primary and secondary hypogonadism helped provide insight into the possible etiology of the low serum T levels. Fourth, this study was performed at a single institution that uses electronic medical records, with almost complete data on patient demographics, PCa treatment, and receipt of TRT or androgen deprivation therapy. Fifth, because this study had the participation of endocrinologists and urologists, the study design helped answer questions pertinent to both medical and surgical specialties.

Conclusion

As life expectancy increases, many survivors of treated PCa present with symptoms of hypogonadism associated with low serum T levels and request TRT. The prevalence of hypogonadism before or after treatment for PCa in this population is not known. This study suggests that many low-risk PCa survivors have hypogonadism. Because hypogonadism negatively impacts quality of life by increasing the risk for sexual dysfunction, mood disturbances, bone fracture, development of metabolic syndrome, frailty, and decline in the feeling of general well-being and may have significant deleterious effects on other body systems, consideration for treatment is warranted.

Patients with PCa may be untreated because the safety of TRT in this population is unknown. Clinical practice guidelines caution against using TRT in this population, and recent literature questions the benefits and risks associated with the long-term safety of TRT, particularly in older men.^28,41 Although further studies are necessary before definitive conclusions can be drawn, increasing evidence, albeit small, suggests that TRT can be cautiously considered in selected hypogonadal men treated with curative intent for PCa and without evidence of active disease. However, because obese patients are at higher risk for aggressive PCa and mortality, it is unclear whether obese PCa survivors have an additional risk in regard to TRT.^42,43 To help clinicians provide information and care for their patients, appropriately designed prospective randomized studies using a collaborative approach and long-term follow-up are urgently needed to determine the safety of TRT in hypogonadal men with a history of low-risk PCa.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the Edward Hines Jr. VA Hospital. Dr. Silva’s work was carried out while she was a postdoctoral fellow supported by the VA Office of Academic Affiliations (TPP 42-013). The authors thank Ahmer V. Farooq, DO, Department of Surgery, Division of Urology, for his help in planning the design of the study. Dr. Agrawal affirms that all coauthors contributed significantly to the work and had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Hypogonadism is characterized by low testosterone levels that can result in symptoms such as reduced libido, erectile dysfunction (ED), fatigue, anemia, decreased bone density, decreased lean body mass, and increased body fat.^1,2 The Endocrine Society defines male hypogonadism as serum total testosterone level (T) < 300 ng/dL, a threshold at which the likelihood of most symptoms associated with hypogonadism increases.¹

Testosterone replacement therapy (TRT) is recommended for treatment of androgen deficiency in symptomatic men with unequivocally low serum T levels. Although current guidelines recommend against using TRT in men with a history of prostate cancer (PCa),^1,3 and the FDA has a black box warning against prescribing TRT for these men, little evidence suggests that TRT stimulates tumor growth in patients treated for low-risk PCa.^4-6 Retrospective studies and case series suggest that TRT can be safe in patients with low-risk PCa treated with radical prostatectomy, brachytherapy, or external beam radiation.^7,8 Despite observed increases in prostate specific antigen (PSA), TRT does not seem to increase PCa recurrence rates when used cautiously, even in men with high-risk disease.⁹

Almost 3 million men living in the U.S. have been diagnosed with PCa. While 1 in 7 men will be diagnosed with PCa during their lifetime, most men diagnosed with PCa do not die of it.¹⁰ More than 90% of patients with PCa have localized or low-grade disease that does not result in PCa-related mortality.¹¹ Active surveillance, brachytherapy, external beam radiation, and radical prostatectomy are considered appropriate monotherapy modalities for low-risk PCa.¹² With successful treatment of early PCa, primary care providers may increasingly encounter PCa survivors with or without symptomatic hypogonadism. Surprisingly, the prevalence of hypogonadism in men with low-risk PCa has not been reported.

The primary objective of this study was to estimate the prevalence of hypogonadism in low-risk PCa survivors who received curative treatment. A second objective was to examine the presence of hypogonadism among subgroups of patients. The authors hypothesized that the prevalence in this population may be high enough to support prospective trials designed to determine the safety of TRT in selected hypogonadal men with a history of PCa.

Methods

This is a cross-sectional study conducted at the Edward Hines, Jr. VA Hospital (EHJVA) that included a convenience sample of 52 veterans aged 25 to 100 years who had been treated for low-risk PCa more than 12 months previously and were currently receiving medical care at EHJVA. Low-risk PCa was defined as tumors with a Gleason score ≤ 6 and PSA at diagnosis < 10 or a (clinical or pathologic) American Joint Committee on Cancer (AJCC) stage I or II. Patients were excluded if they had any of the following: Gleason score > 7, PSA at diagnosis > 10, prior TRT or androgen deprivation therapy, recurrent or active PCa, incomplete treatment of PCa, or history of breast cancer. The study was approved by the institutional review board at EHJVA.

Participant Identification and Recruitment

The EHJVA cancer registry provided a roster of about 600 patients who were diagnosed with AJCC stage I or II PCa after 2002 and had completed treatment by 2011. About 50% of the patients were excluded because they no longer were receiving care at EHJVA. More than 150 patients were excluded because they did not have upcoming appointments at EHJVA, they followed up at community-based outpatient clinics, or they did not meet the remaining parameters of the inclusion criteria.

Between April 2013 and August 2014, the authors approached 75 potentially eligible patients who had upcoming outpatient care appointments at EHJVA and invited them to participate in the study. After explaining the risks and benefits, 15 patients declined to participate. Although 60 eligible patients signed an informed consent, 6 later refused to consent to the medical record review. After the medical record review, 2 patients were excluded because their eligibility could not be confirmed (eg, missing tumor stage or PSA information). A total of 52 men were included in this study.

Data Collection

The study participants were asked to complete a brief validated Androgen Deficiency in the Aging Male (ADAM) questionnaire and provide a blood sample. The standard ADAM questionnaire consists of 10 yes/no questions concerning symptoms of androgen deficiency. A positive questionnaire was defined as a “yes” to any 3 questions.¹³ A blood sample was obtained between 7AM and 9AM for total and free testosterone level, follicle stimulating hormone, and luteinizing hormone (LH) to determine whether the hypogonadism was primary or secondary to a hypothalamicpituitary process. Additional data were collected, including age, height, weight, race, presence of diabetes mellitus (DM), tumor characteristics at diagnosis (ie, PSA, Gleason score, AJCC stage), and first course of cancer treatment.

Main Outcomes and Measures

The primary outcome was hypogonadism. Patients with serum T < 250 ng/dL were identified as having hypogonadism (the lower limit of the reference range in the EHJVA laboratory assay 250-1,100 ng/dL). The type of hypogonadism was further categorized as primary (LH > 10.6 IU/L) or secondary (LH < 10.6 IU/L). Patients with a body mass index (BMI) > 30 kg/m2 were considered obese.

The prevalence of hypogonadism was assessed overall and for subgroups of patients. The 95% confidence interval (CI) was calculated for each estimate. The correlation between BMI and serum T was also determined. Analyses were carried out using SAS 9.2 (SAS Institute Inc., Cary, North Carolina).

Results

The mean age was 69.1 years and patients were primarily white (Table 1). Half the patients were obese, and 40% had DM. The majority of patients had been diagnosed with stage I PCa, had received radiation as their primary treatment, and had completed the PCa treatment more than 5 years ago.

The prevalence of hypogonadism did not differ by race, DM, or tumor stage (Table 3). The oldest age group had the highest prevalence, but it was not statistically significant. However, obese patients were significantly more likely to have hypogonadism than were nonobese patients (57.6% vs 7.6%, P < .001). The negative association between BMI and serum T was more apparent when the correlation (r = -0.37, P < .01) between these 2 factors were examined (Figure). Patients with a higher ADAM score (> 3) were more likely to have hypogonadism than patients with a lower score (40.6% vs 20.0%, P = .14; Table 3). The prevalence of hypogonadism was higher in patients who were treated with radiation compared with patients who had surgery (41.6% vs 13.3%, P = .05). However, obese patients were more likely to have been treated with radiation (Table 4). After stratifying by obesity status, there was no difference in hypogonadism by treatment type.

Discussion

To the authors’ knowledge, this is the first study to assess the prevalence of hypogonadism in treated low-risk PCa survivors. In this sample of 52 men in an outpatient setting, about 1 in 3 had low testosterone levels. Three patients had primary hypogonadism, and 14 had secondary
(hypogonadotrophic) hypogonadism. Obese patients were significantly more likely to have hypogonadism than were nonobese patients. There was no evidence of an associationbetween PCa treatment and hypogonadism.

Estimates of prevalence of hypogonadism in the general population vary in the literature based on different patient demographics, study designs, and geography. A recent review found that the prevalence of hypogonadism in adult men ≥ 18 years had a range of 2.1% to 31.2% since the authors included studies that were population-based, community-based, and primary care or screening-based.¹⁴ The prevalence of hypogonadism was 15.0% to 78.8% in obese people and 21.4% to 33% in men with newly diagnosed PCa.¹⁴

Mulligan and colleagues estimated that 38.7% of men aged ≥ 45 years who visited primary care clinics in the U.S. had hypogonadism.¹⁵ They also found that the prevalence of hypogonadism, defined as serum T < 300 ng/dL, was significantly higher in men with obesity, DM, hypertension, hyperlipidemia, asthma or chronic obstructive pulmonary disease, and prostate disease. The prevalence of hypogonadism in this study was slightly lower (32.6%), but the authors used a different serum T level (< 250 ng/dL).15 Using the Mulligan and colleagues’ definition of serum T level, there was a prevalence of 40.3% in this study’s population of men with treated low-risk PCa.

Other patient characteristics were examined to determine whether the prevalence of hypogonadism differed by age, tumor stage, or mode of treatment. Testosterone levels drop in all men, 1% per year on average after age 30 years.¹⁵ Hypogonadism has been consistently found to increase with age and certain comorbidities. Zarotsky and colleagues found a 17% increase in the risk for hypogonadism with every 10-year increase in age.¹⁴ In this study, the authors did not find a significant difference in the prevalence of hypogonadism in this group by age or DM.

In the Prostate Cancer Outcomes Study (PCOS), the prevalence of erectile dysfunction was almost 90% in the prostatectomy and radiotherapy group after 15 years. It was unclear whether this was due to PCa and its treatment, the normal aging process, or a combination of factors, but no significant differences were observed between the treatment groups. However, it is unclear whether the PCOS men had hypogonadism, because testosterone levels were not reported.¹⁶

In the current study, the association between obesity and hypogonadism is consistent with epidemiologic evidence that suggests complex multidirectional interactions between testosterone, sex hormone-binding globulin, obesity, metabolic syndrome, and type 2 DM (T2DM), mediated by cytokines and adipokines. Several studies show that obesity adversely affects testicular function and is associated with a reduction in sex hormone-binding globulin, serum T, and free testosterone levels.^17,18 In addition, secondary hypogonadism has been shown to be higher in men who are overweight (25-29 kg/m2 BMI) and obese (≥ 30 kg/ m2 BMI) compared with normal weight men.^19,20 Hypogonadism has also been shown to increase insulin resistance, thereby increasing the risk for developing metabolic syndrome, which is a precursor for cardiovascular disease (CVD) and T2DM.²¹ Furthermore, low testosterone concentration may be associated with increased insulin resistance, incidence of CVD events, anemia, and low bone density.^19,22,23

The relationship between obesity, metabolic syndrome, and androgen deficiency remains unclear because of the complex mechanisms involved in this association. Impairment of hypothalamic-pituitary function by decreased LH pulse amplitude, inhibitory effects of estrogen at the
hypothalamus and pituitary, and the effects of leptin, ghrelin, and resistin, both centrally and on testicular Leydig cells, may explain lower testosterone level in obese males.^24,25 Recent studies have suggested a possible increased risk of  CV events among groups of men prescribed TRT.^26,27 However, other studies demonstrate beneficial effects of TRT on CVD risk factors, and research over several decades suggests a strong beneficial relationship between normal T and CV health.26 The evidence to suggest that TRT increases CV morbidity and mortality risks is poor,²⁸ but FDA is investigating the link between TRT and adverse CV outcomes.²⁹

Testosterone replacement therapy is recommended for symptomatic men with androgen deficiency to induce or maintain secondary sex characteristics and improve their sexual function, sense of well-being, muscle mass, strength, and bone mineral density. In a recent study supported by the National Institutes of Health (NIH) in men aged 65 years, increasing serum testosterone levels to mid-normal range for 1 year was associated with a moderate benefit in sexual function and improved mood, but there was no significant benefit in vitality (as measured by a fatigue scale) or walking distance.²⁸ In the NIH study, 4 men in the testosterone group and 1 in the placebo group received a diagnosis of PCa during or within the subsequent year of treatment, but the sample size was inadequate to reliably assess the effect of testosterone
on the risk of PCa.²⁸

With increasing direct-to-consumer marketing of branded pharmaceutical products in the U.S., there is widening interest in testosterone levels and hypogonadism symptoms in middle-aged and older men. Indeed, 2.3 million patients received a prescription for testosterone in 2013, up from 1.3 million in 2010.^29,30 This change has become important because whereas TRT is standard therapy in symptomatic hypogonadal men, it has long been considered taboo for men with a history of PCa, regardless of disease status. Transdermal testosterone is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate, according to the package insert.³¹ Androgens are contraindicated in men with known or suspected carcinoma of the prostate or breast, according to the testosterone cypionate injection package insert.³² Although TRT may increase serum PSA levels in some men, it often remains within clinically acceptable ranges and has not been shown to increase the risk for PCa. A recent observation from 3 registries of more than 1,000 hypogonadal men receiving TRT for up to 17 years concluded that TRT does not increase the risk for PCa.³³

Prostate cancer encompasses a heterogeneous collection of androgen-dependent and independent cells. Androgens have been known to play an important role in PCa biology, but this relationship is more complex than the traditional view that androgens stimulate PCa growth. More than 7 decades ago, Huggins and colleagues showed that disseminated PCa was inhibited by eliminating androgens by castration and activated by androgen injections.³⁴ Recently, the androgen hypothesis and the relationship of testosterone to PCa has been more clearly defined. Although it has been established that effective suppression of serum T levels with surgical or chemical castration remains an essential strategy in the management of advanced PCa, the assertion that testosterone causes growth of PCa has been challenged.^35,36

Recent studies have shown that there may be a more complex relationship between serum T and PCa risk than was previously established.³⁷ Although PCa cells have been shown to become androgen-independent as they progress into the castrate-resistant phase,⁹ several studies have indicated that low-serum T is associated with greater PCa risk and more worrisome features of PCa.^38,39 Hence, a saturation model has been proposed: Changes in serum T concentrations below the point of maximal androgen-androgen receptor (AR) binding will elicit substantial changes in PCa growth, as seen with castration or with serum T administration to castrated men.⁴⁰ However, once maximal androgen-AR binding is reached, the presence of additional androgen produces little further effect, suggesting that there is a limit to the ability of androgens to stimulate growth of PCa.⁴⁰

A meta-analysis of 45 articles studying the relationship between serum T and PCa risk has reported conflicting results.⁴ Eugonadal testosterone levels, whether physiologically or pharmacologically replaced, do not seem to promote PCa growth. It is unclear whether the timing of sex hormone exposure affects PCa or whether the cancer may influence blood levels of sex hormones. Since 2004, there have been case series totaling almost 150 men treated with prostatectomy, brachytherapy, or external beam radiation who have been safely treated with TRT.^6-9 These case studies suggest that after a thorough discussion of risks and benefits, TRT may be safer than previously thought for men who have been successfully treated for PCa, are deemed low risk for recurrence, and are monitored closely. However, no randomized controlled trials are available, and published guidelines recommend against starting TRT in patients with a history of breast or PCa.¹

Limitations

This study has limitations. The sample size is small and, therefore, it may not have had enough power to show differences in prevalence by subgroups. In addition, the population may not be representative of all male veterans who seek care in the VA or of men in other health care settings, because this was a convenience sample of VA patients who received most of their care in the VA. However, the prevalence of hypogonadism, in this outpatient population is very similar to that found among men seen in primary care clinics.¹⁴ Finally, because pretreatment serum T levels were lacking, the authors were unable to assess whether hypogonadism was present before surgery or radiation therapy, and unable to determine whether treatment had any effect on serum T levels.

The study has several strengths. First, to the authors’ knowledge, this is the first study to assess the prevalence of hypogonadism after patients with low-risk PCa have received treatment with curative intent. Second, the authors assessed hypogonadism in every patient by measuring serum T levels in the early morning when levels are known to be at their highest. Third, differentiating primary and secondary hypogonadism helped provide insight into the possible etiology of the low serum T levels. Fourth, this study was performed at a single institution that uses electronic medical records, with almost complete data on patient demographics, PCa treatment, and receipt of TRT or androgen deprivation therapy. Fifth, because this study had the participation of endocrinologists and urologists, the study design helped answer questions pertinent to both medical and surgical specialties.

Conclusion

As life expectancy increases, many survivors of treated PCa present with symptoms of hypogonadism associated with low serum T levels and request TRT. The prevalence of hypogonadism before or after treatment for PCa in this population is not known. This study suggests that many low-risk PCa survivors have hypogonadism. Because hypogonadism negatively impacts quality of life by increasing the risk for sexual dysfunction, mood disturbances, bone fracture, development of metabolic syndrome, frailty, and decline in the feeling of general well-being and may have significant deleterious effects on other body systems, consideration for treatment is warranted.

Patients with PCa may be untreated because the safety of TRT in this population is unknown. Clinical practice guidelines caution against using TRT in this population, and recent literature questions the benefits and risks associated with the long-term safety of TRT, particularly in older men.^28,41 Although further studies are necessary before definitive conclusions can be drawn, increasing evidence, albeit small, suggests that TRT can be cautiously considered in selected hypogonadal men treated with curative intent for PCa and without evidence of active disease. However, because obese patients are at higher risk for aggressive PCa and mortality, it is unclear whether obese PCa survivors have an additional risk in regard to TRT.^42,43 To help clinicians provide information and care for their patients, appropriately designed prospective randomized studies using a collaborative approach and long-term follow-up are urgently needed to determine the safety of TRT in hypogonadal men with a history of low-risk PCa.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the Edward Hines Jr. VA Hospital. Dr. Silva’s work was carried out while she was a postdoctoral fellow supported by the VA Office of Academic Affiliations (TPP 42-013). The authors thank Ahmer V. Farooq, DO, Department of Surgery, Division of Urology, for his help in planning the design of the study. Dr. Agrawal affirms that all coauthors contributed significantly to the work and had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Patient 1

A white  man aged 67 years, with diastolic heart failure and chronic obstructive pulmonary disease, presented to the emergency department (ED) with shortness of breath. The initial laboratory results were significant for a newly elevated creatinine level of 2.06 mg/dL and a brain natriuretic peptide level of 648 pg/mL.

Imaging studies included a chest radiograph, a ventilation/perfusion scan, and an echocardiogram, as well as a right heart catheterization. All were nondiagnostic.

The patient's shortness of breath persisted despite treatment with diuretics, antibiotics, and steroids. Further laboratory workup revealed an elevated lactate dehydrogenase (LDH) level of 1,338 IU/L. A bone marrow biopsy performed because of concern about malignancy was unremarkable. Flow cytometry of the bone marrow aspirate did not reveal clonal B- or T-cell populations. Immunohistochemical staining was not performed. During this hospitalization for shortness of breath, the patient's mental staus began to decline, and his oxygen requirements increased.  The patient was intubated but expired 48 hours after mechanical ventilation was initiated.

Patient 2

A white woman aged 67 years presented to the ED with generalized weakness, fatigue, and nausea. The patient’s medical history was significant for a diagnosis of stage IIIa ovarian cancer. She was treated with surgical resection and completed 6 cycles of adjuvant carboplatin and paclitaxel 3 months prior to this presentation. She had good response to treatment with normalization of CA-125.

After completion of chemotherapy, the patient was found to have persistent anemia and thrombocytopenia. Admission laboratory results were significant for a hemoglobin level of 8.4 g/dL, a platelet count of 20,000/μL, and an LDH level of 1,220 IU/L.

Chest, abdomen, and pelvis CT scans showed mesenteric adenopathy and splenomegaly (Figures 3A, 3B, and 3C) compared with prior imaging. Bone marrow biopsy revealed large lymphoid cells with scant cytoplasm and irregular nuclei, primarily within blood vessels and sinusoids consistent with IVLBCL (Figure 4). Flow cytometry of the bone marrow specimen showed an abnormal B-cell population with expression CD20, CD19, FMC-7, and dim κ light chain restriction. The cells were negative for CD5 and CD10. Immunohistochemical staining was positive for CD20, CD79a, PAX5, BCL-2 , and MUM1.

The patient was treated with 4 cycles of cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab, plus intrathecal methotrexate. The chemotherapy dose was reduced in the final cycle because of neuropathy in the hands and feet. The patient had undergone autologous stem-cell transplantation to allow high-dose chemotherapy. She was doing well more than 5 months after her transplant without evidence of recurrent disease.

Patient 3

A white man aged 76 years presented to the ED with cutaneous nodules, weight loss, fatigue, fevers, and epigastric pain. The patient’s medical history was significant for asymptomatic lymphoplasmacytic lymphoma diagnosed 2 months earlier, which had not required treatment. Laboratory results on admission revealed transaminitis, mild anemia with a hemoglobin level of 11 g/dL, and LDH level of 497 IU/L.

Chest, abdomen, and pelvis CT scans showed a 1.7cm hepatic lesion and mesenteric adenopathy. A bone marrow biopsy was unchanged from prior studies and showed minimal involvement (5%) of marrow space by low grade B-cell lymphoma.

Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans showed multiple areas of uptake in the neck, chest, abdomen, and pelvis (Figures 5 and 6). No increased uptake in the subcutaneous nodules was noted on examination. Laparoscopic biopsy of FDG-avid mesenteric nodes showed clusters of atypical large lymphoid cells resulting in distention of the vascular lumina, resulting in the diagnosis of IVLBCL (Figure 7).

Immunohistochemical stains showed that the intravascular lymphocytes were strongly positive for CD20 and BCL-2 and negative for CD5 and CD10. Flow cytometry on the sample was limited by a low cell count and could not be assessed for clonality. The patient completed 6 cycles of rituximab as well as intrathecal methotrexate. Restaging studies showed a complete remission.

Two months later, the patient developed a skin nodule on the right shoulder. A repeat FDG-PET scan showed increased uptake, and fine-needle biopsy confirmed recurrent disease. The patient is undergoing treatment with ifosfamide, carboplatin, etoposide, and rituximab, as well as workup for autologous stem-cell transplant.

Discussion

Intravascular large B-cell lymphoma, a subtype of diffuse large B-cell lymphoma, is unique because it is primarily extranodal and typically without significant tumor burden.^1-4 Standard imaging modalities, therefore, are often nonspecific and do not aid clinicians in establishing a diagnosis. Fluorodeoxyglucose-positron emission tomography has a known role in the assessment of diffuse large B-cell lymphoma, both at time of diagnosis and in monitoring response to treatment.5 However, the use of FDGPET in the diagnosis and management of IVLBCL has not been clearly established.

In a review of the literature, 26 English-language case reports and small case series reporting individual centers’ experience with the use of this imaging modality in the diagnosis of IVLBCL were identified. Two cases were eliminated from review because they did not discuss the use of FDG-PET in relationship to diagnosis. Of the remaining 24 cases, 21 underwent initial imaging with 1 or more of the following imaging modalities: CT, magnetic resonance, ultrasound, bone scan, and gallium scintigraphy, all of which were nonspecific and did not lead to a definitive diagnosis.^3,6-25 Each of the 21 cases was followed up by FDG-PET; in 19, the FDG-PET scan was positive and resulted in a diagnosis of IVLBCL. In 2 cases, the FDG-PET scan was nonrevealing and was not considered helpful in diagnosis.^11,18 In 3 of the 21 cases, the FDG-PET scan was the primary imaging modality.^6,14,25

In this review, all 3 patients had initial imaging with CT scans of anatomic locations that were largely unrevealing, although later histologic examination showed them to be locations of active disease either by biopsy or on autopsy. One patient who underwent early FDG-PET was found to have increased uptake in the mesenteric lymph nodes, which were later biopsied, as well as uptake in the bilateral adrenal glands, lungs, and bone.

Several characteristic FDG-PET findings that have been described in the literature have been identified in patients with IVLBCL, including diffuse accumulation in bilateral lung fields, accumulation in the renal cortex or adrenal glands, diffuse bony involvement, and hypometabolism in the brain.^{7,10,12,13,17,23,25} These findings show that organs with the richest blood supply, specifically the lungs and kidneys, often are affected. The brain, an obligate glucose metabolizer, would be expected to have high uptake; however, with tumor thrombi occluding small intracranial vessels, micro infarcts ensue and are evidenced by areas of low uptake on FDG-PET scans in patients with IVLBCL.⁷ These characteristic patterns seen on FDG-PET scans can help to support a diagnosis of IVLBCL when clinical suspicion is high. Further, clinicians may be able to use imaging results to guide an appropriate site for biopsy to confirm diagnosis.

Conclusion

Intravascular large B-cell lymphoma remains a diagnostic challenge for clinicians. Prognosis is generally poor and likely related to frequent delays in diagnosis.¹ Clinicians continue to work toward improving their ability to diagnose this disease in its early stages. New diagnostic algorithms and the use of random skin biopsies have shown some promise in improving diagnostic efficiency.^26-28 Based on the authors’ experience and review of the literature, FDG-PET may be another promising tool to aid early diagnosis. Characteristic FDG-PET findings have been well described and may help to support the diagnosis of IVLBCL and guide an appropriate biopsy site when clinical suspicion for IVLBCL exists.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Patient 1

A white  man aged 67 years, with diastolic heart failure and chronic obstructive pulmonary disease, presented to the emergency department (ED) with shortness of breath. The initial laboratory results were significant for a newly elevated creatinine level of 2.06 mg/dL and a brain natriuretic peptide level of 648 pg/mL.

Imaging studies included a chest radiograph, a ventilation/perfusion scan, and an echocardiogram, as well as a right heart catheterization. All were nondiagnostic.

The patient's shortness of breath persisted despite treatment with diuretics, antibiotics, and steroids. Further laboratory workup revealed an elevated lactate dehydrogenase (LDH) level of 1,338 IU/L. A bone marrow biopsy performed because of concern about malignancy was unremarkable. Flow cytometry of the bone marrow aspirate did not reveal clonal B- or T-cell populations. Immunohistochemical staining was not performed. During this hospitalization for shortness of breath, the patient's mental staus began to decline, and his oxygen requirements increased.  The patient was intubated but expired 48 hours after mechanical ventilation was initiated.

Patient 2

A white woman aged 67 years presented to the ED with generalized weakness, fatigue, and nausea. The patient’s medical history was significant for a diagnosis of stage IIIa ovarian cancer. She was treated with surgical resection and completed 6 cycles of adjuvant carboplatin and paclitaxel 3 months prior to this presentation. She had good response to treatment with normalization of CA-125.

After completion of chemotherapy, the patient was found to have persistent anemia and thrombocytopenia. Admission laboratory results were significant for a hemoglobin level of 8.4 g/dL, a platelet count of 20,000/μL, and an LDH level of 1,220 IU/L.

Chest, abdomen, and pelvis CT scans showed mesenteric adenopathy and splenomegaly (Figures 3A, 3B, and 3C) compared with prior imaging. Bone marrow biopsy revealed large lymphoid cells with scant cytoplasm and irregular nuclei, primarily within blood vessels and sinusoids consistent with IVLBCL (Figure 4). Flow cytometry of the bone marrow specimen showed an abnormal B-cell population with expression CD20, CD19, FMC-7, and dim κ light chain restriction. The cells were negative for CD5 and CD10. Immunohistochemical staining was positive for CD20, CD79a, PAX5, BCL-2 , and MUM1.

The patient was treated with 4 cycles of cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab, plus intrathecal methotrexate. The chemotherapy dose was reduced in the final cycle because of neuropathy in the hands and feet. The patient had undergone autologous stem-cell transplantation to allow high-dose chemotherapy. She was doing well more than 5 months after her transplant without evidence of recurrent disease.

Patient 3

A white man aged 76 years presented to the ED with cutaneous nodules, weight loss, fatigue, fevers, and epigastric pain. The patient’s medical history was significant for asymptomatic lymphoplasmacytic lymphoma diagnosed 2 months earlier, which had not required treatment. Laboratory results on admission revealed transaminitis, mild anemia with a hemoglobin level of 11 g/dL, and LDH level of 497 IU/L.

Chest, abdomen, and pelvis CT scans showed a 1.7cm hepatic lesion and mesenteric adenopathy. A bone marrow biopsy was unchanged from prior studies and showed minimal involvement (5%) of marrow space by low grade B-cell lymphoma.

Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans showed multiple areas of uptake in the neck, chest, abdomen, and pelvis (Figures 5 and 6). No increased uptake in the subcutaneous nodules was noted on examination. Laparoscopic biopsy of FDG-avid mesenteric nodes showed clusters of atypical large lymphoid cells resulting in distention of the vascular lumina, resulting in the diagnosis of IVLBCL (Figure 7).

Immunohistochemical stains showed that the intravascular lymphocytes were strongly positive for CD20 and BCL-2 and negative for CD5 and CD10. Flow cytometry on the sample was limited by a low cell count and could not be assessed for clonality. The patient completed 6 cycles of rituximab as well as intrathecal methotrexate. Restaging studies showed a complete remission.

Two months later, the patient developed a skin nodule on the right shoulder. A repeat FDG-PET scan showed increased uptake, and fine-needle biopsy confirmed recurrent disease. The patient is undergoing treatment with ifosfamide, carboplatin, etoposide, and rituximab, as well as workup for autologous stem-cell transplant.

Discussion

Intravascular large B-cell lymphoma, a subtype of diffuse large B-cell lymphoma, is unique because it is primarily extranodal and typically without significant tumor burden.^1-4 Standard imaging modalities, therefore, are often nonspecific and do not aid clinicians in establishing a diagnosis. Fluorodeoxyglucose-positron emission tomography has a known role in the assessment of diffuse large B-cell lymphoma, both at time of diagnosis and in monitoring response to treatment.5 However, the use of FDGPET in the diagnosis and management of IVLBCL has not been clearly established.

In a review of the literature, 26 English-language case reports and small case series reporting individual centers’ experience with the use of this imaging modality in the diagnosis of IVLBCL were identified. Two cases were eliminated from review because they did not discuss the use of FDG-PET in relationship to diagnosis. Of the remaining 24 cases, 21 underwent initial imaging with 1 or more of the following imaging modalities: CT, magnetic resonance, ultrasound, bone scan, and gallium scintigraphy, all of which were nonspecific and did not lead to a definitive diagnosis.^3,6-25 Each of the 21 cases was followed up by FDG-PET; in 19, the FDG-PET scan was positive and resulted in a diagnosis of IVLBCL. In 2 cases, the FDG-PET scan was nonrevealing and was not considered helpful in diagnosis.^11,18 In 3 of the 21 cases, the FDG-PET scan was the primary imaging modality.^6,14,25

In this review, all 3 patients had initial imaging with CT scans of anatomic locations that were largely unrevealing, although later histologic examination showed them to be locations of active disease either by biopsy or on autopsy. One patient who underwent early FDG-PET was found to have increased uptake in the mesenteric lymph nodes, which were later biopsied, as well as uptake in the bilateral adrenal glands, lungs, and bone.

Several characteristic FDG-PET findings that have been described in the literature have been identified in patients with IVLBCL, including diffuse accumulation in bilateral lung fields, accumulation in the renal cortex or adrenal glands, diffuse bony involvement, and hypometabolism in the brain.^{7,10,12,13,17,23,25} These findings show that organs with the richest blood supply, specifically the lungs and kidneys, often are affected. The brain, an obligate glucose metabolizer, would be expected to have high uptake; however, with tumor thrombi occluding small intracranial vessels, micro infarcts ensue and are evidenced by areas of low uptake on FDG-PET scans in patients with IVLBCL.⁷ These characteristic patterns seen on FDG-PET scans can help to support a diagnosis of IVLBCL when clinical suspicion is high. Further, clinicians may be able to use imaging results to guide an appropriate site for biopsy to confirm diagnosis.

Conclusion

Intravascular large B-cell lymphoma remains a diagnostic challenge for clinicians. Prognosis is generally poor and likely related to frequent delays in diagnosis.¹ Clinicians continue to work toward improving their ability to diagnose this disease in its early stages. New diagnostic algorithms and the use of random skin biopsies have shown some promise in improving diagnostic efficiency.^26-28 Based on the authors’ experience and review of the literature, FDG-PET may be another promising tool to aid early diagnosis. Characteristic FDG-PET findings have been well described and may help to support the diagnosis of IVLBCL and guide an appropriate biopsy site when clinical suspicion for IVLBCL exists.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Patient 1

A white  man aged 67 years, with diastolic heart failure and chronic obstructive pulmonary disease, presented to the emergency department (ED) with shortness of breath. The initial laboratory results were significant for a newly elevated creatinine level of 2.06 mg/dL and a brain natriuretic peptide level of 648 pg/mL.

Imaging studies included a chest radiograph, a ventilation/perfusion scan, and an echocardiogram, as well as a right heart catheterization. All were nondiagnostic.

The patient's shortness of breath persisted despite treatment with diuretics, antibiotics, and steroids. Further laboratory workup revealed an elevated lactate dehydrogenase (LDH) level of 1,338 IU/L. A bone marrow biopsy performed because of concern about malignancy was unremarkable. Flow cytometry of the bone marrow aspirate did not reveal clonal B- or T-cell populations. Immunohistochemical staining was not performed. During this hospitalization for shortness of breath, the patient's mental staus began to decline, and his oxygen requirements increased.  The patient was intubated but expired 48 hours after mechanical ventilation was initiated.

Patient 2

A white woman aged 67 years presented to the ED with generalized weakness, fatigue, and nausea. The patient’s medical history was significant for a diagnosis of stage IIIa ovarian cancer. She was treated with surgical resection and completed 6 cycles of adjuvant carboplatin and paclitaxel 3 months prior to this presentation. She had good response to treatment with normalization of CA-125.

After completion of chemotherapy, the patient was found to have persistent anemia and thrombocytopenia. Admission laboratory results were significant for a hemoglobin level of 8.4 g/dL, a platelet count of 20,000/μL, and an LDH level of 1,220 IU/L.

Chest, abdomen, and pelvis CT scans showed mesenteric adenopathy and splenomegaly (Figures 3A, 3B, and 3C) compared with prior imaging. Bone marrow biopsy revealed large lymphoid cells with scant cytoplasm and irregular nuclei, primarily within blood vessels and sinusoids consistent with IVLBCL (Figure 4). Flow cytometry of the bone marrow specimen showed an abnormal B-cell population with expression CD20, CD19, FMC-7, and dim κ light chain restriction. The cells were negative for CD5 and CD10. Immunohistochemical staining was positive for CD20, CD79a, PAX5, BCL-2 , and MUM1.

The patient was treated with 4 cycles of cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab, plus intrathecal methotrexate. The chemotherapy dose was reduced in the final cycle because of neuropathy in the hands and feet. The patient had undergone autologous stem-cell transplantation to allow high-dose chemotherapy. She was doing well more than 5 months after her transplant without evidence of recurrent disease.

Patient 3

A white man aged 76 years presented to the ED with cutaneous nodules, weight loss, fatigue, fevers, and epigastric pain. The patient’s medical history was significant for asymptomatic lymphoplasmacytic lymphoma diagnosed 2 months earlier, which had not required treatment. Laboratory results on admission revealed transaminitis, mild anemia with a hemoglobin level of 11 g/dL, and LDH level of 497 IU/L.

Chest, abdomen, and pelvis CT scans showed a 1.7cm hepatic lesion and mesenteric adenopathy. A bone marrow biopsy was unchanged from prior studies and showed minimal involvement (5%) of marrow space by low grade B-cell lymphoma.

Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans showed multiple areas of uptake in the neck, chest, abdomen, and pelvis (Figures 5 and 6). No increased uptake in the subcutaneous nodules was noted on examination. Laparoscopic biopsy of FDG-avid mesenteric nodes showed clusters of atypical large lymphoid cells resulting in distention of the vascular lumina, resulting in the diagnosis of IVLBCL (Figure 7).

Immunohistochemical stains showed that the intravascular lymphocytes were strongly positive for CD20 and BCL-2 and negative for CD5 and CD10. Flow cytometry on the sample was limited by a low cell count and could not be assessed for clonality. The patient completed 6 cycles of rituximab as well as intrathecal methotrexate. Restaging studies showed a complete remission.

Two months later, the patient developed a skin nodule on the right shoulder. A repeat FDG-PET scan showed increased uptake, and fine-needle biopsy confirmed recurrent disease. The patient is undergoing treatment with ifosfamide, carboplatin, etoposide, and rituximab, as well as workup for autologous stem-cell transplant.

Discussion

Intravascular large B-cell lymphoma, a subtype of diffuse large B-cell lymphoma, is unique because it is primarily extranodal and typically without significant tumor burden.^1-4 Standard imaging modalities, therefore, are often nonspecific and do not aid clinicians in establishing a diagnosis. Fluorodeoxyglucose-positron emission tomography has a known role in the assessment of diffuse large B-cell lymphoma, both at time of diagnosis and in monitoring response to treatment.5 However, the use of FDGPET in the diagnosis and management of IVLBCL has not been clearly established.

In a review of the literature, 26 English-language case reports and small case series reporting individual centers’ experience with the use of this imaging modality in the diagnosis of IVLBCL were identified. Two cases were eliminated from review because they did not discuss the use of FDG-PET in relationship to diagnosis. Of the remaining 24 cases, 21 underwent initial imaging with 1 or more of the following imaging modalities: CT, magnetic resonance, ultrasound, bone scan, and gallium scintigraphy, all of which were nonspecific and did not lead to a definitive diagnosis.^3,6-25 Each of the 21 cases was followed up by FDG-PET; in 19, the FDG-PET scan was positive and resulted in a diagnosis of IVLBCL. In 2 cases, the FDG-PET scan was nonrevealing and was not considered helpful in diagnosis.^11,18 In 3 of the 21 cases, the FDG-PET scan was the primary imaging modality.^6,14,25

In this review, all 3 patients had initial imaging with CT scans of anatomic locations that were largely unrevealing, although later histologic examination showed them to be locations of active disease either by biopsy or on autopsy. One patient who underwent early FDG-PET was found to have increased uptake in the mesenteric lymph nodes, which were later biopsied, as well as uptake in the bilateral adrenal glands, lungs, and bone.

Several characteristic FDG-PET findings that have been described in the literature have been identified in patients with IVLBCL, including diffuse accumulation in bilateral lung fields, accumulation in the renal cortex or adrenal glands, diffuse bony involvement, and hypometabolism in the brain.^{7,10,12,13,17,23,25} These findings show that organs with the richest blood supply, specifically the lungs and kidneys, often are affected. The brain, an obligate glucose metabolizer, would be expected to have high uptake; however, with tumor thrombi occluding small intracranial vessels, micro infarcts ensue and are evidenced by areas of low uptake on FDG-PET scans in patients with IVLBCL.⁷ These characteristic patterns seen on FDG-PET scans can help to support a diagnosis of IVLBCL when clinical suspicion is high. Further, clinicians may be able to use imaging results to guide an appropriate site for biopsy to confirm diagnosis.

Conclusion

Intravascular large B-cell lymphoma remains a diagnostic challenge for clinicians. Prognosis is generally poor and likely related to frequent delays in diagnosis.¹ Clinicians continue to work toward improving their ability to diagnose this disease in its early stages. New diagnostic algorithms and the use of random skin biopsies have shown some promise in improving diagnostic efficiency.^26-28 Based on the authors’ experience and review of the literature, FDG-PET may be another promising tool to aid early diagnosis. Characteristic FDG-PET findings have been well described and may help to support the diagnosis of IVLBCL and guide an appropriate biopsy site when clinical suspicion for IVLBCL exists.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Gamma-delta (γ-δ) T-cell lymphomas (GDTCL) are rare and aggressive cancers with specific morphologic, phenotypic, and functional properties. When discovered in 1984, the T-cell receptor (TCR) was characterized as an alpha-beta (α-β) heterodimer. The γ-δ heterodimer was discovered later, when a third rearranging gene was recognized.¹

Gaulard and colleagues described the first case of peripheral neoplasm with the γ-δ TCR.² Now the present authors report the case of a patient with an autoimmune hemolytic anemia (AIHA) with both cold and warm antibodies—an atypical presentation of this rare form of TCL. Such a case has not been previously reported.

Clinical History

A 77-year-old woman with a past medical history of osteoarthritis, gout, mitral stenosis, bioprosthetic aortic valve replacement, and obesity presented to the emergency department (ED) reporting progressive weakness, confusion, and jaundice. She had been recently discharged from
another hospital after an 18-day stay for gangrenous cholecystitis and shingles. Her home medications were metronidazole and acyclovir. In the ED, she was febrile at 100.5°. Laboratory test results revealed anemia with a hemoglobin level of 50 g/L (83 g/L in clinic 2 weeks earlier) and neutropenia with an absolute neutrophilic count of 500 cells/μL (normal range 1,520-6,370 cells/μL). She also was thrombocytopenic with a platelet count of 71x109/L (normal range 150-450×109/L).

On admission, the hematology service was consulted for pancytopenia. The pertinent workup included a lactate dehydrogenase level of 31.16 μkat/L (normal range 1.7-3.4 μkat/L), a haptoglobin level of < 1,500 mg/L (normal range 260-1,850 mg/L), and a direct bilirubin level of 13.68 μmol/L (normal range 1.7-5.1 μmol/L). A peripheral blood smear was negative for schistocytes. Fibrin split products were 40 mg/L (normal < 10 mg/L), fibrinogen level was 6.94 μmol/L (normal range 5.8-11.8 μmol/L), prothrombin time was 14.6 seconds (normal range 10-14 sec), and international normalized ratio was 1.3 (normal < 1). The concomitant decrease in fibrinogen level and increase in fibrin split product titers were consistent with the diagnosis of acute disseminated intravascular coagulation. Iron studies were consistent with anemia of chronic disease (low reticulocyte count of 0.4%) and vitamin B12 deficiency (level 195). Coombs test results were positive for both cold and warm antibodies, with cold being more prominent. Abdominal ultrasonography revealed hepatosplenomegaly (HSM).

The patient was diagnosed with AIHA with no initial obvious underlying etiology. The differential diagnosis included autoimmune disorder, lymphoproliferative disease, and drug-induced process. She also was diagnosed with sepsis, which was thought to be contributing to the pancytopenia.

Broad-spectrum antibiotics (cefepime, metronidazole) and vitamin B12 supplements were started. After a blood transfusion, the patient developed fever and hypoxia, which required transfer to the medical intensive care unit. The differentials at this time included a transfusion reaction and/or transfusion-associated circulatory overload. Intravenous immunoglobulin was started at 1 g/kg to help with cold agglutinins. Prednisone 1 mg/kg was started as well. Peripheral blood flow cytometry results were positive for an abnormal T-cell population likely consistent with T-cell lineage lymphoma. Bone marrow biopsy results were consistent with GDTCL. Computed tomography (CT) of chest/abdomen/pelvis showed bilateral lung nodules < 1 cm, HSM with multiple spleen infarcts, and a 4.7-cm right adnexal soft-tissue lesion. Liver biopsy results were consistent with GDTCL. Results of a workup for cytomegalovirus and Epstein-Barr virus were negative, as was a mycoplasma screen. The patient was diagnosed with GDTCL with hepatic involvement, and CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone) therapy was started.

Discussion

Peripheral TCL (PTCL) are a rare, typically extranodal group of malignancies. They are aggressive and generally have a poor outcome, with most patients dying of lymphoma within 2 years.³ T-cell lymphomas most commonly express the γ-δ TCR. About 2% to 4% of TCLs express the γ-δ TCR.⁴ In 2008, the World Health Organization recognized 2 distinct GDTCL subgroups: hepatosplenic GDTCL (HSGDTCL) and primary cutaneous GDTCL.⁵ As the patient presented with hepatic involvement, this discussion focused on HSGDTCL.

Hepatosplenic GDTCL are rare types of PTCL. First described as a separate TCL subgroup in the 1990 REAL (Revised European-American Lymphoma) classification,⁶ they are estimated to represent about 1.4% of all TCL, with about 100 cases reported in the literature.⁴

The GDTCL cells tend to live in mucosa, lymphoid tissue, epithelial-rich tissues (skin, gastrointestinal tract), and red pulp of spleen.⁷ They develop from thymic precursors in bone marrow and are CD4-/CD8- and thus known as double negative cells.8 They mimic natural killer cells, behave as cytotoxic cells, and are capable of TCR rearrangement as well as phagocytosis.⁹

Hepatosplenic GDTCL are usually phenotypically CD2+, CD3+, CD4-, CD5-, CD7+, CD8-, and TCR γ-δ+.¹⁰ They are rarely associated with Epstein-Barr virus infection; reported cases seem more common in Asia.¹¹ Peak incidence is in young men (median age 20-25 years; male:female ratio 10:1). At-risk populations include the chronically immunosuppressed, including solid organ transplanted patients and patients under prolonged antigenic stimulation.¹²

The most common clinical features of HSGDTCL include B symptoms (fever of unknown origin, night sweats, loss of > 10% of body weight), marked HSM, and lack of lymphadenopathy. Patients often present with fever, weakness, and abdominal pain. Laboratory test results
typically show abnormal liver function and abnormal lactate dehydrogenase levels. Bone marrow is almost always involved, with possible trilineage cytopenia. Anemia and thrombocytopenia are reported in 75% and 85% of cases, respectively.¹³

Warm (70%) and cold auto-antibodies are the 2 classifications of AIHA.¹⁴ The AIHA can be primary, idiopathic, or a manifestation of underlying disease conditions, including non-Hodgkin lymphomas, systemic autoimmune diseases, chronic infections, postorgan transplantation, and solid tumors. It has also been reported as a complication of treatment with nucleoside analogues.¹⁵

Lacking specific symptoms, HSGDTCL is usually diagnosed late. The diagnosis should be suspected in young men who present with the aforementioned symptoms. However, not everyone with HSGDTCL falls in that group—the present patient was a 77-year-old woman.

Hepatosplenic GDTCL staging is similar to staging of other non-Hodgkin lymphomas. Total-body CT with contrast, bone marrow aspiration/biopsy, and direct lesion biopsy are required. Although positron emission tomography is generally thought to be as useful in TCL as in B-cell lymphomas, there is not enough evidence to support its use specifically in HSGDTCL.16 The staging classification follows the Ann Arbor system, with the majority of cases classified as stage IV.

Hepatosplenic GDTCL are aggressive tumors with a strong tendency to rapidly progress, and they are highly resistant to primary chemotherapy agents. Remission is rarely complete with use of conventional chemotherapy agents. Most patients die of the disease within 2 years of
diagnosis.¹² Although the rarity of HSGDTCL has made it difficult to identify any clear prognostic factors, a correlation between thrombocytopenia severity and disease progression has been found in many studies.¹⁷ There is no standard treatment regimen. Proposed therapies
include splenectomy (for diagnosis or thrombocytopenia management), corticosteroids, alkylating agents, purine analogue, anthracycline-containing regimens, and cytarabine/cisplatin combinations. The anthracycline-based regimen most commonly used as first-line therapy is CHOP, or CHOP derivatives, with complete remission rates between 30% and 45%. However, long-term results remain disappointing (median relapse time 4 months).10 In 3 reviews, median survival was 16 months, 11 months, and 9.5 months.10,17,18 In the International T-Cell Lymphoma Project study, the 5-year failure-free survival rate was 0%, and the overall survival rate was 7%.4 In these studies, the majority of patients received some variation of CHOP-based therapy, and although positive responses were appreciated in many of the cases, they were generally short-lived.

These results have been disappointing, and other modalities have been tried—including high-dose cytarabine regimens, 2'-deoxycoformycin (pentostatin), and anti-CD52 monoclonal antibodies (alemtuzumab).¹⁹ In an HSGDTCL study, 2 of 21 patients treated with platinum/cytarabine-based induction regimens were still in remission at 42 and 52 months.¹⁷ Another study examined a variety of induction regimens used to treat HSGDTCL in 15 patients.¹⁸ Responses tended to be more durable in patients who received a dose-intense Hyper-CVIDDoxil regimen (fractionated cyclophosphamide, liposomal doxorubicin, vincristine, dexamethasone) alternated with methotrexate and cytarabine. Complete response was 50%, and median duration of complete response was 8 months. Over the past 10 years, a few case reports have described successful treatment with autologous or allogeneic stem cell transplantation.²⁰

Conclusion

The present case represents a unique HSGDTCL presentation. To the authors’ knowledge, this is the first report of HSGDTCL presenting with acute disseminated intravascular coagulation and AIHA with both cold and warm antibodies.

Hepatosplenic GDTCL is a rare, novel disease. To understand more about this pathology, investigators need to better characterize the disease process and the manifestations. The hope is that more information will contribute to the development of more effective therapies. The unique presentation reported here may help in further characterizing and understanding this uncommon disease.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.

Click here to read the digital edition.

Gamma-delta (γ-δ) T-cell lymphomas (GDTCL) are rare and aggressive cancers with specific morphologic, phenotypic, and functional properties. When discovered in 1984, the T-cell receptor (TCR) was characterized as an alpha-beta (α-β) heterodimer. The γ-δ heterodimer was discovered later, when a third rearranging gene was recognized.¹

Gaulard and colleagues described the first case of peripheral neoplasm with the γ-δ TCR.² Now the present authors report the case of a patient with an autoimmune hemolytic anemia (AIHA) with both cold and warm antibodies—an atypical presentation of this rare form of TCL. Such a case has not been previously reported.

Clinical History

A 77-year-old woman with a past medical history of osteoarthritis, gout, mitral stenosis, bioprosthetic aortic valve replacement, and obesity presented to the emergency department (ED) reporting progressive weakness, confusion, and jaundice. She had been recently discharged from
another hospital after an 18-day stay for gangrenous cholecystitis and shingles. Her home medications were metronidazole and acyclovir. In the ED, she was febrile at 100.5°. Laboratory test results revealed anemia with a hemoglobin level of 50 g/L (83 g/L in clinic 2 weeks earlier) and neutropenia with an absolute neutrophilic count of 500 cells/μL (normal range 1,520-6,370 cells/μL). She also was thrombocytopenic with a platelet count of 71x109/L (normal range 150-450×109/L).

On admission, the hematology service was consulted for pancytopenia. The pertinent workup included a lactate dehydrogenase level of 31.16 μkat/L (normal range 1.7-3.4 μkat/L), a haptoglobin level of < 1,500 mg/L (normal range 260-1,850 mg/L), and a direct bilirubin level of 13.68 μmol/L (normal range 1.7-5.1 μmol/L). A peripheral blood smear was negative for schistocytes. Fibrin split products were 40 mg/L (normal < 10 mg/L), fibrinogen level was 6.94 μmol/L (normal range 5.8-11.8 μmol/L), prothrombin time was 14.6 seconds (normal range 10-14 sec), and international normalized ratio was 1.3 (normal < 1). The concomitant decrease in fibrinogen level and increase in fibrin split product titers were consistent with the diagnosis of acute disseminated intravascular coagulation. Iron studies were consistent with anemia of chronic disease (low reticulocyte count of 0.4%) and vitamin B12 deficiency (level 195). Coombs test results were positive for both cold and warm antibodies, with cold being more prominent. Abdominal ultrasonography revealed hepatosplenomegaly (HSM).

The patient was diagnosed with AIHA with no initial obvious underlying etiology. The differential diagnosis included autoimmune disorder, lymphoproliferative disease, and drug-induced process. She also was diagnosed with sepsis, which was thought to be contributing to the pancytopenia.

Broad-spectrum antibiotics (cefepime, metronidazole) and vitamin B12 supplements were started. After a blood transfusion, the patient developed fever and hypoxia, which required transfer to the medical intensive care unit. The differentials at this time included a transfusion reaction and/or transfusion-associated circulatory overload. Intravenous immunoglobulin was started at 1 g/kg to help with cold agglutinins. Prednisone 1 mg/kg was started as well. Peripheral blood flow cytometry results were positive for an abnormal T-cell population likely consistent with T-cell lineage lymphoma. Bone marrow biopsy results were consistent with GDTCL. Computed tomography (CT) of chest/abdomen/pelvis showed bilateral lung nodules < 1 cm, HSM with multiple spleen infarcts, and a 4.7-cm right adnexal soft-tissue lesion. Liver biopsy results were consistent with GDTCL. Results of a workup for cytomegalovirus and Epstein-Barr virus were negative, as was a mycoplasma screen. The patient was diagnosed with GDTCL with hepatic involvement, and CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone) therapy was started.

Discussion

Peripheral TCL (PTCL) are a rare, typically extranodal group of malignancies. They are aggressive and generally have a poor outcome, with most patients dying of lymphoma within 2 years.³ T-cell lymphomas most commonly express the γ-δ TCR. About 2% to 4% of TCLs express the γ-δ TCR.⁴ In 2008, the World Health Organization recognized 2 distinct GDTCL subgroups: hepatosplenic GDTCL (HSGDTCL) and primary cutaneous GDTCL.⁵ As the patient presented with hepatic involvement, this discussion focused on HSGDTCL.

Hepatosplenic GDTCL are rare types of PTCL. First described as a separate TCL subgroup in the 1990 REAL (Revised European-American Lymphoma) classification,⁶ they are estimated to represent about 1.4% of all TCL, with about 100 cases reported in the literature.⁴

The GDTCL cells tend to live in mucosa, lymphoid tissue, epithelial-rich tissues (skin, gastrointestinal tract), and red pulp of spleen.⁷ They develop from thymic precursors in bone marrow and are CD4-/CD8- and thus known as double negative cells.8 They mimic natural killer cells, behave as cytotoxic cells, and are capable of TCR rearrangement as well as phagocytosis.⁹

Hepatosplenic GDTCL are usually phenotypically CD2+, CD3+, CD4-, CD5-, CD7+, CD8-, and TCR γ-δ+.¹⁰ They are rarely associated with Epstein-Barr virus infection; reported cases seem more common in Asia.¹¹ Peak incidence is in young men (median age 20-25 years; male:female ratio 10:1). At-risk populations include the chronically immunosuppressed, including solid organ transplanted patients and patients under prolonged antigenic stimulation.¹²

The most common clinical features of HSGDTCL include B symptoms (fever of unknown origin, night sweats, loss of > 10% of body weight), marked HSM, and lack of lymphadenopathy. Patients often present with fever, weakness, and abdominal pain. Laboratory test results
typically show abnormal liver function and abnormal lactate dehydrogenase levels. Bone marrow is almost always involved, with possible trilineage cytopenia. Anemia and thrombocytopenia are reported in 75% and 85% of cases, respectively.¹³

Warm (70%) and cold auto-antibodies are the 2 classifications of AIHA.¹⁴ The AIHA can be primary, idiopathic, or a manifestation of underlying disease conditions, including non-Hodgkin lymphomas, systemic autoimmune diseases, chronic infections, postorgan transplantation, and solid tumors. It has also been reported as a complication of treatment with nucleoside analogues.¹⁵

Lacking specific symptoms, HSGDTCL is usually diagnosed late. The diagnosis should be suspected in young men who present with the aforementioned symptoms. However, not everyone with HSGDTCL falls in that group—the present patient was a 77-year-old woman.

Hepatosplenic GDTCL staging is similar to staging of other non-Hodgkin lymphomas. Total-body CT with contrast, bone marrow aspiration/biopsy, and direct lesion biopsy are required. Although positron emission tomography is generally thought to be as useful in TCL as in B-cell lymphomas, there is not enough evidence to support its use specifically in HSGDTCL.16 The staging classification follows the Ann Arbor system, with the majority of cases classified as stage IV.

Hepatosplenic GDTCL are aggressive tumors with a strong tendency to rapidly progress, and they are highly resistant to primary chemotherapy agents. Remission is rarely complete with use of conventional chemotherapy agents. Most patients die of the disease within 2 years of
diagnosis.¹² Although the rarity of HSGDTCL has made it difficult to identify any clear prognostic factors, a correlation between thrombocytopenia severity and disease progression has been found in many studies.¹⁷ There is no standard treatment regimen. Proposed therapies
include splenectomy (for diagnosis or thrombocytopenia management), corticosteroids, alkylating agents, purine analogue, anthracycline-containing regimens, and cytarabine/cisplatin combinations. The anthracycline-based regimen most commonly used as first-line therapy is CHOP, or CHOP derivatives, with complete remission rates between 30% and 45%. However, long-term results remain disappointing (median relapse time 4 months).10 In 3 reviews, median survival was 16 months, 11 months, and 9.5 months.10,17,18 In the International T-Cell Lymphoma Project study, the 5-year failure-free survival rate was 0%, and the overall survival rate was 7%.4 In these studies, the majority of patients received some variation of CHOP-based therapy, and although positive responses were appreciated in many of the cases, they were generally short-lived.

These results have been disappointing, and other modalities have been tried—including high-dose cytarabine regimens, 2'-deoxycoformycin (pentostatin), and anti-CD52 monoclonal antibodies (alemtuzumab).¹⁹ In an HSGDTCL study, 2 of 21 patients treated with platinum/cytarabine-based induction regimens were still in remission at 42 and 52 months.¹⁷ Another study examined a variety of induction regimens used to treat HSGDTCL in 15 patients.¹⁸ Responses tended to be more durable in patients who received a dose-intense Hyper-CVIDDoxil regimen (fractionated cyclophosphamide, liposomal doxorubicin, vincristine, dexamethasone) alternated with methotrexate and cytarabine. Complete response was 50%, and median duration of complete response was 8 months. Over the past 10 years, a few case reports have described successful treatment with autologous or allogeneic stem cell transplantation.²⁰

Conclusion

The present case represents a unique HSGDTCL presentation. To the authors’ knowledge, this is the first report of HSGDTCL presenting with acute disseminated intravascular coagulation and AIHA with both cold and warm antibodies.

Hepatosplenic GDTCL is a rare, novel disease. To understand more about this pathology, investigators need to better characterize the disease process and the manifestations. The hope is that more information will contribute to the development of more effective therapies. The unique presentation reported here may help in further characterizing and understanding this uncommon disease.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.

Click here to read the digital edition.

Gamma-delta (γ-δ) T-cell lymphomas (GDTCL) are rare and aggressive cancers with specific morphologic, phenotypic, and functional properties. When discovered in 1984, the T-cell receptor (TCR) was characterized as an alpha-beta (α-β) heterodimer. The γ-δ heterodimer was discovered later, when a third rearranging gene was recognized.¹

Gaulard and colleagues described the first case of peripheral neoplasm with the γ-δ TCR.² Now the present authors report the case of a patient with an autoimmune hemolytic anemia (AIHA) with both cold and warm antibodies—an atypical presentation of this rare form of TCL. Such a case has not been previously reported.

Clinical History

A 77-year-old woman with a past medical history of osteoarthritis, gout, mitral stenosis, bioprosthetic aortic valve replacement, and obesity presented to the emergency department (ED) reporting progressive weakness, confusion, and jaundice. She had been recently discharged from
another hospital after an 18-day stay for gangrenous cholecystitis and shingles. Her home medications were metronidazole and acyclovir. In the ED, she was febrile at 100.5°. Laboratory test results revealed anemia with a hemoglobin level of 50 g/L (83 g/L in clinic 2 weeks earlier) and neutropenia with an absolute neutrophilic count of 500 cells/μL (normal range 1,520-6,370 cells/μL). She also was thrombocytopenic with a platelet count of 71x109/L (normal range 150-450×109/L).

On admission, the hematology service was consulted for pancytopenia. The pertinent workup included a lactate dehydrogenase level of 31.16 μkat/L (normal range 1.7-3.4 μkat/L), a haptoglobin level of < 1,500 mg/L (normal range 260-1,850 mg/L), and a direct bilirubin level of 13.68 μmol/L (normal range 1.7-5.1 μmol/L). A peripheral blood smear was negative for schistocytes. Fibrin split products were 40 mg/L (normal < 10 mg/L), fibrinogen level was 6.94 μmol/L (normal range 5.8-11.8 μmol/L), prothrombin time was 14.6 seconds (normal range 10-14 sec), and international normalized ratio was 1.3 (normal < 1). The concomitant decrease in fibrinogen level and increase in fibrin split product titers were consistent with the diagnosis of acute disseminated intravascular coagulation. Iron studies were consistent with anemia of chronic disease (low reticulocyte count of 0.4%) and vitamin B12 deficiency (level 195). Coombs test results were positive for both cold and warm antibodies, with cold being more prominent. Abdominal ultrasonography revealed hepatosplenomegaly (HSM).

The patient was diagnosed with AIHA with no initial obvious underlying etiology. The differential diagnosis included autoimmune disorder, lymphoproliferative disease, and drug-induced process. She also was diagnosed with sepsis, which was thought to be contributing to the pancytopenia.

Broad-spectrum antibiotics (cefepime, metronidazole) and vitamin B12 supplements were started. After a blood transfusion, the patient developed fever and hypoxia, which required transfer to the medical intensive care unit. The differentials at this time included a transfusion reaction and/or transfusion-associated circulatory overload. Intravenous immunoglobulin was started at 1 g/kg to help with cold agglutinins. Prednisone 1 mg/kg was started as well. Peripheral blood flow cytometry results were positive for an abnormal T-cell population likely consistent with T-cell lineage lymphoma. Bone marrow biopsy results were consistent with GDTCL. Computed tomography (CT) of chest/abdomen/pelvis showed bilateral lung nodules < 1 cm, HSM with multiple spleen infarcts, and a 4.7-cm right adnexal soft-tissue lesion. Liver biopsy results were consistent with GDTCL. Results of a workup for cytomegalovirus and Epstein-Barr virus were negative, as was a mycoplasma screen. The patient was diagnosed with GDTCL with hepatic involvement, and CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone) therapy was started.

Discussion

Peripheral TCL (PTCL) are a rare, typically extranodal group of malignancies. They are aggressive and generally have a poor outcome, with most patients dying of lymphoma within 2 years.³ T-cell lymphomas most commonly express the γ-δ TCR. About 2% to 4% of TCLs express the γ-δ TCR.⁴ In 2008, the World Health Organization recognized 2 distinct GDTCL subgroups: hepatosplenic GDTCL (HSGDTCL) and primary cutaneous GDTCL.⁵ As the patient presented with hepatic involvement, this discussion focused on HSGDTCL.

Hepatosplenic GDTCL are rare types of PTCL. First described as a separate TCL subgroup in the 1990 REAL (Revised European-American Lymphoma) classification,⁶ they are estimated to represent about 1.4% of all TCL, with about 100 cases reported in the literature.⁴

The GDTCL cells tend to live in mucosa, lymphoid tissue, epithelial-rich tissues (skin, gastrointestinal tract), and red pulp of spleen.⁷ They develop from thymic precursors in bone marrow and are CD4-/CD8- and thus known as double negative cells.8 They mimic natural killer cells, behave as cytotoxic cells, and are capable of TCR rearrangement as well as phagocytosis.⁹

Hepatosplenic GDTCL are usually phenotypically CD2+, CD3+, CD4-, CD5-, CD7+, CD8-, and TCR γ-δ+.¹⁰ They are rarely associated with Epstein-Barr virus infection; reported cases seem more common in Asia.¹¹ Peak incidence is in young men (median age 20-25 years; male:female ratio 10:1). At-risk populations include the chronically immunosuppressed, including solid organ transplanted patients and patients under prolonged antigenic stimulation.¹²

The most common clinical features of HSGDTCL include B symptoms (fever of unknown origin, night sweats, loss of > 10% of body weight), marked HSM, and lack of lymphadenopathy. Patients often present with fever, weakness, and abdominal pain. Laboratory test results
typically show abnormal liver function and abnormal lactate dehydrogenase levels. Bone marrow is almost always involved, with possible trilineage cytopenia. Anemia and thrombocytopenia are reported in 75% and 85% of cases, respectively.¹³

Warm (70%) and cold auto-antibodies are the 2 classifications of AIHA.¹⁴ The AIHA can be primary, idiopathic, or a manifestation of underlying disease conditions, including non-Hodgkin lymphomas, systemic autoimmune diseases, chronic infections, postorgan transplantation, and solid tumors. It has also been reported as a complication of treatment with nucleoside analogues.¹⁵

Lacking specific symptoms, HSGDTCL is usually diagnosed late. The diagnosis should be suspected in young men who present with the aforementioned symptoms. However, not everyone with HSGDTCL falls in that group—the present patient was a 77-year-old woman.

Hepatosplenic GDTCL staging is similar to staging of other non-Hodgkin lymphomas. Total-body CT with contrast, bone marrow aspiration/biopsy, and direct lesion biopsy are required. Although positron emission tomography is generally thought to be as useful in TCL as in B-cell lymphomas, there is not enough evidence to support its use specifically in HSGDTCL.16 The staging classification follows the Ann Arbor system, with the majority of cases classified as stage IV.

Hepatosplenic GDTCL are aggressive tumors with a strong tendency to rapidly progress, and they are highly resistant to primary chemotherapy agents. Remission is rarely complete with use of conventional chemotherapy agents. Most patients die of the disease within 2 years of
diagnosis.¹² Although the rarity of HSGDTCL has made it difficult to identify any clear prognostic factors, a correlation between thrombocytopenia severity and disease progression has been found in many studies.¹⁷ There is no standard treatment regimen. Proposed therapies
include splenectomy (for diagnosis or thrombocytopenia management), corticosteroids, alkylating agents, purine analogue, anthracycline-containing regimens, and cytarabine/cisplatin combinations. The anthracycline-based regimen most commonly used as first-line therapy is CHOP, or CHOP derivatives, with complete remission rates between 30% and 45%. However, long-term results remain disappointing (median relapse time 4 months).10 In 3 reviews, median survival was 16 months, 11 months, and 9.5 months.10,17,18 In the International T-Cell Lymphoma Project study, the 5-year failure-free survival rate was 0%, and the overall survival rate was 7%.4 In these studies, the majority of patients received some variation of CHOP-based therapy, and although positive responses were appreciated in many of the cases, they were generally short-lived.

These results have been disappointing, and other modalities have been tried—including high-dose cytarabine regimens, 2'-deoxycoformycin (pentostatin), and anti-CD52 monoclonal antibodies (alemtuzumab).¹⁹ In an HSGDTCL study, 2 of 21 patients treated with platinum/cytarabine-based induction regimens were still in remission at 42 and 52 months.¹⁷ Another study examined a variety of induction regimens used to treat HSGDTCL in 15 patients.¹⁸ Responses tended to be more durable in patients who received a dose-intense Hyper-CVIDDoxil regimen (fractionated cyclophosphamide, liposomal doxorubicin, vincristine, dexamethasone) alternated with methotrexate and cytarabine. Complete response was 50%, and median duration of complete response was 8 months. Over the past 10 years, a few case reports have described successful treatment with autologous or allogeneic stem cell transplantation.²⁰

Conclusion

The present case represents a unique HSGDTCL presentation. To the authors’ knowledge, this is the first report of HSGDTCL presenting with acute disseminated intravascular coagulation and AIHA with both cold and warm antibodies.

Hepatosplenic GDTCL is a rare, novel disease. To understand more about this pathology, investigators need to better characterize the disease process and the manifestations. The hope is that more information will contribute to the development of more effective therapies. The unique presentation reported here may help in further characterizing and understanding this uncommon disease.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.

Click here to read the digital edition.

The authors would like to acknowledge Tony Quang, MD, JD, for the advice given on this project.

Palliative radiotherapy for bone metastases is typically delivered either as a short course of 1 to 5 fractions or protracted over longer courses of up to 20 treatments. These longer courses can be burdensome and discourage its utilization, despite a 50% to 80% likelihood of meaningful pain relief from only a single fraction of radiation therapy. Meanwhile, there are multiple randomized studies that have demonstrated that shorter course(s) are equivalent for pain control.

Although the VHA currently has 143 medical facilities that have cancer diagnostic and treatment capabilities, only 40 have radiation oncology services on-site.¹ Thus, access to palliative radiotherapy may be limited for veterans who do not live close by, and many may seek care outside the VHA. At VHA radiation oncology centers, single-fraction radiation therapy (SFRT) is routinely offered by the majority of radiation oncologists.^2,3 However, the longer course is commonly preferred outside the VA, and a recent SEER-Medicare analysis of more than 3,000 patients demonstrated that the majority of patients treated outside the VA actually receive more than 10 treatments.⁴ For this reason, the VA National Palliative Radiotherapy Task Force prepared this document to provide guidance for clinicians within and outside the VA to increase awareness of the appropriateness, effectiveness, and convenience of SFRT as opposed to longer courses of treatment that increase the burden of care at the end of life and often are unnecessary.

Veterans, Cancer, and Metastases

Within the VA, an estimated 40,000 new cancer cases are diagnosed each year, and 175,000 veterans undergo cancer care within the VHA annually.¹ Unfortunately, the majority will develop bone metastases with postmortem examinations, suggesting that the rate can be as high as 90% at the end of life.^5-7 For many, including veterans with cancer, pain control can be difficult, and access to palliative radiotherapy is critical.⁸

Single-Fraction Palliatiev Radiation Therapy

Historically, patients with painful bone metastases have been treated with courses of palliative radiotherapy ranging between 2 and 4 weeks of daily treatments. However, several large randomized clinical trials comparing a single treatment with multiple treatments have established that SFRT provides equivalent rates of pain relief even when it may be required for a second time.^9-12 Recommendations based on these trials have been incorporated into various treatment guidelines that widely acknowledge the efficacy of SFRT.^13-15

For this reason, SFRT is often preferred at many centers because it is substantially more convenient for patients with cancer. It reduces travel time for daily radiation clinic visits, which allows for more time with loved ones outside the medical establishment. Furthermore, SFRT improves patient access to radiotherapy and reduces costs. The benefits can be direct as well as indirect to those who have to take time for numerous visits.

Longer courses of palliative radiotherapy can be burdensome for patients and primary care providers. Unnecessarily protracted courses of palliative radiotherapy also delay the receipt of systemic therapies because they are typically considered unsafe to administer concurrently. Moreover, when SFRT is unavailable, the burden of long-course palliation is known to discourage health care providers from referring patients since opioid therapy is more convenient, even though it exchanges lucidity for analgesia.^16,17

For this reason, the authors believe that it is in the best interest for veterans with terminal cancers and their providers to be aware of the shorter SFRT for effective, convenient pain relief. This treatment option is particularly relevant for patients with a poor performance status, patients already in hospice care, or patient who travel long distances.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

The authors would like to acknowledge Tony Quang, MD, JD, for the advice given on this project.

Palliative radiotherapy for bone metastases is typically delivered either as a short course of 1 to 5 fractions or protracted over longer courses of up to 20 treatments. These longer courses can be burdensome and discourage its utilization, despite a 50% to 80% likelihood of meaningful pain relief from only a single fraction of radiation therapy. Meanwhile, there are multiple randomized studies that have demonstrated that shorter course(s) are equivalent for pain control.

Although the VHA currently has 143 medical facilities that have cancer diagnostic and treatment capabilities, only 40 have radiation oncology services on-site.¹ Thus, access to palliative radiotherapy may be limited for veterans who do not live close by, and many may seek care outside the VHA. At VHA radiation oncology centers, single-fraction radiation therapy (SFRT) is routinely offered by the majority of radiation oncologists.^2,3 However, the longer course is commonly preferred outside the VA, and a recent SEER-Medicare analysis of more than 3,000 patients demonstrated that the majority of patients treated outside the VA actually receive more than 10 treatments.⁴ For this reason, the VA National Palliative Radiotherapy Task Force prepared this document to provide guidance for clinicians within and outside the VA to increase awareness of the appropriateness, effectiveness, and convenience of SFRT as opposed to longer courses of treatment that increase the burden of care at the end of life and often are unnecessary.

Veterans, Cancer, and Metastases

Within the VA, an estimated 40,000 new cancer cases are diagnosed each year, and 175,000 veterans undergo cancer care within the VHA annually.¹ Unfortunately, the majority will develop bone metastases with postmortem examinations, suggesting that the rate can be as high as 90% at the end of life.^5-7 For many, including veterans with cancer, pain control can be difficult, and access to palliative radiotherapy is critical.⁸

Single-Fraction Palliatiev Radiation Therapy

Historically, patients with painful bone metastases have been treated with courses of palliative radiotherapy ranging between 2 and 4 weeks of daily treatments. However, several large randomized clinical trials comparing a single treatment with multiple treatments have established that SFRT provides equivalent rates of pain relief even when it may be required for a second time.^9-12 Recommendations based on these trials have been incorporated into various treatment guidelines that widely acknowledge the efficacy of SFRT.^13-15

For this reason, SFRT is often preferred at many centers because it is substantially more convenient for patients with cancer. It reduces travel time for daily radiation clinic visits, which allows for more time with loved ones outside the medical establishment. Furthermore, SFRT improves patient access to radiotherapy and reduces costs. The benefits can be direct as well as indirect to those who have to take time for numerous visits.

Longer courses of palliative radiotherapy can be burdensome for patients and primary care providers. Unnecessarily protracted courses of palliative radiotherapy also delay the receipt of systemic therapies because they are typically considered unsafe to administer concurrently. Moreover, when SFRT is unavailable, the burden of long-course palliation is known to discourage health care providers from referring patients since opioid therapy is more convenient, even though it exchanges lucidity for analgesia.^16,17

For this reason, the authors believe that it is in the best interest for veterans with terminal cancers and their providers to be aware of the shorter SFRT for effective, convenient pain relief. This treatment option is particularly relevant for patients with a poor performance status, patients already in hospice care, or patient who travel long distances.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

The authors would like to acknowledge Tony Quang, MD, JD, for the advice given on this project.

Palliative radiotherapy for bone metastases is typically delivered either as a short course of 1 to 5 fractions or protracted over longer courses of up to 20 treatments. These longer courses can be burdensome and discourage its utilization, despite a 50% to 80% likelihood of meaningful pain relief from only a single fraction of radiation therapy. Meanwhile, there are multiple randomized studies that have demonstrated that shorter course(s) are equivalent for pain control.

Although the VHA currently has 143 medical facilities that have cancer diagnostic and treatment capabilities, only 40 have radiation oncology services on-site.¹ Thus, access to palliative radiotherapy may be limited for veterans who do not live close by, and many may seek care outside the VHA. At VHA radiation oncology centers, single-fraction radiation therapy (SFRT) is routinely offered by the majority of radiation oncologists.^2,3 However, the longer course is commonly preferred outside the VA, and a recent SEER-Medicare analysis of more than 3,000 patients demonstrated that the majority of patients treated outside the VA actually receive more than 10 treatments.⁴ For this reason, the VA National Palliative Radiotherapy Task Force prepared this document to provide guidance for clinicians within and outside the VA to increase awareness of the appropriateness, effectiveness, and convenience of SFRT as opposed to longer courses of treatment that increase the burden of care at the end of life and often are unnecessary.

Veterans, Cancer, and Metastases

Within the VA, an estimated 40,000 new cancer cases are diagnosed each year, and 175,000 veterans undergo cancer care within the VHA annually.¹ Unfortunately, the majority will develop bone metastases with postmortem examinations, suggesting that the rate can be as high as 90% at the end of life.^5-7 For many, including veterans with cancer, pain control can be difficult, and access to palliative radiotherapy is critical.⁸

Single-Fraction Palliatiev Radiation Therapy

Historically, patients with painful bone metastases have been treated with courses of palliative radiotherapy ranging between 2 and 4 weeks of daily treatments. However, several large randomized clinical trials comparing a single treatment with multiple treatments have established that SFRT provides equivalent rates of pain relief even when it may be required for a second time.^9-12 Recommendations based on these trials have been incorporated into various treatment guidelines that widely acknowledge the efficacy of SFRT.^13-15

For this reason, SFRT is often preferred at many centers because it is substantially more convenient for patients with cancer. It reduces travel time for daily radiation clinic visits, which allows for more time with loved ones outside the medical establishment. Furthermore, SFRT improves patient access to radiotherapy and reduces costs. The benefits can be direct as well as indirect to those who have to take time for numerous visits.

Longer courses of palliative radiotherapy can be burdensome for patients and primary care providers. Unnecessarily protracted courses of palliative radiotherapy also delay the receipt of systemic therapies because they are typically considered unsafe to administer concurrently. Moreover, when SFRT is unavailable, the burden of long-course palliation is known to discourage health care providers from referring patients since opioid therapy is more convenient, even though it exchanges lucidity for analgesia.^16,17

For this reason, the authors believe that it is in the best interest for veterans with terminal cancers and their providers to be aware of the shorter SFRT for effective, convenient pain relief. This treatment option is particularly relevant for patients with a poor performance status, patients already in hospice care, or patient who travel long distances.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

On April 8, 2015, HSS released updated HIV treatment guidelines.¹ The original 1998 guidelines for the use of antiretroviral agents for treating adults and adolescents infected with HIV emphasized the benefit of potent combination antiretroviral therapies (ARTs) that included protease inhibitors (PIs).^2,3 Since then there have been more than 25 HSS guidelines focusing primarily on when to initiate ART and which ART to prescribe. The question of when to start ART had been controversial, but the most recently issued guidelines have addressed this question. For the first time, HSS recommends ART for all individuals infected with HIV regardless of CD4+ T-cell count.¹ The timely initiation of effective ART with an associated reduction in HIV viremia benefits patients infected with HIV and substantially decreases transmission of HIV to uninfected sexual partners.³

Three large, international randomized placebo-controlled studies conducted between 2002 and 2015 provide evidence that the benefits of ART outweigh the potential deleterious effects of long-term ART. The Strategies for Management of Antiretroviral Therapy (SMART) was the first published study in this trifecta.^4,5 Given concern about the adverse effects (AEs) of ART, particularly PIs, this study was designed to investigate whether long-term ART was associated with more toxicities than was deferred therapy, determined by CD4+ cell counts. The study was halted prematurely, because the risk of death or grade-4 toxicity was statistically greater among those receiving episodic ART than among those on continuous therapy. The SMART trial demonstrated that ART therapy was beneficial, but it did not determine when to initiate ART, particularly in asymptomatic persons.⁵

It was thought that the risk of transmission of HIV through sexual contact or shared drug paraphernalia was significantly lower for patients on ART who achieve viral suppression compared with those with uncontrolled viremia. The HIV Prevention Trials Network study enrolled HIV-serodiscordant couples to examine transmission of HIV. The trial compared HIV-positive patients who initiated ART when their CD4+ cell count was between 350 to 550 cells/mm3 with patients who began therapy when their CD4+ cell count was < 250 cells/mm3 or when an AIDS-defining illness was diagnosed. The difference in the rate of transmission to a HIV-negative partner was dramatic. The rate was 96% less among those in the early-therapy group vs those in the deferred-therapy group. In addition, there was a 40% reduction in the progression of HIV-related disease in the participants randomized to the early-therapy group.⁶

In March 2011, the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), which conducted SMART, initiated the Strategic Timing of AntiRetroviral Treatment (START) study to define the optimal time to begin ART among asymptomatic patients with a CD4+ count of > 350 cells/mm3. Patients with a CD4+ cell count of > 500 cells/mm3 were randomized to either initiate ART, or defer ART until the CD4+ cell count fell to < 350 cells/mm3 or until an AIDS-defining illness occurred^.7 On May 15, 2015, the study was terminated early. Based on an interim analysis, the data safety and monitoring board announced that the risk for a serious AIDS-related event, serious non-AIDS-related event, or death from any cause was 57% less in the early treatment group. When compared with patients who delayed ART, for those on ART, serious AIDS-related events were reduced 72%, and serious non-AIDS events were reduced 39%.⁸ A similar study conducted in the Ivory Coast from March 2008 to January 2015 also favored early rather than deferred ART^.9

Experience in clinical practice, these landmark clinical trials, and several cohort studies served as the basis of the changes in the new HSS guidelines that endorse ART for all HIV-infected persons. The World Health Organization (WHO) has recently published similar guidelines.¹⁰ It is yet to be determined whether the guidelines have been implemented successfully. Nonetheless, for both the clinician and the patient where access to ongoing care and ART are available, the new guidelines greatly simplify the treatment choices.

What's New in the Guidelines?

The Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents presents significant changes in several of the tables that are most clinically useful, including Tables 6, 7, and 8.¹ Table 6 presents recommended, alternative, and other antiretroviral regimen options. The guidelines also added new tables describing antiretroviral regimen considerations for initial therapy and the mechanisms of antiretroviral-associated drug interactions.

Initial Combination Regimens for the Antiretroviral-Naïve Patient

Five regimens are now recommended for ART-naïve patients: 4 are integrase strand transfer inhibitor-based regimens, and 1 is a ritonavir-boosted PI-based regimen (Table 1). A nonnucleoside reverse transcriptase inhibitor-based regimen is no longer recommended. The guidelines include regimens that are now considered less favorable for a variety of reasons, including reduced virologic activity and greater risk of toxicities, higher pill burden, and more potential drug interactions. Several regimens that have been widely used are now included in this latter option, in particular efavirenz plus abacavir/lamivudine (3TC), lopinavir/ritonavir plus abacavir (ABC)/3TC, and tenofovir fumarate (TDF)/emtricitabine (FTC).

The most significant change in the guideline is the reclassification of efavirenz from a recommended to an alternative therapy. The principal reasons for this change are central nervous system (CNS) AEs, which can include depression and a reported 2-fold increase in the risk of suicide or suicidal ideation.¹¹

In November 2015, the FDA approved Genvoya, a once-daily, fixed-dose combination tablet containing elvitegravir, cobicistat, FTC, and tenofovir alafenamide (TAF).¹² With this approval, there are now 5 once-daily HIV treatment options. This new drug is similar to elvitegravir/cobicistat/TDF/FTC, but it substitutes TAF for TDF. The benefits of this substitution include less bone loss and decreased renal toxicity.^13-15 Genvoya may be prescribed in patients with a 30 mL/min creatinine clearance. The TAF-containing once-daily formulation achieves higher intracellular levels and lower blood levels of TAF. Therefore, the cholesterol-lowering benefits are less than those of the TDF-containing alternative.

In the 2015 guidelines, Table 7 provides concise guidance on the selection of an ART regimen based on patient and regimen characteristics, including food-based AEs; the presence of other medical and/or psychiatric conditions; and the presence of co-infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), and tuberculosis.¹ In addition, Table 8 outlines the advantages and disadvantages of the different classes of ART.¹ For example, dolutegravir may have a higher barrier to resistance than that of elvitegravir or raltegravir.¹⁶ It is now possible for those living with HIV to have ongoing viral suppression, which will not only improve their lives, but also decrease the risk of HIV transmission to sexual partners. Starting from the time of diagnosis, achieving viral suppression is dependent on a link to care with initiation of ART and retention in care. The 5 once-daily options should improve adherence. The infrastructure to ensure lifelong retention in care, medication availability, and adherence still poses many challenges.

Treatment-Experienced Patients

The guidelines were updated to include more direction on virologic failure to a first-line regimen as well as a second-line regimen failure or beyond. It includes a discussion of treatment options for achieving full virologic suppression. There also are treatment recommendations for patients with multidrug viral resistance in whom maximal viral suppression may not be achieved. For such patients, ART should be continued to preserve immunologic function, lessen clinical progression, and minimize resistance to drug classes that could include new efficacious drugs.^17,18

There is also a discussion in the guidelines of the issues surrounding isolated CNS virologic failure and the onset of new neurologic symptoms. With CNS virologic failure, magnetic resonance brain imaging may be abnormal with a lymphocytic pleocytosis in the cerebrospinal fluid (CSF). If available to guide therapy, CSF HIV RNA should be measured, and HIV drug resistance in the CSF should be tested. Central nervous system viral escape should be differentiated from other CNS conditions, such as herpes zoster infection; incidental mild CSF HIV RNA increases; or the now relatively common but chronic neurocognitive impairment seen with HIV infection.^19,20

Poor CD4+ Recovery and Persistent Inflammation Despite Viral Suppression

For patients on ART who achieve viral suppression but fail to have a significant increase in CD4+ cell count over time (particularly for the patient with a CD4+ cell count < 200 cells/mm3), the guidelines do not endorse additional ARTs or switching the regimen. However, there may be an increased risk of non-AIDS mortality and morbidity, including cardiovascular disease. For such patients, interleukin-2 adjunctive therapy has no demonstrated clinical benefit.²¹ Interleukin-7 and recombinant human growth hormone should be used only as part of a clinical trial.

It is now evident that immune activation and inflammation, although lessened, persist despite ART-mediated viral suppression.^22,23 There is no recommendation to monitor markers of immune activation and inflammation. Efforts should focus on risk factor modifications, such as smoking cessation, improved diet, treatment of alcohol abuse and dependence, regular exercise, and maintenance of appropriate weight. Emphasis should be on treating chronic comorbidities, such as hypertension, diabetes, osteoporosis, and hyperlipidemia.

HIV/HCV Co-infection

According to the WHO, 130 to 150 million people worldwide have chronic HCV infection.²⁴ In the U.S., it is estimated that up to one-quarter of HIV-infected persons have HCV co-infection.²⁵ With the currently available oral direct-acting agents (DAAs) for the treatment of chronic HCV infection in patients with HIV/HCV co-infection, rates of sustained virologic response to treatment are comparable in patients with HIV/HCV co-infection with those of patients with HCV monoinfection.²⁶ Accordingly, all HIV-infected patients should be screened for HCV infection, and HIV ART should not be deferred for most patients.

For patients with a CD4+ cell count of < 200 cells/mm3, treatment of HCV should be deferred until the patients are on a stable and effective ART regimen. Whereas for those with a CD4+ cell count > 500 cells/mm3, HCV can be treated before initiating HIV ART. When initiating
HCV therapy, clinicians must pay attention to drug-drug interactions. Patients with cirrhosis are particularly at risk. The most recent guidelines for the treatment of HCV co-infection should be reviewed when selecting a DAA to treat HCV.²⁷ Many patients are now being treated successfully for HCV co-infection. Extending such therapy to all patients with HIV/HCV co-infection for whom treatment is appropriate should be a priority for clinicians, insurance providers, and policy makers.

Drug Interactions

Given the availability of numerous once-daily ART regimens, prescribing ART has been greatly simplified. Nonetheless, there are many pharmacokinetic drug-drug interactions between antiretroviral drugs and concomitant medications. When changing either the ART or adding or changing other medications, the clinician must always pay attention to potential drug-drug interactions. Consideration must be given to the interaction with drugs that affect antiretroviral absorption—particularly, acid-reducing agents and products that contain polyvalent cations, including calcium and magnesium.

When antiretrovirals that undergo hepatic metabolism are given with other drugs that also are metabolized by the cytochrome P450 enzyme system or other hepatic enzymes, the levels of antiretrovirals or other drug may be significantly increased or decreased.¹ The 2 booster—cobicistat and ritonavir—used to increase certain antiretrovirals levels also may alter the metabolism of other drugs.^28,29 The new guidelines contain updated and detailed tables on drug-drug interactions. Given the comorbid conditions, particularly among those aging with HIV, polypharmacy is an increasingly common concern. It is essential for clinicians to work with knowledgeable HIV pharmacists to ensure the correct and safe prescribing of all medications.

HIV/AIDS Demographics in U.S.

Of the more than 1.2 million people aged > 13 years in the U.S. living with HIV, about 1 in 8 are unaware of their infection.³⁰ The Centers for Disease Control and Prevention (CDC) estimates that about 50,000 people are newly infected every year.³¹ Men who have sex with men (MSM) are the group most impacted by HIV, and African American MSM are disproportionately represented. Although MSM were only about 4% of the U.S. male population in 2010, 78% of the newly diagnosed HIV infections among males were in MSM (63% of all new HIV infections).^32,33 The groups at greatest risk of HIV infection are now young black and Latino MSM aged 13 to 24 years.³³ Decreasing the rate of new HIV infections in this high-risk population remains challenging.

Across the U.S., the HIV epidemic continues to disproportionately impact southern states. An estimated 44% of all people living with HIV in the U.S. reside in the District of Columbia and in 16 southern states.³⁴ Among the 10 states with the highest death rate for persons diagnosed with HIV, 7 are southern states–Louisiana, Alabama, Mississippi, South Carolina, Kentucky, and Maryland.^35,36 The HIV epidemic in southern states is not confined to urban centers but instead extends across rural areas that have limited access to adequate health care and high rates of poverty.³⁷

HIV Care Continuum

In July 2013, President Obama established the HIV Continuum Care Initiative directing federal departments to accelerate efforts and direct resources to increase the proportion of HIV-infected persons successfully receiving care in each stage of the continuum as part of the National HIV/AIDS Strategy.^38,39 In November 2014, the CDC released a report on HIV in the U.S. that found about 14% of those with HIV infection have never been diagnosed, and only 40% are receiving HIV medical care.⁴⁰ Despite the much improved and simplified ART regimens, only 30% of those living with HIV infection in the U.S. have achieved viral suppression. The CDC has outlined 4 steps for achieving viral suppression, the ultimate goal of all HIV treatment (Table 2).⁴¹

In the U.S. and Canada, a person diagnosed with HIV aged 20 years who adheres to a HIV ART regimen has a life expectancy of 71 years. The same person not taking ART has a dramatically shortened life expectancy of 32 years.⁴² The successful implementation of ART can help those living with HIV to enjoy an average life expectancy no different from that of persons without HIV infection.

The Future of the HIV/AIDS Epidemic

In 2014, the Joint United Nations Program on HIV/ AIDS estimated that 35 million people were living with HIV/AIDS and that 13 million were receiving ART globally. Three of 5 people with HIV infection, about 22 million, did not have access to ART. Less than one quarter of HIV-infected children are on ART.⁴³ Changing the course of the HIV/AIDS pandemic in the U.S. and worldwide is within reach, and the new HSS and WHO guidelines provide an evidence-based framework to alter this course. Significantly expanding screening for HIV and ensuring treatment access
for all persons diagnosed with HIV as well as appropriate provision of pre-exposure prophylaxis would irrevocably alter the lives of the millions of people living with HIV/AIDS and others in their communities. It remains to be seen whether the goal to eliminate AIDS by 2020, set in both the National HIV/AIDS Strategy and the UN global commitment will be achieved.

Click here to read the digital edition.

On April 8, 2015, HSS released updated HIV treatment guidelines.¹ The original 1998 guidelines for the use of antiretroviral agents for treating adults and adolescents infected with HIV emphasized the benefit of potent combination antiretroviral therapies (ARTs) that included protease inhibitors (PIs).^2,3 Since then there have been more than 25 HSS guidelines focusing primarily on when to initiate ART and which ART to prescribe. The question of when to start ART had been controversial, but the most recently issued guidelines have addressed this question. For the first time, HSS recommends ART for all individuals infected with HIV regardless of CD4+ T-cell count.¹ The timely initiation of effective ART with an associated reduction in HIV viremia benefits patients infected with HIV and substantially decreases transmission of HIV to uninfected sexual partners.³

Three large, international randomized placebo-controlled studies conducted between 2002 and 2015 provide evidence that the benefits of ART outweigh the potential deleterious effects of long-term ART. The Strategies for Management of Antiretroviral Therapy (SMART) was the first published study in this trifecta.^4,5 Given concern about the adverse effects (AEs) of ART, particularly PIs, this study was designed to investigate whether long-term ART was associated with more toxicities than was deferred therapy, determined by CD4+ cell counts. The study was halted prematurely, because the risk of death or grade-4 toxicity was statistically greater among those receiving episodic ART than among those on continuous therapy. The SMART trial demonstrated that ART therapy was beneficial, but it did not determine when to initiate ART, particularly in asymptomatic persons.⁵

It was thought that the risk of transmission of HIV through sexual contact or shared drug paraphernalia was significantly lower for patients on ART who achieve viral suppression compared with those with uncontrolled viremia. The HIV Prevention Trials Network study enrolled HIV-serodiscordant couples to examine transmission of HIV. The trial compared HIV-positive patients who initiated ART when their CD4+ cell count was between 350 to 550 cells/mm3 with patients who began therapy when their CD4+ cell count was < 250 cells/mm3 or when an AIDS-defining illness was diagnosed. The difference in the rate of transmission to a HIV-negative partner was dramatic. The rate was 96% less among those in the early-therapy group vs those in the deferred-therapy group. In addition, there was a 40% reduction in the progression of HIV-related disease in the participants randomized to the early-therapy group.⁶

In March 2011, the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), which conducted SMART, initiated the Strategic Timing of AntiRetroviral Treatment (START) study to define the optimal time to begin ART among asymptomatic patients with a CD4+ count of > 350 cells/mm3. Patients with a CD4+ cell count of > 500 cells/mm3 were randomized to either initiate ART, or defer ART until the CD4+ cell count fell to < 350 cells/mm3 or until an AIDS-defining illness occurred^.7 On May 15, 2015, the study was terminated early. Based on an interim analysis, the data safety and monitoring board announced that the risk for a serious AIDS-related event, serious non-AIDS-related event, or death from any cause was 57% less in the early treatment group. When compared with patients who delayed ART, for those on ART, serious AIDS-related events were reduced 72%, and serious non-AIDS events were reduced 39%.⁸ A similar study conducted in the Ivory Coast from March 2008 to January 2015 also favored early rather than deferred ART^.9

Experience in clinical practice, these landmark clinical trials, and several cohort studies served as the basis of the changes in the new HSS guidelines that endorse ART for all HIV-infected persons. The World Health Organization (WHO) has recently published similar guidelines.¹⁰ It is yet to be determined whether the guidelines have been implemented successfully. Nonetheless, for both the clinician and the patient where access to ongoing care and ART are available, the new guidelines greatly simplify the treatment choices.

What's New in the Guidelines?

The Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents presents significant changes in several of the tables that are most clinically useful, including Tables 6, 7, and 8.¹ Table 6 presents recommended, alternative, and other antiretroviral regimen options. The guidelines also added new tables describing antiretroviral regimen considerations for initial therapy and the mechanisms of antiretroviral-associated drug interactions.

Initial Combination Regimens for the Antiretroviral-Naïve Patient

Five regimens are now recommended for ART-naïve patients: 4 are integrase strand transfer inhibitor-based regimens, and 1 is a ritonavir-boosted PI-based regimen (Table 1). A nonnucleoside reverse transcriptase inhibitor-based regimen is no longer recommended. The guidelines include regimens that are now considered less favorable for a variety of reasons, including reduced virologic activity and greater risk of toxicities, higher pill burden, and more potential drug interactions. Several regimens that have been widely used are now included in this latter option, in particular efavirenz plus abacavir/lamivudine (3TC), lopinavir/ritonavir plus abacavir (ABC)/3TC, and tenofovir fumarate (TDF)/emtricitabine (FTC).

The most significant change in the guideline is the reclassification of efavirenz from a recommended to an alternative therapy. The principal reasons for this change are central nervous system (CNS) AEs, which can include depression and a reported 2-fold increase in the risk of suicide or suicidal ideation.¹¹

In November 2015, the FDA approved Genvoya, a once-daily, fixed-dose combination tablet containing elvitegravir, cobicistat, FTC, and tenofovir alafenamide (TAF).¹² With this approval, there are now 5 once-daily HIV treatment options. This new drug is similar to elvitegravir/cobicistat/TDF/FTC, but it substitutes TAF for TDF. The benefits of this substitution include less bone loss and decreased renal toxicity.^13-15 Genvoya may be prescribed in patients with a 30 mL/min creatinine clearance. The TAF-containing once-daily formulation achieves higher intracellular levels and lower blood levels of TAF. Therefore, the cholesterol-lowering benefits are less than those of the TDF-containing alternative.

In the 2015 guidelines, Table 7 provides concise guidance on the selection of an ART regimen based on patient and regimen characteristics, including food-based AEs; the presence of other medical and/or psychiatric conditions; and the presence of co-infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), and tuberculosis.¹ In addition, Table 8 outlines the advantages and disadvantages of the different classes of ART.¹ For example, dolutegravir may have a higher barrier to resistance than that of elvitegravir or raltegravir.¹⁶ It is now possible for those living with HIV to have ongoing viral suppression, which will not only improve their lives, but also decrease the risk of HIV transmission to sexual partners. Starting from the time of diagnosis, achieving viral suppression is dependent on a link to care with initiation of ART and retention in care. The 5 once-daily options should improve adherence. The infrastructure to ensure lifelong retention in care, medication availability, and adherence still poses many challenges.

Treatment-Experienced Patients

The guidelines were updated to include more direction on virologic failure to a first-line regimen as well as a second-line regimen failure or beyond. It includes a discussion of treatment options for achieving full virologic suppression. There also are treatment recommendations for patients with multidrug viral resistance in whom maximal viral suppression may not be achieved. For such patients, ART should be continued to preserve immunologic function, lessen clinical progression, and minimize resistance to drug classes that could include new efficacious drugs.^17,18

There is also a discussion in the guidelines of the issues surrounding isolated CNS virologic failure and the onset of new neurologic symptoms. With CNS virologic failure, magnetic resonance brain imaging may be abnormal with a lymphocytic pleocytosis in the cerebrospinal fluid (CSF). If available to guide therapy, CSF HIV RNA should be measured, and HIV drug resistance in the CSF should be tested. Central nervous system viral escape should be differentiated from other CNS conditions, such as herpes zoster infection; incidental mild CSF HIV RNA increases; or the now relatively common but chronic neurocognitive impairment seen with HIV infection.^19,20

Poor CD4+ Recovery and Persistent Inflammation Despite Viral Suppression

For patients on ART who achieve viral suppression but fail to have a significant increase in CD4+ cell count over time (particularly for the patient with a CD4+ cell count < 200 cells/mm3), the guidelines do not endorse additional ARTs or switching the regimen. However, there may be an increased risk of non-AIDS mortality and morbidity, including cardiovascular disease. For such patients, interleukin-2 adjunctive therapy has no demonstrated clinical benefit.²¹ Interleukin-7 and recombinant human growth hormone should be used only as part of a clinical trial.

It is now evident that immune activation and inflammation, although lessened, persist despite ART-mediated viral suppression.^22,23 There is no recommendation to monitor markers of immune activation and inflammation. Efforts should focus on risk factor modifications, such as smoking cessation, improved diet, treatment of alcohol abuse and dependence, regular exercise, and maintenance of appropriate weight. Emphasis should be on treating chronic comorbidities, such as hypertension, diabetes, osteoporosis, and hyperlipidemia.

HIV/HCV Co-infection

According to the WHO, 130 to 150 million people worldwide have chronic HCV infection.²⁴ In the U.S., it is estimated that up to one-quarter of HIV-infected persons have HCV co-infection.²⁵ With the currently available oral direct-acting agents (DAAs) for the treatment of chronic HCV infection in patients with HIV/HCV co-infection, rates of sustained virologic response to treatment are comparable in patients with HIV/HCV co-infection with those of patients with HCV monoinfection.²⁶ Accordingly, all HIV-infected patients should be screened for HCV infection, and HIV ART should not be deferred for most patients.

For patients with a CD4+ cell count of < 200 cells/mm3, treatment of HCV should be deferred until the patients are on a stable and effective ART regimen. Whereas for those with a CD4+ cell count > 500 cells/mm3, HCV can be treated before initiating HIV ART. When initiating
HCV therapy, clinicians must pay attention to drug-drug interactions. Patients with cirrhosis are particularly at risk. The most recent guidelines for the treatment of HCV co-infection should be reviewed when selecting a DAA to treat HCV.²⁷ Many patients are now being treated successfully for HCV co-infection. Extending such therapy to all patients with HIV/HCV co-infection for whom treatment is appropriate should be a priority for clinicians, insurance providers, and policy makers.

Drug Interactions

Given the availability of numerous once-daily ART regimens, prescribing ART has been greatly simplified. Nonetheless, there are many pharmacokinetic drug-drug interactions between antiretroviral drugs and concomitant medications. When changing either the ART or adding or changing other medications, the clinician must always pay attention to potential drug-drug interactions. Consideration must be given to the interaction with drugs that affect antiretroviral absorption—particularly, acid-reducing agents and products that contain polyvalent cations, including calcium and magnesium.

When antiretrovirals that undergo hepatic metabolism are given with other drugs that also are metabolized by the cytochrome P450 enzyme system or other hepatic enzymes, the levels of antiretrovirals or other drug may be significantly increased or decreased.¹ The 2 booster—cobicistat and ritonavir—used to increase certain antiretrovirals levels also may alter the metabolism of other drugs.^28,29 The new guidelines contain updated and detailed tables on drug-drug interactions. Given the comorbid conditions, particularly among those aging with HIV, polypharmacy is an increasingly common concern. It is essential for clinicians to work with knowledgeable HIV pharmacists to ensure the correct and safe prescribing of all medications.

HIV/AIDS Demographics in U.S.

Of the more than 1.2 million people aged > 13 years in the U.S. living with HIV, about 1 in 8 are unaware of their infection.³⁰ The Centers for Disease Control and Prevention (CDC) estimates that about 50,000 people are newly infected every year.³¹ Men who have sex with men (MSM) are the group most impacted by HIV, and African American MSM are disproportionately represented. Although MSM were only about 4% of the U.S. male population in 2010, 78% of the newly diagnosed HIV infections among males were in MSM (63% of all new HIV infections).^32,33 The groups at greatest risk of HIV infection are now young black and Latino MSM aged 13 to 24 years.³³ Decreasing the rate of new HIV infections in this high-risk population remains challenging.

Across the U.S., the HIV epidemic continues to disproportionately impact southern states. An estimated 44% of all people living with HIV in the U.S. reside in the District of Columbia and in 16 southern states.³⁴ Among the 10 states with the highest death rate for persons diagnosed with HIV, 7 are southern states–Louisiana, Alabama, Mississippi, South Carolina, Kentucky, and Maryland.^35,36 The HIV epidemic in southern states is not confined to urban centers but instead extends across rural areas that have limited access to adequate health care and high rates of poverty.³⁷

HIV Care Continuum

In July 2013, President Obama established the HIV Continuum Care Initiative directing federal departments to accelerate efforts and direct resources to increase the proportion of HIV-infected persons successfully receiving care in each stage of the continuum as part of the National HIV/AIDS Strategy.^38,39 In November 2014, the CDC released a report on HIV in the U.S. that found about 14% of those with HIV infection have never been diagnosed, and only 40% are receiving HIV medical care.⁴⁰ Despite the much improved and simplified ART regimens, only 30% of those living with HIV infection in the U.S. have achieved viral suppression. The CDC has outlined 4 steps for achieving viral suppression, the ultimate goal of all HIV treatment (Table 2).⁴¹

In the U.S. and Canada, a person diagnosed with HIV aged 20 years who adheres to a HIV ART regimen has a life expectancy of 71 years. The same person not taking ART has a dramatically shortened life expectancy of 32 years.⁴² The successful implementation of ART can help those living with HIV to enjoy an average life expectancy no different from that of persons without HIV infection.

The Future of the HIV/AIDS Epidemic

In 2014, the Joint United Nations Program on HIV/ AIDS estimated that 35 million people were living with HIV/AIDS and that 13 million were receiving ART globally. Three of 5 people with HIV infection, about 22 million, did not have access to ART. Less than one quarter of HIV-infected children are on ART.⁴³ Changing the course of the HIV/AIDS pandemic in the U.S. and worldwide is within reach, and the new HSS and WHO guidelines provide an evidence-based framework to alter this course. Significantly expanding screening for HIV and ensuring treatment access
for all persons diagnosed with HIV as well as appropriate provision of pre-exposure prophylaxis would irrevocably alter the lives of the millions of people living with HIV/AIDS and others in their communities. It remains to be seen whether the goal to eliminate AIDS by 2020, set in both the National HIV/AIDS Strategy and the UN global commitment will be achieved.

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On April 8, 2015, HSS released updated HIV treatment guidelines.¹ The original 1998 guidelines for the use of antiretroviral agents for treating adults and adolescents infected with HIV emphasized the benefit of potent combination antiretroviral therapies (ARTs) that included protease inhibitors (PIs).^2,3 Since then there have been more than 25 HSS guidelines focusing primarily on when to initiate ART and which ART to prescribe. The question of when to start ART had been controversial, but the most recently issued guidelines have addressed this question. For the first time, HSS recommends ART for all individuals infected with HIV regardless of CD4+ T-cell count.¹ The timely initiation of effective ART with an associated reduction in HIV viremia benefits patients infected with HIV and substantially decreases transmission of HIV to uninfected sexual partners.³

Three large, international randomized placebo-controlled studies conducted between 2002 and 2015 provide evidence that the benefits of ART outweigh the potential deleterious effects of long-term ART. The Strategies for Management of Antiretroviral Therapy (SMART) was the first published study in this trifecta.^4,5 Given concern about the adverse effects (AEs) of ART, particularly PIs, this study was designed to investigate whether long-term ART was associated with more toxicities than was deferred therapy, determined by CD4+ cell counts. The study was halted prematurely, because the risk of death or grade-4 toxicity was statistically greater among those receiving episodic ART than among those on continuous therapy. The SMART trial demonstrated that ART therapy was beneficial, but it did not determine when to initiate ART, particularly in asymptomatic persons.⁵

It was thought that the risk of transmission of HIV through sexual contact or shared drug paraphernalia was significantly lower for patients on ART who achieve viral suppression compared with those with uncontrolled viremia. The HIV Prevention Trials Network study enrolled HIV-serodiscordant couples to examine transmission of HIV. The trial compared HIV-positive patients who initiated ART when their CD4+ cell count was between 350 to 550 cells/mm3 with patients who began therapy when their CD4+ cell count was < 250 cells/mm3 or when an AIDS-defining illness was diagnosed. The difference in the rate of transmission to a HIV-negative partner was dramatic. The rate was 96% less among those in the early-therapy group vs those in the deferred-therapy group. In addition, there was a 40% reduction in the progression of HIV-related disease in the participants randomized to the early-therapy group.⁶

In March 2011, the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), which conducted SMART, initiated the Strategic Timing of AntiRetroviral Treatment (START) study to define the optimal time to begin ART among asymptomatic patients with a CD4+ count of > 350 cells/mm3. Patients with a CD4+ cell count of > 500 cells/mm3 were randomized to either initiate ART, or defer ART until the CD4+ cell count fell to < 350 cells/mm3 or until an AIDS-defining illness occurred^.7 On May 15, 2015, the study was terminated early. Based on an interim analysis, the data safety and monitoring board announced that the risk for a serious AIDS-related event, serious non-AIDS-related event, or death from any cause was 57% less in the early treatment group. When compared with patients who delayed ART, for those on ART, serious AIDS-related events were reduced 72%, and serious non-AIDS events were reduced 39%.⁸ A similar study conducted in the Ivory Coast from March 2008 to January 2015 also favored early rather than deferred ART^.9

Experience in clinical practice, these landmark clinical trials, and several cohort studies served as the basis of the changes in the new HSS guidelines that endorse ART for all HIV-infected persons. The World Health Organization (WHO) has recently published similar guidelines.¹⁰ It is yet to be determined whether the guidelines have been implemented successfully. Nonetheless, for both the clinician and the patient where access to ongoing care and ART are available, the new guidelines greatly simplify the treatment choices.

What's New in the Guidelines?

The Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents presents significant changes in several of the tables that are most clinically useful, including Tables 6, 7, and 8.¹ Table 6 presents recommended, alternative, and other antiretroviral regimen options. The guidelines also added new tables describing antiretroviral regimen considerations for initial therapy and the mechanisms of antiretroviral-associated drug interactions.

Initial Combination Regimens for the Antiretroviral-Naïve Patient

Five regimens are now recommended for ART-naïve patients: 4 are integrase strand transfer inhibitor-based regimens, and 1 is a ritonavir-boosted PI-based regimen (Table 1). A nonnucleoside reverse transcriptase inhibitor-based regimen is no longer recommended. The guidelines include regimens that are now considered less favorable for a variety of reasons, including reduced virologic activity and greater risk of toxicities, higher pill burden, and more potential drug interactions. Several regimens that have been widely used are now included in this latter option, in particular efavirenz plus abacavir/lamivudine (3TC), lopinavir/ritonavir plus abacavir (ABC)/3TC, and tenofovir fumarate (TDF)/emtricitabine (FTC).

The most significant change in the guideline is the reclassification of efavirenz from a recommended to an alternative therapy. The principal reasons for this change are central nervous system (CNS) AEs, which can include depression and a reported 2-fold increase in the risk of suicide or suicidal ideation.¹¹

In November 2015, the FDA approved Genvoya, a once-daily, fixed-dose combination tablet containing elvitegravir, cobicistat, FTC, and tenofovir alafenamide (TAF).¹² With this approval, there are now 5 once-daily HIV treatment options. This new drug is similar to elvitegravir/cobicistat/TDF/FTC, but it substitutes TAF for TDF. The benefits of this substitution include less bone loss and decreased renal toxicity.^13-15 Genvoya may be prescribed in patients with a 30 mL/min creatinine clearance. The TAF-containing once-daily formulation achieves higher intracellular levels and lower blood levels of TAF. Therefore, the cholesterol-lowering benefits are less than those of the TDF-containing alternative.

In the 2015 guidelines, Table 7 provides concise guidance on the selection of an ART regimen based on patient and regimen characteristics, including food-based AEs; the presence of other medical and/or psychiatric conditions; and the presence of co-infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), and tuberculosis.¹ In addition, Table 8 outlines the advantages and disadvantages of the different classes of ART.¹ For example, dolutegravir may have a higher barrier to resistance than that of elvitegravir or raltegravir.¹⁶ It is now possible for those living with HIV to have ongoing viral suppression, which will not only improve their lives, but also decrease the risk of HIV transmission to sexual partners. Starting from the time of diagnosis, achieving viral suppression is dependent on a link to care with initiation of ART and retention in care. The 5 once-daily options should improve adherence. The infrastructure to ensure lifelong retention in care, medication availability, and adherence still poses many challenges.

Treatment-Experienced Patients

The guidelines were updated to include more direction on virologic failure to a first-line regimen as well as a second-line regimen failure or beyond. It includes a discussion of treatment options for achieving full virologic suppression. There also are treatment recommendations for patients with multidrug viral resistance in whom maximal viral suppression may not be achieved. For such patients, ART should be continued to preserve immunologic function, lessen clinical progression, and minimize resistance to drug classes that could include new efficacious drugs.^17,18

There is also a discussion in the guidelines of the issues surrounding isolated CNS virologic failure and the onset of new neurologic symptoms. With CNS virologic failure, magnetic resonance brain imaging may be abnormal with a lymphocytic pleocytosis in the cerebrospinal fluid (CSF). If available to guide therapy, CSF HIV RNA should be measured, and HIV drug resistance in the CSF should be tested. Central nervous system viral escape should be differentiated from other CNS conditions, such as herpes zoster infection; incidental mild CSF HIV RNA increases; or the now relatively common but chronic neurocognitive impairment seen with HIV infection.^19,20

Poor CD4+ Recovery and Persistent Inflammation Despite Viral Suppression

For patients on ART who achieve viral suppression but fail to have a significant increase in CD4+ cell count over time (particularly for the patient with a CD4+ cell count < 200 cells/mm3), the guidelines do not endorse additional ARTs or switching the regimen. However, there may be an increased risk of non-AIDS mortality and morbidity, including cardiovascular disease. For such patients, interleukin-2 adjunctive therapy has no demonstrated clinical benefit.²¹ Interleukin-7 and recombinant human growth hormone should be used only as part of a clinical trial.

It is now evident that immune activation and inflammation, although lessened, persist despite ART-mediated viral suppression.^22,23 There is no recommendation to monitor markers of immune activation and inflammation. Efforts should focus on risk factor modifications, such as smoking cessation, improved diet, treatment of alcohol abuse and dependence, regular exercise, and maintenance of appropriate weight. Emphasis should be on treating chronic comorbidities, such as hypertension, diabetes, osteoporosis, and hyperlipidemia.

HIV/HCV Co-infection

According to the WHO, 130 to 150 million people worldwide have chronic HCV infection.²⁴ In the U.S., it is estimated that up to one-quarter of HIV-infected persons have HCV co-infection.²⁵ With the currently available oral direct-acting agents (DAAs) for the treatment of chronic HCV infection in patients with HIV/HCV co-infection, rates of sustained virologic response to treatment are comparable in patients with HIV/HCV co-infection with those of patients with HCV monoinfection.²⁶ Accordingly, all HIV-infected patients should be screened for HCV infection, and HIV ART should not be deferred for most patients.

For patients with a CD4+ cell count of < 200 cells/mm3, treatment of HCV should be deferred until the patients are on a stable and effective ART regimen. Whereas for those with a CD4+ cell count > 500 cells/mm3, HCV can be treated before initiating HIV ART. When initiating
HCV therapy, clinicians must pay attention to drug-drug interactions. Patients with cirrhosis are particularly at risk. The most recent guidelines for the treatment of HCV co-infection should be reviewed when selecting a DAA to treat HCV.²⁷ Many patients are now being treated successfully for HCV co-infection. Extending such therapy to all patients with HIV/HCV co-infection for whom treatment is appropriate should be a priority for clinicians, insurance providers, and policy makers.

Drug Interactions

Given the availability of numerous once-daily ART regimens, prescribing ART has been greatly simplified. Nonetheless, there are many pharmacokinetic drug-drug interactions between antiretroviral drugs and concomitant medications. When changing either the ART or adding or changing other medications, the clinician must always pay attention to potential drug-drug interactions. Consideration must be given to the interaction with drugs that affect antiretroviral absorption—particularly, acid-reducing agents and products that contain polyvalent cations, including calcium and magnesium.

When antiretrovirals that undergo hepatic metabolism are given with other drugs that also are metabolized by the cytochrome P450 enzyme system or other hepatic enzymes, the levels of antiretrovirals or other drug may be significantly increased or decreased.¹ The 2 booster—cobicistat and ritonavir—used to increase certain antiretrovirals levels also may alter the metabolism of other drugs.^28,29 The new guidelines contain updated and detailed tables on drug-drug interactions. Given the comorbid conditions, particularly among those aging with HIV, polypharmacy is an increasingly common concern. It is essential for clinicians to work with knowledgeable HIV pharmacists to ensure the correct and safe prescribing of all medications.

HIV/AIDS Demographics in U.S.

Of the more than 1.2 million people aged > 13 years in the U.S. living with HIV, about 1 in 8 are unaware of their infection.³⁰ The Centers for Disease Control and Prevention (CDC) estimates that about 50,000 people are newly infected every year.³¹ Men who have sex with men (MSM) are the group most impacted by HIV, and African American MSM are disproportionately represented. Although MSM were only about 4% of the U.S. male population in 2010, 78% of the newly diagnosed HIV infections among males were in MSM (63% of all new HIV infections).^32,33 The groups at greatest risk of HIV infection are now young black and Latino MSM aged 13 to 24 years.³³ Decreasing the rate of new HIV infections in this high-risk population remains challenging.

Across the U.S., the HIV epidemic continues to disproportionately impact southern states. An estimated 44% of all people living with HIV in the U.S. reside in the District of Columbia and in 16 southern states.³⁴ Among the 10 states with the highest death rate for persons diagnosed with HIV, 7 are southern states–Louisiana, Alabama, Mississippi, South Carolina, Kentucky, and Maryland.^35,36 The HIV epidemic in southern states is not confined to urban centers but instead extends across rural areas that have limited access to adequate health care and high rates of poverty.³⁷

HIV Care Continuum

In July 2013, President Obama established the HIV Continuum Care Initiative directing federal departments to accelerate efforts and direct resources to increase the proportion of HIV-infected persons successfully receiving care in each stage of the continuum as part of the National HIV/AIDS Strategy.^38,39 In November 2014, the CDC released a report on HIV in the U.S. that found about 14% of those with HIV infection have never been diagnosed, and only 40% are receiving HIV medical care.⁴⁰ Despite the much improved and simplified ART regimens, only 30% of those living with HIV infection in the U.S. have achieved viral suppression. The CDC has outlined 4 steps for achieving viral suppression, the ultimate goal of all HIV treatment (Table 2).⁴¹

In the U.S. and Canada, a person diagnosed with HIV aged 20 years who adheres to a HIV ART regimen has a life expectancy of 71 years. The same person not taking ART has a dramatically shortened life expectancy of 32 years.⁴² The successful implementation of ART can help those living with HIV to enjoy an average life expectancy no different from that of persons without HIV infection.

The Future of the HIV/AIDS Epidemic

In 2014, the Joint United Nations Program on HIV/ AIDS estimated that 35 million people were living with HIV/AIDS and that 13 million were receiving ART globally. Three of 5 people with HIV infection, about 22 million, did not have access to ART. Less than one quarter of HIV-infected children are on ART.⁴³ Changing the course of the HIV/AIDS pandemic in the U.S. and worldwide is within reach, and the new HSS and WHO guidelines provide an evidence-based framework to alter this course. Significantly expanding screening for HIV and ensuring treatment access
for all persons diagnosed with HIV as well as appropriate provision of pre-exposure prophylaxis would irrevocably alter the lives of the millions of people living with HIV/AIDS and others in their communities. It remains to be seen whether the goal to eliminate AIDS by 2020, set in both the National HIV/AIDS Strategy and the UN global commitment will be achieved.

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Together with prophylaxis for opportunistic infections, the widespread use of combination antiretroviral therapy (ART)—known as highly active antiretroviral therapy (HAART)—led to substantial gains in the life expectancy of patients infected with human immunodeficiency virus type 1 (HIV-1).^1-3 The emergence of HAARTs has decreased mortality, increased viral suppression, and significantly reduced the risk of the sexual transmission of HIV.^4-6

Since its introduction, HAART has evolved significantly with more options for triple therapy combinations that show improved efficacy, convenience, and tolerability. Single-tablet regimens (STRs) are the culmination of this evolution. The first STR was introduced in 2006, and to date, there are 5 STR options approved for use. In this review, the authors discuss the rationale and path to development of STRs, compare the currently available STRs, and discuss practical considerations in their use for the treatment of HIV-1 infection.

Is Triple Therapy The Sweet Spot?

Because current ART cannot eradicate HIV-1 infection due to latently infected CD4+ T-cell reservoirs, the primary goals of ART according to the HHS guidelines are to (1) reduce HIV-associated morbidity and prolong the duration and quality of survival; (2) restore and preserve immunologic function; (3) maximally and durably suppress plasma HIV viral load; and (4) prevent HIV transmission.⁷

These goals currently seem to be optimally achieved by treatment with 3 active agents, usually consisting of 2 nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) as a backbone plus a drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a nonnucleoside reverse-transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) boosted with ritonavir or cobicistat. The most widely used NRTI backbones are abacavir plus lamivudine (ABC/3TC) or tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC). Attempts to increase the number of active drugs in a regimen (≥ 4) have generally failed to yield additional virologic or immunologic benefits. Conversely, recent attempts to decrease the number of drugs in a regimen (≤ 2) have met with mixed success.

Mega-HAART

The AIDS Clinical Trial Group (ACTG) 5095 was a randomized controlled trial (RCT) to compare the safety and efficacy of a 3-drug regimen (zidovudine/lamivudine [AZT/3TC] plus efavirenz [EFV]) vs a 4-drug regimen (AZT/3TC/ABC plus EFV) in the initial treatment of HIV-1 infection.⁸ There were no significant differences in virologic efficacy between the 3-drug and 4-drug regimens, findings that have been corroborated in subsequent studies.^9,10 Intensified (≥ 4 drugs) regimens have also failed to lead to significant decay in viral reservoir.^10,11

Dual Therapy With Newer Agents

Recent clinical studies have explored the use of fewer medications in treatment-naïve HIV-infected patients. In the GARDEL study, dual therapy consisting of lopinavir/ritonavir (LPV/RTV) plus 3TC proved to be virologically noninferior to triple therapy of LPV/RTV plus 2 NRTIs in a fixed-dose combination.¹² In a large European clinical trial (NEAT001/ANRS143), the combination of darunavir/ritonavir (DRV/RTV) plus raltegravir (RAL) was noninferior to DRV/RTV plus TDF/FTC, although more virologic failures were seen in the dual-therapy arm for patients with high baseline HIV-1 RNA viral loads or low baseline CD4+ counts.¹³

Suboptimal virologic responses also were observed with the DRV/RTV plus RAL regimen in several smaller studies: ACTG 5262 and RADAR.^14,15 Finally, a combination of DRV/RTV plus maraviroc proved virologically inferior to standard DRV/RTV plus TDF/FTC in the MODERN trial.¹⁶ Although some dual-agent regimens have shown promise, none have established consistent and durable virologic efficacy sufficient to supplant triple therapy, which is currently endorsed by treatment guidelines and forms the basis for current STRs.

Current Single-Tablet Regimens

There are currently 5 STRs available for the treatment of HIV-1 infection, 3 are among the recommended regimens for ART in treatment-naïve patients. An older, triple NRTI-based STR (AZT/3TC/ABC) has fallen out of routine use due to inferior virologic efficacy, toxicities, and better-tolerated alternative agents.¹⁷ A review of the indications for use, major clinical trials, and unique features of available STRs follows and is summarized in the Table.

Efavirenz/tenofovir DF/emtricitabine

The first widely used STR, Atripla (Bristol-Myers Squibb and Gilead Sciences) combines the NRTIs tenofovir DF and FTC with the NNRTI EFV and was released in 2006. It is indicated for use alone or in combination with other ARTs for treatment of HIV-1 infection in adults or children aged > 12 years.¹⁸ Contraindications include hypersensitivity to efavirenz or coadministration with voriconazole. Major precautions are required for patients with severe psychiatric disease or suicidality; new or worsening renal impairment; women in the first trimester of pregnancy or of childbearing age not on effective contraception; or osteoporosis or history of fragility fractures. Patients with chronic liver disease also should be monitored for hepatotoxicity.

Large RCTs confirmed the potency and durability of viral suppression of EFV/TDF/FTC in treatment-naïve patients^19,20 or in the context of antiretroviral switching for treatment simplification in patients previously suppressed with NNRTI- or PI-based regimens.²¹ This combination
has been shown to be noninferior or superior to multiple PI-based,²² NNRTI-based,²³ and INSTI-based regimens.¹⁸ However, it recently was found to be associated with lower virologic response than was the INSTI-based regimen of ABC/3TC plus dolutegravir (DTG) and higher discontinuation rates than that of a TDF/FTC plus RAL regimen.^24,25 Due to lingering concerns about an EFV association with suicidality²⁶ and neural tube defects with first trimester exposure,²⁷ EFV/TDF/FTC was downgraded to an alternative regimen for treatmentnaïve patients, because other available regimens are better tolerated with equal or superior efficacy.⁷

Rilpivirine/tenofovir DF/emtricitabine

Approved in 2011, Complera was the second STR (Gilead Sciences), combining the NNRTI rilpivirine (RPV) with the NRTI backbone TDF/FTC. It is indicated for use in (1) treatment-naïve adults with a baseline HIV-1 RNA ≤ 100,000 copies/mL and baseline CD4+ > 200 cells/mm3; or (2) switch therapy (changing from a previous antiretroviral regimen) in patients virologically suppressed (HIV-1 RNA ≤ 50 copies/mL) for at least 6 months without history of virologic failure or resistance to any of the component drugs.28 Contraindications include administration with other drugs that significantly lower RPV concentrations, such as certain acid-lowering drugs. Although not associated with as many neuropsychiatric or teratogenic effects as EFV/TDF/FTC, this combination still requires caution in circumstances of preexisting renal impairment, severe hepatic disease, or bone disease.

Two phase 3 studies and 1 open-label phase 3b study confirmed that RPV-based STRs were noninferior to EFVbased STRs overall.^23,29 Importantly, patients with higher baseline viral loads experienced higher rates of virologic failure and higher rates of NRTI backbone resistance. Patients with baseline CD4+ < 200 cells/mm3 also had higher virologic failure rates. Because of these virologic and immunologic prerequisites for use, RPV/TDF/FTC is considered an alternative regimen for treatment-naïve patients.⁷ On the other hand, in the aforementioned studies,
fewer patients in the RPV arms discontinued therapy due to adverse events (AEs), and a switch from EFV/TDF/FTC to RPV/TDF/FTC was shown to be safe and effective.³⁰ Its greater tolerability and safety profile make RPV/TDF/FTC an option for patients who do not tolerate EFV/TDF/3TC, who are pregnant, and who have a psychiatric illness.

Elvitegravir/cobicistat/tenofovir DF/emtricitabine

Released in 2012, Stribild (Gilead Sciences) was the first treatment to combine an INSTI and elvitegravir (EVG) with the pharmacologic booster cobicistat and the TDF/FTC backbone. It is indicated for use in treatmentnaïve adults or as switch therapy in patients virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months without a history of virologic failure or resistance to any of the components.³¹

Two double-blind, active-controlled trials established that EVG/c/TDF/FTC was virologically noninferior and had greater safety and tolerability than that of EFV/TDF/FTC³² and ATV/RTV plus DF/FTC³³ in treatment-naïve patients. It also maintained virologic suppression in patients switching from a boosted PI³⁴ or an NNRTI-based regimen.³⁵ On the basis of this efficacy and safety data, EVG/c/TDF/FTC is considered a recommended regimen for initial ART treatment.⁷ However, limitations to this regimen include significant drug-drug interactions due to potent CYP3A inhibition by cobicistat, potential renal and bone toxicity due to TDF, and cobicistat-induced inhibition of renal tubular creatinine secretion, which can lead to a mild creatinine increase (≤ 0.4 mg/dL) and may complicate renal function monitoring. Therefore, it is contraindicated
in patients concomitantly taking medications that are strong inducers of CYP3A or that are heavily metabolized by CYP3A for clearance, patients with reduced renal function (estimated creatinine clearance [CrCl] < 70 mL/min), and those receiving polyvalent cationic antacids or supplements.

Dolutegravir/abacavir/lamivudine

Approved in 2014, Triumeq (ViiV Healthcare) is the first and only currently available STR with an NRTI backbone of ABC/3TC rather than a tenofovir (TFV) derivative, combined with the INSTI DTG. It is indicated for the treatment of HIV-1 infection in patients without prior resistance to the INSTI class of ART or the other component drugs in this combination pill.³⁶ The major contraindication is presence of the HLA-B*5701 allele, a polymorphism that predicts abacavir-related hypersensitivity, or moderate-tosevere hepatic impairment.³⁷ Caution is required in patients with hepatitis B virus (HBV) co-infection due to the risk of 3TC drug resistance and subsequent acute exacerbation of HBV. Coadministration with dofetilide is contraindicated, and coadministration of some medications, most notably rifampin, requires an additional dose of DTG alone be given.³⁶ Dolutegravir absorption is also decreased when coadministered with polyvalent cationic antacids or laxatives.

Dolutegravir-based regimens have been shown to be noninferior to RAL-based regimens³⁸ and superior to EFV/TDF/FTC24 and boosted DRV-based regimens.³⁹ Treatment-emergent resistance to DTG has been rare, suggesting a high genetic barrier to resistance compared with that of other INSTIs. On this basis, DTG/ABC/3TC is considered a recommended regimen for initial ART treatment.⁷ Another advantage of DTG/ABC/3TC is fewer drug-drug interactions than those of PI- or NNRTI-based regimens or the EVG/c/TDF/FTC STR.^24,38,39 Limitations include the requirement to confirm a negative HLAB* 5701 allele, the potential association of abacavir with cardiovascular (CV) events seen in some but not all studies, and a small increase in creatinine due to DTG effects on renal tubular secretion.^40-43

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine

The latest STR, Genvoya (Gilead Sciences), approved in 2015, combines the INSTI elvitegravir and cobicistat with the novel NRTI backbone alafenamide(TAF)/FTC. Like TDF, TAF is an oral prodrug of TFV, but it achieves lower plasma and higher intracellular TFV levels than does TDF, potentially leading to improved bone and renal tolerability. This combination pill is indicated for use in treatment-naïve adults and children aged ≥ 12 years as switch therapy for patients virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months without a history of virologic failure or resistance to any of the components.⁴⁴ Contraindications include use of concomitant medications that are strong inducers of CYP3A or that are heavily metabolized by CYP3A for clearance. Initiation of this STR is also not recommended in patients with an estimated CrCl < 30 mL/min or with severe hepatic impairment.

In 2 phase 3 RCTs in treatment naïve patients, EVG/c/TAF/FTC was virologically noninferior to EVG/c/TDF/FTC.⁴⁵ Patients in the TAF arms had smaller declines in estimated glomerular filtration (eGFR) and reductions in bone mineral density (BMD) but higher fasting lipids compared with that of patients in the TDF arms. Switching virologically suppressed patients with mild-tomoderate renal insufficiency (eGFR 30-69 mL/min) from TDF-containing regimens to EVG/c/TDF/FTC also has demonstrated maintenance of virologic response while improving BMD and markers of renal function.46

In November 2015, EVG/c/TAF/FTC was added as a recommended regimen for initial ART treatment in patients with CrCl ≥ 30 mL/min.⁷ Advantages of this regimen include its favorable safety profile mentioned earlier and the indication for use in patients with mildto-moderate renal impairment, which is unique among the STRs. However, limitations still remain, including significant drug-drug interactions due to potent CYP3A inhibition and cobicistat-induced inhibition of renal tubular creatinine secretion. Also, more clinical data are needed to confirm the durability of this regimen and to assess whether its improved safety profile translates into fewer clinical outcomes such as renal failure or fractures.

Single-Tablet Regimen Pros and Cons

The proportion of patients on STRs has significantly increased over the past several years. A recently published report of the Women’s Interagency HIV Study (WIHS), a longitudinal study of HIV infection in U.S. women, has analyzed the use of STR. The study showed that the use of STR among ART users increased from 7% in 2006 to 27% in 2013.⁴⁷

Advantages of STRs

Potential advantages of STRs include simplicity, convenience, and adherence, especially by eliminating the risk of selective nonadherence to components of the regimens. Observational cohorts and meta-analyses are beginning to confirm these theoretical advantages. A meta-analysis of 19 RCTs including 6,312 patients demonstrated that regimens with lower pill burdens and once-daily dosing were both associated with better adherence, and fewer pills also led to improved virologic suppression.⁴⁸ In the analysis of the WIHS cohort, STR use was significantly associated with increasedadherence (adjusted risk ratio: 1.05; 95% confidence interval: 1.03 to 1.08) and virologic suppression (risk ratio: 1.06; 95% confidence interval: 1.01 to 1.11).47 Another observational cohort analysis of commercially insured HIV-infected patients showed that patients on STRs were 1.3 times more likely to achieve at least 90% adherence.⁴⁹

A recent RCT, which assigned 300 patients on stable ART to continue their current regimen or switch to EFV/TDF/FTC as an STR, demonstrated no difference in virologic suppression or patient-reported adherence between the 2 groups.²¹ However, 91% of patients in this study reported a preference for the STR regimen.⁵⁰ Single-tablet regimen recipients also have been shown to be less likely to develop treatment-emergent, drug-resistance mutations (DRMs) at the time of virologic failure. In a recently published study, patients receiving the STR EFV/FTC/TDF had a significantly lower risk of DRMs on failure than did those receiving the same components individually in a non-STR regimen.⁵¹ Finally, recent data showed that prescription errors in inpatient ART are common and often go undetected, but coformulated regimens were associated with lower error rates.⁵²

Disadvantages of STRs

Although outweighed by the advantages, there are potential disadvantages to the use of STRs. These include the inability to adjust dosages of components of the regimen for drug-drug or drug-food interactions. In particular, patients with preexisting renal impairment (estimated CrCl < 50 mL/min) have limited options and safety data for STRs. Also, STRs do not exist currently for all NRTI-anchor drug pairings. Notably, there is no available 2 NRTI plus boosted PI STR. This limitation may be important in treatment-experienced patients where PI-based regimens may be needed or in patients with comorbidities where a NRTI-sparing regimen would be considered.

Finally, at the population level, the potential benefits of STRs must be balanced with the increased costs compared with that of generic ART regimens with multiple pills. For example, a mathematical simulation model based on 2009 U.S. data suggested that switching all patients in the U.S. from the branded STR EFV/TDF/FTC to a triple regimen of generic EFV, 3TC, and branded TDF would have saved almost $1 billion per year with only a small decrement in virologic efficacy.53 More costeffectiveness analyses are needed, especially for the developing world, to inform strategies for the use of STRs to improve outcomes in the most costeffective way globally.

When to Use STRS?

For initial ART in treatment-naïve patients, 3 of the available STRs are listed as recommended regimens by the HHS guidelines: EVG/c/TDF/FTC, DTG/ABC/3TC, or EVG/c/TAF/FTC.⁷ In choosing an initial regimen, a number of factors must be considered, including baseline HIV-1 resistance, drug-drug interactions, medical comorbidities, food restrictions, patient preference and convenience, and cost. Patients with drug-resistant HIV-1 or significant renal impairment are less ideal candidates for STRs for initial therapy. Otherwise, the determination typically depends on which of the NRTI backbone drugs, TDF or TAF vs ABC, is most appropriate. Clinicians may favor TDF-containing or TAFcontaining regimens in patients with HBV coinfection, clinically significant CV disease, or patients with the HLA-B*5701 genetic polymorphism.

Conversely, clinicians may favor ABC-containing or TAF-containing regimens in patients at high risk or with preexisting metabolic bone disease or more mild renal impairment. Drug-drug and drug-supplement interactions must be carefully considered in all cases. Although listed as alternative regimens, the other available STRs—EFV/TDF/FTC or RPV/TDF/FTC—may still be the preferred regimen in select individual patients.

In patients already on ART, a switch to a STR may be considered in the following scenarios, with the caveat that most of the clinical trials evaluating switch therapy have been in patients who were virologically suppressed for 6 months on their prior regimens:

1. Improve tolerability. In the STRATEGY-NNRTI trial, patients on a stable EFV-containing regimen experienced significant improvements in neuropsychiatric AEs after switching to EVG/c/TDF/FTC.³⁵
2. Virologically suppressed patients with multiple comorbidities. Difficulty managing dyslipidemia or high CV risk might necessitate a switch from a PI-containing regimen. From the results of the SPIRIT trial⁵⁴ and the STRATEGY-PI trial,³⁴ these patients could be switched safely to RPV/TDF/FTC or EVG/c/TDF/FTC, respectively.
3. Management of virologic failure. This may be beneficial provided that drug resistance has not compromised the components of the regimen.

Conclusion

The potency and once-daily dosing of EFV-based regimens ushered in the era of STRs. The list of STRs has now expanded with the introduction of an RPV-based STR and, lately, 3 different INSTI-based STRs. In the current HHS guidelines, only the INSTI-based STRs are included in the recommended list, mostly because of poor tolerability of EFV/TDF/FTC and lower efficacy of RPV/TDF/FTC in patients with high baseline viremia. In general, the safety profile of STRs has been improving with newer iterations. Their main advantages are convenience, simplicity and improvements in adherence, and possibly reductions in medication errors. Due to these advantages, the percentage of patients on STRs is likely to continue rising. Further expansions of the ART armamentarium may include the development of boosted PI-based STRs as well as novel delivery strategies, such as long-acting injectable regimens.⁵⁵ In the meantime, clinicians should develop a greater familiarity with the use of the currently available STRs.

Click here to read the digital edition.

Together with prophylaxis for opportunistic infections, the widespread use of combination antiretroviral therapy (ART)—known as highly active antiretroviral therapy (HAART)—led to substantial gains in the life expectancy of patients infected with human immunodeficiency virus type 1 (HIV-1).^1-3 The emergence of HAARTs has decreased mortality, increased viral suppression, and significantly reduced the risk of the sexual transmission of HIV.^4-6

Since its introduction, HAART has evolved significantly with more options for triple therapy combinations that show improved efficacy, convenience, and tolerability. Single-tablet regimens (STRs) are the culmination of this evolution. The first STR was introduced in 2006, and to date, there are 5 STR options approved for use. In this review, the authors discuss the rationale and path to development of STRs, compare the currently available STRs, and discuss practical considerations in their use for the treatment of HIV-1 infection.

Is Triple Therapy The Sweet Spot?

Because current ART cannot eradicate HIV-1 infection due to latently infected CD4+ T-cell reservoirs, the primary goals of ART according to the HHS guidelines are to (1) reduce HIV-associated morbidity and prolong the duration and quality of survival; (2) restore and preserve immunologic function; (3) maximally and durably suppress plasma HIV viral load; and (4) prevent HIV transmission.⁷

These goals currently seem to be optimally achieved by treatment with 3 active agents, usually consisting of 2 nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) as a backbone plus a drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a nonnucleoside reverse-transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) boosted with ritonavir or cobicistat. The most widely used NRTI backbones are abacavir plus lamivudine (ABC/3TC) or tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC). Attempts to increase the number of active drugs in a regimen (≥ 4) have generally failed to yield additional virologic or immunologic benefits. Conversely, recent attempts to decrease the number of drugs in a regimen (≤ 2) have met with mixed success.

Mega-HAART

The AIDS Clinical Trial Group (ACTG) 5095 was a randomized controlled trial (RCT) to compare the safety and efficacy of a 3-drug regimen (zidovudine/lamivudine [AZT/3TC] plus efavirenz [EFV]) vs a 4-drug regimen (AZT/3TC/ABC plus EFV) in the initial treatment of HIV-1 infection.⁸ There were no significant differences in virologic efficacy between the 3-drug and 4-drug regimens, findings that have been corroborated in subsequent studies.^9,10 Intensified (≥ 4 drugs) regimens have also failed to lead to significant decay in viral reservoir.^10,11

Dual Therapy With Newer Agents

Recent clinical studies have explored the use of fewer medications in treatment-naïve HIV-infected patients. In the GARDEL study, dual therapy consisting of lopinavir/ritonavir (LPV/RTV) plus 3TC proved to be virologically noninferior to triple therapy of LPV/RTV plus 2 NRTIs in a fixed-dose combination.¹² In a large European clinical trial (NEAT001/ANRS143), the combination of darunavir/ritonavir (DRV/RTV) plus raltegravir (RAL) was noninferior to DRV/RTV plus TDF/FTC, although more virologic failures were seen in the dual-therapy arm for patients with high baseline HIV-1 RNA viral loads or low baseline CD4+ counts.¹³

Suboptimal virologic responses also were observed with the DRV/RTV plus RAL regimen in several smaller studies: ACTG 5262 and RADAR.^14,15 Finally, a combination of DRV/RTV plus maraviroc proved virologically inferior to standard DRV/RTV plus TDF/FTC in the MODERN trial.¹⁶ Although some dual-agent regimens have shown promise, none have established consistent and durable virologic efficacy sufficient to supplant triple therapy, which is currently endorsed by treatment guidelines and forms the basis for current STRs.

Current Single-Tablet Regimens

There are currently 5 STRs available for the treatment of HIV-1 infection, 3 are among the recommended regimens for ART in treatment-naïve patients. An older, triple NRTI-based STR (AZT/3TC/ABC) has fallen out of routine use due to inferior virologic efficacy, toxicities, and better-tolerated alternative agents.¹⁷ A review of the indications for use, major clinical trials, and unique features of available STRs follows and is summarized in the Table.

Efavirenz/tenofovir DF/emtricitabine

The first widely used STR, Atripla (Bristol-Myers Squibb and Gilead Sciences) combines the NRTIs tenofovir DF and FTC with the NNRTI EFV and was released in 2006. It is indicated for use alone or in combination with other ARTs for treatment of HIV-1 infection in adults or children aged > 12 years.¹⁸ Contraindications include hypersensitivity to efavirenz or coadministration with voriconazole. Major precautions are required for patients with severe psychiatric disease or suicidality; new or worsening renal impairment; women in the first trimester of pregnancy or of childbearing age not on effective contraception; or osteoporosis or history of fragility fractures. Patients with chronic liver disease also should be monitored for hepatotoxicity.

Large RCTs confirmed the potency and durability of viral suppression of EFV/TDF/FTC in treatment-naïve patients^19,20 or in the context of antiretroviral switching for treatment simplification in patients previously suppressed with NNRTI- or PI-based regimens.²¹ This combination
has been shown to be noninferior or superior to multiple PI-based,²² NNRTI-based,²³ and INSTI-based regimens.¹⁸ However, it recently was found to be associated with lower virologic response than was the INSTI-based regimen of ABC/3TC plus dolutegravir (DTG) and higher discontinuation rates than that of a TDF/FTC plus RAL regimen.^24,25 Due to lingering concerns about an EFV association with suicidality²⁶ and neural tube defects with first trimester exposure,²⁷ EFV/TDF/FTC was downgraded to an alternative regimen for treatmentnaïve patients, because other available regimens are better tolerated with equal or superior efficacy.⁷

Rilpivirine/tenofovir DF/emtricitabine

Approved in 2011, Complera was the second STR (Gilead Sciences), combining the NNRTI rilpivirine (RPV) with the NRTI backbone TDF/FTC. It is indicated for use in (1) treatment-naïve adults with a baseline HIV-1 RNA ≤ 100,000 copies/mL and baseline CD4+ > 200 cells/mm3; or (2) switch therapy (changing from a previous antiretroviral regimen) in patients virologically suppressed (HIV-1 RNA ≤ 50 copies/mL) for at least 6 months without history of virologic failure or resistance to any of the component drugs.28 Contraindications include administration with other drugs that significantly lower RPV concentrations, such as certain acid-lowering drugs. Although not associated with as many neuropsychiatric or teratogenic effects as EFV/TDF/FTC, this combination still requires caution in circumstances of preexisting renal impairment, severe hepatic disease, or bone disease.

Two phase 3 studies and 1 open-label phase 3b study confirmed that RPV-based STRs were noninferior to EFVbased STRs overall.^23,29 Importantly, patients with higher baseline viral loads experienced higher rates of virologic failure and higher rates of NRTI backbone resistance. Patients with baseline CD4+ < 200 cells/mm3 also had higher virologic failure rates. Because of these virologic and immunologic prerequisites for use, RPV/TDF/FTC is considered an alternative regimen for treatment-naïve patients.⁷ On the other hand, in the aforementioned studies,
fewer patients in the RPV arms discontinued therapy due to adverse events (AEs), and a switch from EFV/TDF/FTC to RPV/TDF/FTC was shown to be safe and effective.³⁰ Its greater tolerability and safety profile make RPV/TDF/FTC an option for patients who do not tolerate EFV/TDF/3TC, who are pregnant, and who have a psychiatric illness.

Elvitegravir/cobicistat/tenofovir DF/emtricitabine

Released in 2012, Stribild (Gilead Sciences) was the first treatment to combine an INSTI and elvitegravir (EVG) with the pharmacologic booster cobicistat and the TDF/FTC backbone. It is indicated for use in treatmentnaïve adults or as switch therapy in patients virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months without a history of virologic failure or resistance to any of the components.³¹

Two double-blind, active-controlled trials established that EVG/c/TDF/FTC was virologically noninferior and had greater safety and tolerability than that of EFV/TDF/FTC³² and ATV/RTV plus DF/FTC³³ in treatment-naïve patients. It also maintained virologic suppression in patients switching from a boosted PI³⁴ or an NNRTI-based regimen.³⁵ On the basis of this efficacy and safety data, EVG/c/TDF/FTC is considered a recommended regimen for initial ART treatment.⁷ However, limitations to this regimen include significant drug-drug interactions due to potent CYP3A inhibition by cobicistat, potential renal and bone toxicity due to TDF, and cobicistat-induced inhibition of renal tubular creatinine secretion, which can lead to a mild creatinine increase (≤ 0.4 mg/dL) and may complicate renal function monitoring. Therefore, it is contraindicated
in patients concomitantly taking medications that are strong inducers of CYP3A or that are heavily metabolized by CYP3A for clearance, patients with reduced renal function (estimated creatinine clearance [CrCl] < 70 mL/min), and those receiving polyvalent cationic antacids or supplements.

Dolutegravir/abacavir/lamivudine

Approved in 2014, Triumeq (ViiV Healthcare) is the first and only currently available STR with an NRTI backbone of ABC/3TC rather than a tenofovir (TFV) derivative, combined with the INSTI DTG. It is indicated for the treatment of HIV-1 infection in patients without prior resistance to the INSTI class of ART or the other component drugs in this combination pill.³⁶ The major contraindication is presence of the HLA-B*5701 allele, a polymorphism that predicts abacavir-related hypersensitivity, or moderate-tosevere hepatic impairment.³⁷ Caution is required in patients with hepatitis B virus (HBV) co-infection due to the risk of 3TC drug resistance and subsequent acute exacerbation of HBV. Coadministration with dofetilide is contraindicated, and coadministration of some medications, most notably rifampin, requires an additional dose of DTG alone be given.³⁶ Dolutegravir absorption is also decreased when coadministered with polyvalent cationic antacids or laxatives.

Dolutegravir-based regimens have been shown to be noninferior to RAL-based regimens³⁸ and superior to EFV/TDF/FTC24 and boosted DRV-based regimens.³⁹ Treatment-emergent resistance to DTG has been rare, suggesting a high genetic barrier to resistance compared with that of other INSTIs. On this basis, DTG/ABC/3TC is considered a recommended regimen for initial ART treatment.⁷ Another advantage of DTG/ABC/3TC is fewer drug-drug interactions than those of PI- or NNRTI-based regimens or the EVG/c/TDF/FTC STR.^24,38,39 Limitations include the requirement to confirm a negative HLAB* 5701 allele, the potential association of abacavir with cardiovascular (CV) events seen in some but not all studies, and a small increase in creatinine due to DTG effects on renal tubular secretion.^40-43

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine

The latest STR, Genvoya (Gilead Sciences), approved in 2015, combines the INSTI elvitegravir and cobicistat with the novel NRTI backbone alafenamide(TAF)/FTC. Like TDF, TAF is an oral prodrug of TFV, but it achieves lower plasma and higher intracellular TFV levels than does TDF, potentially leading to improved bone and renal tolerability. This combination pill is indicated for use in treatment-naïve adults and children aged ≥ 12 years as switch therapy for patients virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months without a history of virologic failure or resistance to any of the components.⁴⁴ Contraindications include use of concomitant medications that are strong inducers of CYP3A or that are heavily metabolized by CYP3A for clearance. Initiation of this STR is also not recommended in patients with an estimated CrCl < 30 mL/min or with severe hepatic impairment.

In 2 phase 3 RCTs in treatment naïve patients, EVG/c/TAF/FTC was virologically noninferior to EVG/c/TDF/FTC.⁴⁵ Patients in the TAF arms had smaller declines in estimated glomerular filtration (eGFR) and reductions in bone mineral density (BMD) but higher fasting lipids compared with that of patients in the TDF arms. Switching virologically suppressed patients with mild-tomoderate renal insufficiency (eGFR 30-69 mL/min) from TDF-containing regimens to EVG/c/TDF/FTC also has demonstrated maintenance of virologic response while improving BMD and markers of renal function.46

In November 2015, EVG/c/TAF/FTC was added as a recommended regimen for initial ART treatment in patients with CrCl ≥ 30 mL/min.⁷ Advantages of this regimen include its favorable safety profile mentioned earlier and the indication for use in patients with mildto-moderate renal impairment, which is unique among the STRs. However, limitations still remain, including significant drug-drug interactions due to potent CYP3A inhibition and cobicistat-induced inhibition of renal tubular creatinine secretion. Also, more clinical data are needed to confirm the durability of this regimen and to assess whether its improved safety profile translates into fewer clinical outcomes such as renal failure or fractures.

Single-Tablet Regimen Pros and Cons

The proportion of patients on STRs has significantly increased over the past several years. A recently published report of the Women’s Interagency HIV Study (WIHS), a longitudinal study of HIV infection in U.S. women, has analyzed the use of STR. The study showed that the use of STR among ART users increased from 7% in 2006 to 27% in 2013.⁴⁷

Advantages of STRs

Potential advantages of STRs include simplicity, convenience, and adherence, especially by eliminating the risk of selective nonadherence to components of the regimens. Observational cohorts and meta-analyses are beginning to confirm these theoretical advantages. A meta-analysis of 19 RCTs including 6,312 patients demonstrated that regimens with lower pill burdens and once-daily dosing were both associated with better adherence, and fewer pills also led to improved virologic suppression.⁴⁸ In the analysis of the WIHS cohort, STR use was significantly associated with increasedadherence (adjusted risk ratio: 1.05; 95% confidence interval: 1.03 to 1.08) and virologic suppression (risk ratio: 1.06; 95% confidence interval: 1.01 to 1.11).47 Another observational cohort analysis of commercially insured HIV-infected patients showed that patients on STRs were 1.3 times more likely to achieve at least 90% adherence.⁴⁹

A recent RCT, which assigned 300 patients on stable ART to continue their current regimen or switch to EFV/TDF/FTC as an STR, demonstrated no difference in virologic suppression or patient-reported adherence between the 2 groups.²¹ However, 91% of patients in this study reported a preference for the STR regimen.⁵⁰ Single-tablet regimen recipients also have been shown to be less likely to develop treatment-emergent, drug-resistance mutations (DRMs) at the time of virologic failure. In a recently published study, patients receiving the STR EFV/FTC/TDF had a significantly lower risk of DRMs on failure than did those receiving the same components individually in a non-STR regimen.⁵¹ Finally, recent data showed that prescription errors in inpatient ART are common and often go undetected, but coformulated regimens were associated with lower error rates.⁵²

Disadvantages of STRs

Although outweighed by the advantages, there are potential disadvantages to the use of STRs. These include the inability to adjust dosages of components of the regimen for drug-drug or drug-food interactions. In particular, patients with preexisting renal impairment (estimated CrCl < 50 mL/min) have limited options and safety data for STRs. Also, STRs do not exist currently for all NRTI-anchor drug pairings. Notably, there is no available 2 NRTI plus boosted PI STR. This limitation may be important in treatment-experienced patients where PI-based regimens may be needed or in patients with comorbidities where a NRTI-sparing regimen would be considered.

Finally, at the population level, the potential benefits of STRs must be balanced with the increased costs compared with that of generic ART regimens with multiple pills. For example, a mathematical simulation model based on 2009 U.S. data suggested that switching all patients in the U.S. from the branded STR EFV/TDF/FTC to a triple regimen of generic EFV, 3TC, and branded TDF would have saved almost $1 billion per year with only a small decrement in virologic efficacy.53 More costeffectiveness analyses are needed, especially for the developing world, to inform strategies for the use of STRs to improve outcomes in the most costeffective way globally.

When to Use STRS?

For initial ART in treatment-naïve patients, 3 of the available STRs are listed as recommended regimens by the HHS guidelines: EVG/c/TDF/FTC, DTG/ABC/3TC, or EVG/c/TAF/FTC.⁷ In choosing an initial regimen, a number of factors must be considered, including baseline HIV-1 resistance, drug-drug interactions, medical comorbidities, food restrictions, patient preference and convenience, and cost. Patients with drug-resistant HIV-1 or significant renal impairment are less ideal candidates for STRs for initial therapy. Otherwise, the determination typically depends on which of the NRTI backbone drugs, TDF or TAF vs ABC, is most appropriate. Clinicians may favor TDF-containing or TAFcontaining regimens in patients with HBV coinfection, clinically significant CV disease, or patients with the HLA-B*5701 genetic polymorphism.

Conversely, clinicians may favor ABC-containing or TAF-containing regimens in patients at high risk or with preexisting metabolic bone disease or more mild renal impairment. Drug-drug and drug-supplement interactions must be carefully considered in all cases. Although listed as alternative regimens, the other available STRs—EFV/TDF/FTC or RPV/TDF/FTC—may still be the preferred regimen in select individual patients.

In patients already on ART, a switch to a STR may be considered in the following scenarios, with the caveat that most of the clinical trials evaluating switch therapy have been in patients who were virologically suppressed for 6 months on their prior regimens:

1. Improve tolerability. In the STRATEGY-NNRTI trial, patients on a stable EFV-containing regimen experienced significant improvements in neuropsychiatric AEs after switching to EVG/c/TDF/FTC.³⁵
2. Virologically suppressed patients with multiple comorbidities. Difficulty managing dyslipidemia or high CV risk might necessitate a switch from a PI-containing regimen. From the results of the SPIRIT trial⁵⁴ and the STRATEGY-PI trial,³⁴ these patients could be switched safely to RPV/TDF/FTC or EVG/c/TDF/FTC, respectively.
3. Management of virologic failure. This may be beneficial provided that drug resistance has not compromised the components of the regimen.

Conclusion

The potency and once-daily dosing of EFV-based regimens ushered in the era of STRs. The list of STRs has now expanded with the introduction of an RPV-based STR and, lately, 3 different INSTI-based STRs. In the current HHS guidelines, only the INSTI-based STRs are included in the recommended list, mostly because of poor tolerability of EFV/TDF/FTC and lower efficacy of RPV/TDF/FTC in patients with high baseline viremia. In general, the safety profile of STRs has been improving with newer iterations. Their main advantages are convenience, simplicity and improvements in adherence, and possibly reductions in medication errors. Due to these advantages, the percentage of patients on STRs is likely to continue rising. Further expansions of the ART armamentarium may include the development of boosted PI-based STRs as well as novel delivery strategies, such as long-acting injectable regimens.⁵⁵ In the meantime, clinicians should develop a greater familiarity with the use of the currently available STRs.

Click here to read the digital edition.

Together with prophylaxis for opportunistic infections, the widespread use of combination antiretroviral therapy (ART)—known as highly active antiretroviral therapy (HAART)—led to substantial gains in the life expectancy of patients infected with human immunodeficiency virus type 1 (HIV-1).^1-3 The emergence of HAARTs has decreased mortality, increased viral suppression, and significantly reduced the risk of the sexual transmission of HIV.^4-6

Since its introduction, HAART has evolved significantly with more options for triple therapy combinations that show improved efficacy, convenience, and tolerability. Single-tablet regimens (STRs) are the culmination of this evolution. The first STR was introduced in 2006, and to date, there are 5 STR options approved for use. In this review, the authors discuss the rationale and path to development of STRs, compare the currently available STRs, and discuss practical considerations in their use for the treatment of HIV-1 infection.

Is Triple Therapy The Sweet Spot?

Because current ART cannot eradicate HIV-1 infection due to latently infected CD4+ T-cell reservoirs, the primary goals of ART according to the HHS guidelines are to (1) reduce HIV-associated morbidity and prolong the duration and quality of survival; (2) restore and preserve immunologic function; (3) maximally and durably suppress plasma HIV viral load; and (4) prevent HIV transmission.⁷

These goals currently seem to be optimally achieved by treatment with 3 active agents, usually consisting of 2 nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) as a backbone plus a drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a nonnucleoside reverse-transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) boosted with ritonavir or cobicistat. The most widely used NRTI backbones are abacavir plus lamivudine (ABC/3TC) or tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC). Attempts to increase the number of active drugs in a regimen (≥ 4) have generally failed to yield additional virologic or immunologic benefits. Conversely, recent attempts to decrease the number of drugs in a regimen (≤ 2) have met with mixed success.

Mega-HAART

The AIDS Clinical Trial Group (ACTG) 5095 was a randomized controlled trial (RCT) to compare the safety and efficacy of a 3-drug regimen (zidovudine/lamivudine [AZT/3TC] plus efavirenz [EFV]) vs a 4-drug regimen (AZT/3TC/ABC plus EFV) in the initial treatment of HIV-1 infection.⁸ There were no significant differences in virologic efficacy between the 3-drug and 4-drug regimens, findings that have been corroborated in subsequent studies.^9,10 Intensified (≥ 4 drugs) regimens have also failed to lead to significant decay in viral reservoir.^10,11

Dual Therapy With Newer Agents

Recent clinical studies have explored the use of fewer medications in treatment-naïve HIV-infected patients. In the GARDEL study, dual therapy consisting of lopinavir/ritonavir (LPV/RTV) plus 3TC proved to be virologically noninferior to triple therapy of LPV/RTV plus 2 NRTIs in a fixed-dose combination.¹² In a large European clinical trial (NEAT001/ANRS143), the combination of darunavir/ritonavir (DRV/RTV) plus raltegravir (RAL) was noninferior to DRV/RTV plus TDF/FTC, although more virologic failures were seen in the dual-therapy arm for patients with high baseline HIV-1 RNA viral loads or low baseline CD4+ counts.¹³

Suboptimal virologic responses also were observed with the DRV/RTV plus RAL regimen in several smaller studies: ACTG 5262 and RADAR.^14,15 Finally, a combination of DRV/RTV plus maraviroc proved virologically inferior to standard DRV/RTV plus TDF/FTC in the MODERN trial.¹⁶ Although some dual-agent regimens have shown promise, none have established consistent and durable virologic efficacy sufficient to supplant triple therapy, which is currently endorsed by treatment guidelines and forms the basis for current STRs.

Current Single-Tablet Regimens

There are currently 5 STRs available for the treatment of HIV-1 infection, 3 are among the recommended regimens for ART in treatment-naïve patients. An older, triple NRTI-based STR (AZT/3TC/ABC) has fallen out of routine use due to inferior virologic efficacy, toxicities, and better-tolerated alternative agents.¹⁷ A review of the indications for use, major clinical trials, and unique features of available STRs follows and is summarized in the Table.

Efavirenz/tenofovir DF/emtricitabine

The first widely used STR, Atripla (Bristol-Myers Squibb and Gilead Sciences) combines the NRTIs tenofovir DF and FTC with the NNRTI EFV and was released in 2006. It is indicated for use alone or in combination with other ARTs for treatment of HIV-1 infection in adults or children aged > 12 years.¹⁸ Contraindications include hypersensitivity to efavirenz or coadministration with voriconazole. Major precautions are required for patients with severe psychiatric disease or suicidality; new or worsening renal impairment; women in the first trimester of pregnancy or of childbearing age not on effective contraception; or osteoporosis or history of fragility fractures. Patients with chronic liver disease also should be monitored for hepatotoxicity.

Large RCTs confirmed the potency and durability of viral suppression of EFV/TDF/FTC in treatment-naïve patients^19,20 or in the context of antiretroviral switching for treatment simplification in patients previously suppressed with NNRTI- or PI-based regimens.²¹ This combination
has been shown to be noninferior or superior to multiple PI-based,²² NNRTI-based,²³ and INSTI-based regimens.¹⁸ However, it recently was found to be associated with lower virologic response than was the INSTI-based regimen of ABC/3TC plus dolutegravir (DTG) and higher discontinuation rates than that of a TDF/FTC plus RAL regimen.^24,25 Due to lingering concerns about an EFV association with suicidality²⁶ and neural tube defects with first trimester exposure,²⁷ EFV/TDF/FTC was downgraded to an alternative regimen for treatmentnaïve patients, because other available regimens are better tolerated with equal or superior efficacy.⁷

Rilpivirine/tenofovir DF/emtricitabine

Approved in 2011, Complera was the second STR (Gilead Sciences), combining the NNRTI rilpivirine (RPV) with the NRTI backbone TDF/FTC. It is indicated for use in (1) treatment-naïve adults with a baseline HIV-1 RNA ≤ 100,000 copies/mL and baseline CD4+ > 200 cells/mm3; or (2) switch therapy (changing from a previous antiretroviral regimen) in patients virologically suppressed (HIV-1 RNA ≤ 50 copies/mL) for at least 6 months without history of virologic failure or resistance to any of the component drugs.28 Contraindications include administration with other drugs that significantly lower RPV concentrations, such as certain acid-lowering drugs. Although not associated with as many neuropsychiatric or teratogenic effects as EFV/TDF/FTC, this combination still requires caution in circumstances of preexisting renal impairment, severe hepatic disease, or bone disease.

Two phase 3 studies and 1 open-label phase 3b study confirmed that RPV-based STRs were noninferior to EFVbased STRs overall.^23,29 Importantly, patients with higher baseline viral loads experienced higher rates of virologic failure and higher rates of NRTI backbone resistance. Patients with baseline CD4+ < 200 cells/mm3 also had higher virologic failure rates. Because of these virologic and immunologic prerequisites for use, RPV/TDF/FTC is considered an alternative regimen for treatment-naïve patients.⁷ On the other hand, in the aforementioned studies,
fewer patients in the RPV arms discontinued therapy due to adverse events (AEs), and a switch from EFV/TDF/FTC to RPV/TDF/FTC was shown to be safe and effective.³⁰ Its greater tolerability and safety profile make RPV/TDF/FTC an option for patients who do not tolerate EFV/TDF/3TC, who are pregnant, and who have a psychiatric illness.

Elvitegravir/cobicistat/tenofovir DF/emtricitabine

Released in 2012, Stribild (Gilead Sciences) was the first treatment to combine an INSTI and elvitegravir (EVG) with the pharmacologic booster cobicistat and the TDF/FTC backbone. It is indicated for use in treatmentnaïve adults or as switch therapy in patients virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months without a history of virologic failure or resistance to any of the components.³¹

Two double-blind, active-controlled trials established that EVG/c/TDF/FTC was virologically noninferior and had greater safety and tolerability than that of EFV/TDF/FTC³² and ATV/RTV plus DF/FTC³³ in treatment-naïve patients. It also maintained virologic suppression in patients switching from a boosted PI³⁴ or an NNRTI-based regimen.³⁵ On the basis of this efficacy and safety data, EVG/c/TDF/FTC is considered a recommended regimen for initial ART treatment.⁷ However, limitations to this regimen include significant drug-drug interactions due to potent CYP3A inhibition by cobicistat, potential renal and bone toxicity due to TDF, and cobicistat-induced inhibition of renal tubular creatinine secretion, which can lead to a mild creatinine increase (≤ 0.4 mg/dL) and may complicate renal function monitoring. Therefore, it is contraindicated
in patients concomitantly taking medications that are strong inducers of CYP3A or that are heavily metabolized by CYP3A for clearance, patients with reduced renal function (estimated creatinine clearance [CrCl] < 70 mL/min), and those receiving polyvalent cationic antacids or supplements.

Dolutegravir/abacavir/lamivudine

Approved in 2014, Triumeq (ViiV Healthcare) is the first and only currently available STR with an NRTI backbone of ABC/3TC rather than a tenofovir (TFV) derivative, combined with the INSTI DTG. It is indicated for the treatment of HIV-1 infection in patients without prior resistance to the INSTI class of ART or the other component drugs in this combination pill.³⁶ The major contraindication is presence of the HLA-B*5701 allele, a polymorphism that predicts abacavir-related hypersensitivity, or moderate-tosevere hepatic impairment.³⁷ Caution is required in patients with hepatitis B virus (HBV) co-infection due to the risk of 3TC drug resistance and subsequent acute exacerbation of HBV. Coadministration with dofetilide is contraindicated, and coadministration of some medications, most notably rifampin, requires an additional dose of DTG alone be given.³⁶ Dolutegravir absorption is also decreased when coadministered with polyvalent cationic antacids or laxatives.

Dolutegravir-based regimens have been shown to be noninferior to RAL-based regimens³⁸ and superior to EFV/TDF/FTC24 and boosted DRV-based regimens.³⁹ Treatment-emergent resistance to DTG has been rare, suggesting a high genetic barrier to resistance compared with that of other INSTIs. On this basis, DTG/ABC/3TC is considered a recommended regimen for initial ART treatment.⁷ Another advantage of DTG/ABC/3TC is fewer drug-drug interactions than those of PI- or NNRTI-based regimens or the EVG/c/TDF/FTC STR.^24,38,39 Limitations include the requirement to confirm a negative HLAB* 5701 allele, the potential association of abacavir with cardiovascular (CV) events seen in some but not all studies, and a small increase in creatinine due to DTG effects on renal tubular secretion.^40-43

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine

The latest STR, Genvoya (Gilead Sciences), approved in 2015, combines the INSTI elvitegravir and cobicistat with the novel NRTI backbone alafenamide(TAF)/FTC. Like TDF, TAF is an oral prodrug of TFV, but it achieves lower plasma and higher intracellular TFV levels than does TDF, potentially leading to improved bone and renal tolerability. This combination pill is indicated for use in treatment-naïve adults and children aged ≥ 12 years as switch therapy for patients virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months without a history of virologic failure or resistance to any of the components.⁴⁴ Contraindications include use of concomitant medications that are strong inducers of CYP3A or that are heavily metabolized by CYP3A for clearance. Initiation of this STR is also not recommended in patients with an estimated CrCl < 30 mL/min or with severe hepatic impairment.

In 2 phase 3 RCTs in treatment naïve patients, EVG/c/TAF/FTC was virologically noninferior to EVG/c/TDF/FTC.⁴⁵ Patients in the TAF arms had smaller declines in estimated glomerular filtration (eGFR) and reductions in bone mineral density (BMD) but higher fasting lipids compared with that of patients in the TDF arms. Switching virologically suppressed patients with mild-tomoderate renal insufficiency (eGFR 30-69 mL/min) from TDF-containing regimens to EVG/c/TDF/FTC also has demonstrated maintenance of virologic response while improving BMD and markers of renal function.46

In November 2015, EVG/c/TAF/FTC was added as a recommended regimen for initial ART treatment in patients with CrCl ≥ 30 mL/min.⁷ Advantages of this regimen include its favorable safety profile mentioned earlier and the indication for use in patients with mildto-moderate renal impairment, which is unique among the STRs. However, limitations still remain, including significant drug-drug interactions due to potent CYP3A inhibition and cobicistat-induced inhibition of renal tubular creatinine secretion. Also, more clinical data are needed to confirm the durability of this regimen and to assess whether its improved safety profile translates into fewer clinical outcomes such as renal failure or fractures.

Single-Tablet Regimen Pros and Cons

The proportion of patients on STRs has significantly increased over the past several years. A recently published report of the Women’s Interagency HIV Study (WIHS), a longitudinal study of HIV infection in U.S. women, has analyzed the use of STR. The study showed that the use of STR among ART users increased from 7% in 2006 to 27% in 2013.⁴⁷

Advantages of STRs

Potential advantages of STRs include simplicity, convenience, and adherence, especially by eliminating the risk of selective nonadherence to components of the regimens. Observational cohorts and meta-analyses are beginning to confirm these theoretical advantages. A meta-analysis of 19 RCTs including 6,312 patients demonstrated that regimens with lower pill burdens and once-daily dosing were both associated with better adherence, and fewer pills also led to improved virologic suppression.⁴⁸ In the analysis of the WIHS cohort, STR use was significantly associated with increasedadherence (adjusted risk ratio: 1.05; 95% confidence interval: 1.03 to 1.08) and virologic suppression (risk ratio: 1.06; 95% confidence interval: 1.01 to 1.11).47 Another observational cohort analysis of commercially insured HIV-infected patients showed that patients on STRs were 1.3 times more likely to achieve at least 90% adherence.⁴⁹

A recent RCT, which assigned 300 patients on stable ART to continue their current regimen or switch to EFV/TDF/FTC as an STR, demonstrated no difference in virologic suppression or patient-reported adherence between the 2 groups.²¹ However, 91% of patients in this study reported a preference for the STR regimen.⁵⁰ Single-tablet regimen recipients also have been shown to be less likely to develop treatment-emergent, drug-resistance mutations (DRMs) at the time of virologic failure. In a recently published study, patients receiving the STR EFV/FTC/TDF had a significantly lower risk of DRMs on failure than did those receiving the same components individually in a non-STR regimen.⁵¹ Finally, recent data showed that prescription errors in inpatient ART are common and often go undetected, but coformulated regimens were associated with lower error rates.⁵²

Disadvantages of STRs

Although outweighed by the advantages, there are potential disadvantages to the use of STRs. These include the inability to adjust dosages of components of the regimen for drug-drug or drug-food interactions. In particular, patients with preexisting renal impairment (estimated CrCl < 50 mL/min) have limited options and safety data for STRs. Also, STRs do not exist currently for all NRTI-anchor drug pairings. Notably, there is no available 2 NRTI plus boosted PI STR. This limitation may be important in treatment-experienced patients where PI-based regimens may be needed or in patients with comorbidities where a NRTI-sparing regimen would be considered.

Finally, at the population level, the potential benefits of STRs must be balanced with the increased costs compared with that of generic ART regimens with multiple pills. For example, a mathematical simulation model based on 2009 U.S. data suggested that switching all patients in the U.S. from the branded STR EFV/TDF/FTC to a triple regimen of generic EFV, 3TC, and branded TDF would have saved almost $1 billion per year with only a small decrement in virologic efficacy.53 More costeffectiveness analyses are needed, especially for the developing world, to inform strategies for the use of STRs to improve outcomes in the most costeffective way globally.

When to Use STRS?

For initial ART in treatment-naïve patients, 3 of the available STRs are listed as recommended regimens by the HHS guidelines: EVG/c/TDF/FTC, DTG/ABC/3TC, or EVG/c/TAF/FTC.⁷ In choosing an initial regimen, a number of factors must be considered, including baseline HIV-1 resistance, drug-drug interactions, medical comorbidities, food restrictions, patient preference and convenience, and cost. Patients with drug-resistant HIV-1 or significant renal impairment are less ideal candidates for STRs for initial therapy. Otherwise, the determination typically depends on which of the NRTI backbone drugs, TDF or TAF vs ABC, is most appropriate. Clinicians may favor TDF-containing or TAFcontaining regimens in patients with HBV coinfection, clinically significant CV disease, or patients with the HLA-B*5701 genetic polymorphism.

Conversely, clinicians may favor ABC-containing or TAF-containing regimens in patients at high risk or with preexisting metabolic bone disease or more mild renal impairment. Drug-drug and drug-supplement interactions must be carefully considered in all cases. Although listed as alternative regimens, the other available STRs—EFV/TDF/FTC or RPV/TDF/FTC—may still be the preferred regimen in select individual patients.

In patients already on ART, a switch to a STR may be considered in the following scenarios, with the caveat that most of the clinical trials evaluating switch therapy have been in patients who were virologically suppressed for 6 months on their prior regimens:

1. Improve tolerability. In the STRATEGY-NNRTI trial, patients on a stable EFV-containing regimen experienced significant improvements in neuropsychiatric AEs after switching to EVG/c/TDF/FTC.³⁵
2. Virologically suppressed patients with multiple comorbidities. Difficulty managing dyslipidemia or high CV risk might necessitate a switch from a PI-containing regimen. From the results of the SPIRIT trial⁵⁴ and the STRATEGY-PI trial,³⁴ these patients could be switched safely to RPV/TDF/FTC or EVG/c/TDF/FTC, respectively.
3. Management of virologic failure. This may be beneficial provided that drug resistance has not compromised the components of the regimen.

Conclusion

The potency and once-daily dosing of EFV-based regimens ushered in the era of STRs. The list of STRs has now expanded with the introduction of an RPV-based STR and, lately, 3 different INSTI-based STRs. In the current HHS guidelines, only the INSTI-based STRs are included in the recommended list, mostly because of poor tolerability of EFV/TDF/FTC and lower efficacy of RPV/TDF/FTC in patients with high baseline viremia. In general, the safety profile of STRs has been improving with newer iterations. Their main advantages are convenience, simplicity and improvements in adherence, and possibly reductions in medication errors. Due to these advantages, the percentage of patients on STRs is likely to continue rising. Further expansions of the ART armamentarium may include the development of boosted PI-based STRs as well as novel delivery strategies, such as long-acting injectable regimens.⁵⁵ In the meantime, clinicians should develop a greater familiarity with the use of the currently available STRs.

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Globally, chronic hepatitis B virus (HBV) infection is the leading cause of liver-related morbidity and mortality. Worldwide, more than 2 billion people have been exposed to HBV, and about 250 million are chronically infected.¹

The prevalence of hepatitis B surface antigen (HBsAg), the serologic marker of chronicity, varies significantly worldwide. The highest rates of HBsAg are reported in Asia, Sub-Saharan Africa, and the Amazon basin. The overall prevalence of chronic HBV infection in the U.S. is low, 800,000 to 1.4 million persons. The disease is predominantly seen in immigrants, with > 90% of cases in persons from countries of intermediate or high HBV prevalence, such as East Asia, Africa, Pacific Islands, parts of Africa, and Eastern Europe.²

The prevalence of chronic HBV infection in the U.S. may be underestimated and closer to 2.2 million persons, because many foreign-born persons are generally excluded from national prevalence surveys.³ More worrisome, studies suggest that a majority of individuals with chronic HBV infection are unaware of their diagnosis, and consequently, many patients who might benefit from therapy do not receive appropriate care or treatment.⁴ This review will discuss screening recommendations for HBV in the U.S., identify knowledge gaps regarding the disease, and present a cogent argument for why treatment-eligible patients should be entered into management programs and evaluated for therapy.

Hepatitis B Screening

Chronic hepatitis B meets the criteria established by the World Health Organization as a disease for which screening would be beneficial to public health. Chronic HBV infection is an important health problem that can result in serious sequelae, such as cirrhosis, hepatocellular carcinoma, and liver-related mortality. Moreover, persons unaware of their diagnosis may unwittingly transmit the virus to unprotected individuals.

A simple, relatively inexpensive test is widely available to identify chronic HBV infection. The test allows physicians to confirm a diagnosis before symptoms develop and offer a safe and effective therapy. Modeling studies suggest that screening populations with a prevalence of chronic HBV infection ≥ 2% also would be cost-effective in reducing the burden of HBV-associated liver cancer and chronic liver disease in high-risk populations.5,6 However, a number of barriers exist that limit screening (Table 1).

Who to Screen?

All guidelines recommend that persons at high risk for HBV infection should be screened. Broadly, these include persons from geographic areas with a high prevalence of chronic infection, persons at high risk for acquiring HBV infection, persons with increased risk of transmitting HBV, and persons at risk for reactivation of HBV. In addition to previous recommendations, the Centers for Disease Control and Prevention (CDC) updated 2008 guidelines now recommend testing all persons born in geographic areas with a HBsAg prevalence of ≥ 2%, U.S.-born persons not vaccinated as infants whose parents were born in regions with HBsAg prevalence ≥ 8%, persons who inject drugs, men who have sex with men, persons with elevated alanine transaminase and aspartate transaminase of unknown etiology, and persons with selected medical conditions that require immunosuppressive therapy (Table 2).⁷ In 2014, the U.S. Preventive Services Task Force provided updated guidance on screening of nonpregnant adolescents and adults that aligned with the CDC guidelines and also recommended screening individuals at high risk for HBV infection.⁸ The American Association for the Study of Liver Diseases and other professional liver organizations support these recommendations.⁹

Which Test to Use

Serologic testing for HBsAg is the recommended method to identify persons with chronic HBV infection. Testing for HBV infection in high-risk groups should be performed with a FDA-licensed or FDA-approved serologic assay for HBsAg (sensitivity and specificity of > 98%) according to the manufacturer’s recommendations. Initially, reactive specimens should be confirmed with a licensed confirmatory test.

A positive HBsAg result indicates active infection, either acute or chronic. Other serological markers of HBV infection, such as presence of hepatitis B core IgM antibody, and the clinical context are used to differentiate between acute, chronic, or resolving infection. For identification of individuals who are at risk for chronic infection, the screening strategy should be with HBsAg only. For identifying susceptible persons who should be offered HBV vaccination, or patients that are at risk of reactivation or transmission of HBV, screening should include
testing for HBsAg, hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti-HBs).

The interpretation of HBV screening serology is shown in Table 3. Persons with chronic HBV infection are treated, if needed, per practice guidelines based on the initial test results and interpretation of the stage of the disease and counseled regarding transmission of infection. ^9,10 Vaccination is recommended for uninfected persons.

Hepatitis B Education

There is relatively poor awareness of HBV among highrisk individuals and health care professionals (HCPs). A study examining the prevalence of chronic hepatitis B in an Asian and Pacific Islander population reported that about 15% of participants had not been previously tested for hepatitis B.¹¹ Another study that surveyed 3,163 Asian American adults in the San Francisco Bay Area found that of those screened and identified with chronic HBV infection (8.9%), two-thirds were unaware that they were infected.¹²

Primary care providers in San Francisco correctly identified that Chinese immigrants have a higher prevalence of chronic hepatitis B than that of non-Hispanic white or U.S.-born Chinese people, but the providers incorrectly identified persons with HIV infection, men who have sex with men, and persons who inject drugs as having higher prevalence than that of Chinese immigrants in a survey.¹³ Lack of awareness probably contributes to poor outcomes from the infection among at-risk persons as well as continued transmission to susceptible individuals. Furthermore, lack of knowledge is a barrier to testing, prevention, and care. Increased awareness to identify the at-risk population and early treatment is an important step to prevent morbidity and mortality from chronic hepatitis B.

Public Awareness

Many at-risk populations are unaware of HBV, its possible routes of transmission, or that a safe and effective vaccine exists for HBV prevention. Moreover, many foreign-born persons with chronic HBV infection feel stigmatized by others or have cultural barriers against Western medicine and prefer alternative therapies. As a result, the Institute of Medicine (IOM) has suggested that innovative approaches need to be developed to promote a better understanding of transmission, prevent and treat HBV, increase HBV vaccination rates among children and at-risk adults, educate women about vertical transmission risk, reduce stigmatization, and provide culturally sensitive and understandable educational material.¹⁴

Awareness Among Health Care Professionals

Studies have identified knowledge gaps among HCPs regarding the prevalence of HBV in the general U.S. population, outcome of infection, who should be screened and vaccinated against HBV, appropriate methods for screening and interpretation of serologic tests for HBV, and proper treatment of persons with chronic infection. As a consequence, the IOM recommended educational programs for HCPs on the prevalence of HBV infection in the general U.S. population and at-risk populations, particularly foreign-born persons. In addition, these educational programs should target all levels of HCPs, including undergraduates and postgraduates, and include information on screening and prevention, testing, and interpretation of tests.¹⁴

Need to Treat

The global HBV disease burden remains high despite the existence of an effective vaccine. Worldwide, there are an estimated 4.5 million new infections and 780,000 HBVrelated deaths each year.¹⁵ In the U.S., the highest rates of mortality are seen in Asians and Pacific Islanders and among persons aged 55 to 64 years. Asians and Pacific Islanders also have the highest rate of liver cancer deaths.^16,17

The natural history of chronic hepatitis B is highly variable and dependent on a complex interplay between the virus and the host immune response. It is estimated that between 25% and 40% of persons with chronic hepatitis B will be at risk for progression to cirrhosis.^7,18,19 In a study among persons with cirrhosis, the 5-year cumulative risk of developing hepatocellular carcinoma was 17% in Asian patients and 10% in white Americans and Europeans. The 5-year liver-related death rate was 14% among East Asians and 15% among white Europeans.¹⁸

A significant proportion of individuals infected with HBV are unaware of their diagnosis, not enrolled in care, or not receiving therapy.^7,12,20-24 Data from several prospective and retrospective cohort studies have demonstrated that prolonged viral suppression achieved with therapy is associated with regression of fibrosis and reversal of cirrhosis in a substantial proportion of individuals.^25,26 Treatment has also been associated with a reduction in rates of liver decompensation, HCC, liverrelated, and all-cause mortality among patients with liver cirrhosis.²⁷

Given the risk of serious complications and the availability of safe and effective therapy, it is imperative that persons identified as having chronic hepatitis B be referred for evaluation to determine whether therapy is warranted. However, it is also important to recognize that a cure for HBV infection is currently not available, and most patients who initiate therapy will require longterm treatment. In addition, persons who are not currently treatment candidates may become candidates due to changes in disease activity. This underscores the point that patients with chronic hepatitis B require lifelong monitoring regardless of whether they are receiving treatment.

Conclusions

The primary reasons to screen for HBV are to reduce morbidity and mortality related to liver disease and to prevent transmission. Significant barriers remain to screening and referral for care for HBV in the U.S. Educational programs to increase knowledge and awareness among HCPs and the public together with improved access to care are critical to improve disease outcomes and prevent transmission. Despite the availability of an effective vaccine for 3 decades, the global prevalence of HBV has not substantially declined. Further research is needed to explore strategies to overcome screening barriers, improve vaccination rates, and to develop new models of health care delivery to reduce the burden of disease-related to HBV.

Click here to read the digital edition.

Globally, chronic hepatitis B virus (HBV) infection is the leading cause of liver-related morbidity and mortality. Worldwide, more than 2 billion people have been exposed to HBV, and about 250 million are chronically infected.¹

The prevalence of hepatitis B surface antigen (HBsAg), the serologic marker of chronicity, varies significantly worldwide. The highest rates of HBsAg are reported in Asia, Sub-Saharan Africa, and the Amazon basin. The overall prevalence of chronic HBV infection in the U.S. is low, 800,000 to 1.4 million persons. The disease is predominantly seen in immigrants, with > 90% of cases in persons from countries of intermediate or high HBV prevalence, such as East Asia, Africa, Pacific Islands, parts of Africa, and Eastern Europe.²

The prevalence of chronic HBV infection in the U.S. may be underestimated and closer to 2.2 million persons, because many foreign-born persons are generally excluded from national prevalence surveys.³ More worrisome, studies suggest that a majority of individuals with chronic HBV infection are unaware of their diagnosis, and consequently, many patients who might benefit from therapy do not receive appropriate care or treatment.⁴ This review will discuss screening recommendations for HBV in the U.S., identify knowledge gaps regarding the disease, and present a cogent argument for why treatment-eligible patients should be entered into management programs and evaluated for therapy.

Hepatitis B Screening

Chronic hepatitis B meets the criteria established by the World Health Organization as a disease for which screening would be beneficial to public health. Chronic HBV infection is an important health problem that can result in serious sequelae, such as cirrhosis, hepatocellular carcinoma, and liver-related mortality. Moreover, persons unaware of their diagnosis may unwittingly transmit the virus to unprotected individuals.

A simple, relatively inexpensive test is widely available to identify chronic HBV infection. The test allows physicians to confirm a diagnosis before symptoms develop and offer a safe and effective therapy. Modeling studies suggest that screening populations with a prevalence of chronic HBV infection ≥ 2% also would be cost-effective in reducing the burden of HBV-associated liver cancer and chronic liver disease in high-risk populations.5,6 However, a number of barriers exist that limit screening (Table 1).

Who to Screen?

All guidelines recommend that persons at high risk for HBV infection should be screened. Broadly, these include persons from geographic areas with a high prevalence of chronic infection, persons at high risk for acquiring HBV infection, persons with increased risk of transmitting HBV, and persons at risk for reactivation of HBV. In addition to previous recommendations, the Centers for Disease Control and Prevention (CDC) updated 2008 guidelines now recommend testing all persons born in geographic areas with a HBsAg prevalence of ≥ 2%, U.S.-born persons not vaccinated as infants whose parents were born in regions with HBsAg prevalence ≥ 8%, persons who inject drugs, men who have sex with men, persons with elevated alanine transaminase and aspartate transaminase of unknown etiology, and persons with selected medical conditions that require immunosuppressive therapy (Table 2).⁷ In 2014, the U.S. Preventive Services Task Force provided updated guidance on screening of nonpregnant adolescents and adults that aligned with the CDC guidelines and also recommended screening individuals at high risk for HBV infection.⁸ The American Association for the Study of Liver Diseases and other professional liver organizations support these recommendations.⁹

Which Test to Use

Serologic testing for HBsAg is the recommended method to identify persons with chronic HBV infection. Testing for HBV infection in high-risk groups should be performed with a FDA-licensed or FDA-approved serologic assay for HBsAg (sensitivity and specificity of > 98%) according to the manufacturer’s recommendations. Initially, reactive specimens should be confirmed with a licensed confirmatory test.

A positive HBsAg result indicates active infection, either acute or chronic. Other serological markers of HBV infection, such as presence of hepatitis B core IgM antibody, and the clinical context are used to differentiate between acute, chronic, or resolving infection. For identification of individuals who are at risk for chronic infection, the screening strategy should be with HBsAg only. For identifying susceptible persons who should be offered HBV vaccination, or patients that are at risk of reactivation or transmission of HBV, screening should include
testing for HBsAg, hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti-HBs).

The interpretation of HBV screening serology is shown in Table 3. Persons with chronic HBV infection are treated, if needed, per practice guidelines based on the initial test results and interpretation of the stage of the disease and counseled regarding transmission of infection. ^9,10 Vaccination is recommended for uninfected persons.

Hepatitis B Education

There is relatively poor awareness of HBV among highrisk individuals and health care professionals (HCPs). A study examining the prevalence of chronic hepatitis B in an Asian and Pacific Islander population reported that about 15% of participants had not been previously tested for hepatitis B.¹¹ Another study that surveyed 3,163 Asian American adults in the San Francisco Bay Area found that of those screened and identified with chronic HBV infection (8.9%), two-thirds were unaware that they were infected.¹²

Primary care providers in San Francisco correctly identified that Chinese immigrants have a higher prevalence of chronic hepatitis B than that of non-Hispanic white or U.S.-born Chinese people, but the providers incorrectly identified persons with HIV infection, men who have sex with men, and persons who inject drugs as having higher prevalence than that of Chinese immigrants in a survey.¹³ Lack of awareness probably contributes to poor outcomes from the infection among at-risk persons as well as continued transmission to susceptible individuals. Furthermore, lack of knowledge is a barrier to testing, prevention, and care. Increased awareness to identify the at-risk population and early treatment is an important step to prevent morbidity and mortality from chronic hepatitis B.

Public Awareness

Many at-risk populations are unaware of HBV, its possible routes of transmission, or that a safe and effective vaccine exists for HBV prevention. Moreover, many foreign-born persons with chronic HBV infection feel stigmatized by others or have cultural barriers against Western medicine and prefer alternative therapies. As a result, the Institute of Medicine (IOM) has suggested that innovative approaches need to be developed to promote a better understanding of transmission, prevent and treat HBV, increase HBV vaccination rates among children and at-risk adults, educate women about vertical transmission risk, reduce stigmatization, and provide culturally sensitive and understandable educational material.¹⁴

Awareness Among Health Care Professionals

Studies have identified knowledge gaps among HCPs regarding the prevalence of HBV in the general U.S. population, outcome of infection, who should be screened and vaccinated against HBV, appropriate methods for screening and interpretation of serologic tests for HBV, and proper treatment of persons with chronic infection. As a consequence, the IOM recommended educational programs for HCPs on the prevalence of HBV infection in the general U.S. population and at-risk populations, particularly foreign-born persons. In addition, these educational programs should target all levels of HCPs, including undergraduates and postgraduates, and include information on screening and prevention, testing, and interpretation of tests.¹⁴

Need to Treat

The global HBV disease burden remains high despite the existence of an effective vaccine. Worldwide, there are an estimated 4.5 million new infections and 780,000 HBVrelated deaths each year.¹⁵ In the U.S., the highest rates of mortality are seen in Asians and Pacific Islanders and among persons aged 55 to 64 years. Asians and Pacific Islanders also have the highest rate of liver cancer deaths.^16,17

The natural history of chronic hepatitis B is highly variable and dependent on a complex interplay between the virus and the host immune response. It is estimated that between 25% and 40% of persons with chronic hepatitis B will be at risk for progression to cirrhosis.^7,18,19 In a study among persons with cirrhosis, the 5-year cumulative risk of developing hepatocellular carcinoma was 17% in Asian patients and 10% in white Americans and Europeans. The 5-year liver-related death rate was 14% among East Asians and 15% among white Europeans.¹⁸

A significant proportion of individuals infected with HBV are unaware of their diagnosis, not enrolled in care, or not receiving therapy.^7,12,20-24 Data from several prospective and retrospective cohort studies have demonstrated that prolonged viral suppression achieved with therapy is associated with regression of fibrosis and reversal of cirrhosis in a substantial proportion of individuals.^25,26 Treatment has also been associated with a reduction in rates of liver decompensation, HCC, liverrelated, and all-cause mortality among patients with liver cirrhosis.²⁷

Given the risk of serious complications and the availability of safe and effective therapy, it is imperative that persons identified as having chronic hepatitis B be referred for evaluation to determine whether therapy is warranted. However, it is also important to recognize that a cure for HBV infection is currently not available, and most patients who initiate therapy will require longterm treatment. In addition, persons who are not currently treatment candidates may become candidates due to changes in disease activity. This underscores the point that patients with chronic hepatitis B require lifelong monitoring regardless of whether they are receiving treatment.

Conclusions

The primary reasons to screen for HBV are to reduce morbidity and mortality related to liver disease and to prevent transmission. Significant barriers remain to screening and referral for care for HBV in the U.S. Educational programs to increase knowledge and awareness among HCPs and the public together with improved access to care are critical to improve disease outcomes and prevent transmission. Despite the availability of an effective vaccine for 3 decades, the global prevalence of HBV has not substantially declined. Further research is needed to explore strategies to overcome screening barriers, improve vaccination rates, and to develop new models of health care delivery to reduce the burden of disease-related to HBV.

Click here to read the digital edition.

Globally, chronic hepatitis B virus (HBV) infection is the leading cause of liver-related morbidity and mortality. Worldwide, more than 2 billion people have been exposed to HBV, and about 250 million are chronically infected.¹

The prevalence of hepatitis B surface antigen (HBsAg), the serologic marker of chronicity, varies significantly worldwide. The highest rates of HBsAg are reported in Asia, Sub-Saharan Africa, and the Amazon basin. The overall prevalence of chronic HBV infection in the U.S. is low, 800,000 to 1.4 million persons. The disease is predominantly seen in immigrants, with > 90% of cases in persons from countries of intermediate or high HBV prevalence, such as East Asia, Africa, Pacific Islands, parts of Africa, and Eastern Europe.²

The prevalence of chronic HBV infection in the U.S. may be underestimated and closer to 2.2 million persons, because many foreign-born persons are generally excluded from national prevalence surveys.³ More worrisome, studies suggest that a majority of individuals with chronic HBV infection are unaware of their diagnosis, and consequently, many patients who might benefit from therapy do not receive appropriate care or treatment.⁴ This review will discuss screening recommendations for HBV in the U.S., identify knowledge gaps regarding the disease, and present a cogent argument for why treatment-eligible patients should be entered into management programs and evaluated for therapy.

Hepatitis B Screening

Chronic hepatitis B meets the criteria established by the World Health Organization as a disease for which screening would be beneficial to public health. Chronic HBV infection is an important health problem that can result in serious sequelae, such as cirrhosis, hepatocellular carcinoma, and liver-related mortality. Moreover, persons unaware of their diagnosis may unwittingly transmit the virus to unprotected individuals.

A simple, relatively inexpensive test is widely available to identify chronic HBV infection. The test allows physicians to confirm a diagnosis before symptoms develop and offer a safe and effective therapy. Modeling studies suggest that screening populations with a prevalence of chronic HBV infection ≥ 2% also would be cost-effective in reducing the burden of HBV-associated liver cancer and chronic liver disease in high-risk populations.5,6 However, a number of barriers exist that limit screening (Table 1).

Who to Screen?

All guidelines recommend that persons at high risk for HBV infection should be screened. Broadly, these include persons from geographic areas with a high prevalence of chronic infection, persons at high risk for acquiring HBV infection, persons with increased risk of transmitting HBV, and persons at risk for reactivation of HBV. In addition to previous recommendations, the Centers for Disease Control and Prevention (CDC) updated 2008 guidelines now recommend testing all persons born in geographic areas with a HBsAg prevalence of ≥ 2%, U.S.-born persons not vaccinated as infants whose parents were born in regions with HBsAg prevalence ≥ 8%, persons who inject drugs, men who have sex with men, persons with elevated alanine transaminase and aspartate transaminase of unknown etiology, and persons with selected medical conditions that require immunosuppressive therapy (Table 2).⁷ In 2014, the U.S. Preventive Services Task Force provided updated guidance on screening of nonpregnant adolescents and adults that aligned with the CDC guidelines and also recommended screening individuals at high risk for HBV infection.⁸ The American Association for the Study of Liver Diseases and other professional liver organizations support these recommendations.⁹

Which Test to Use

Serologic testing for HBsAg is the recommended method to identify persons with chronic HBV infection. Testing for HBV infection in high-risk groups should be performed with a FDA-licensed or FDA-approved serologic assay for HBsAg (sensitivity and specificity of > 98%) according to the manufacturer’s recommendations. Initially, reactive specimens should be confirmed with a licensed confirmatory test.

A positive HBsAg result indicates active infection, either acute or chronic. Other serological markers of HBV infection, such as presence of hepatitis B core IgM antibody, and the clinical context are used to differentiate between acute, chronic, or resolving infection. For identification of individuals who are at risk for chronic infection, the screening strategy should be with HBsAg only. For identifying susceptible persons who should be offered HBV vaccination, or patients that are at risk of reactivation or transmission of HBV, screening should include
testing for HBsAg, hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti-HBs).

The interpretation of HBV screening serology is shown in Table 3. Persons with chronic HBV infection are treated, if needed, per practice guidelines based on the initial test results and interpretation of the stage of the disease and counseled regarding transmission of infection. ^9,10 Vaccination is recommended for uninfected persons.

Hepatitis B Education

There is relatively poor awareness of HBV among highrisk individuals and health care professionals (HCPs). A study examining the prevalence of chronic hepatitis B in an Asian and Pacific Islander population reported that about 15% of participants had not been previously tested for hepatitis B.¹¹ Another study that surveyed 3,163 Asian American adults in the San Francisco Bay Area found that of those screened and identified with chronic HBV infection (8.9%), two-thirds were unaware that they were infected.¹²

Primary care providers in San Francisco correctly identified that Chinese immigrants have a higher prevalence of chronic hepatitis B than that of non-Hispanic white or U.S.-born Chinese people, but the providers incorrectly identified persons with HIV infection, men who have sex with men, and persons who inject drugs as having higher prevalence than that of Chinese immigrants in a survey.¹³ Lack of awareness probably contributes to poor outcomes from the infection among at-risk persons as well as continued transmission to susceptible individuals. Furthermore, lack of knowledge is a barrier to testing, prevention, and care. Increased awareness to identify the at-risk population and early treatment is an important step to prevent morbidity and mortality from chronic hepatitis B.

Public Awareness

Many at-risk populations are unaware of HBV, its possible routes of transmission, or that a safe and effective vaccine exists for HBV prevention. Moreover, many foreign-born persons with chronic HBV infection feel stigmatized by others or have cultural barriers against Western medicine and prefer alternative therapies. As a result, the Institute of Medicine (IOM) has suggested that innovative approaches need to be developed to promote a better understanding of transmission, prevent and treat HBV, increase HBV vaccination rates among children and at-risk adults, educate women about vertical transmission risk, reduce stigmatization, and provide culturally sensitive and understandable educational material.¹⁴

Awareness Among Health Care Professionals

Studies have identified knowledge gaps among HCPs regarding the prevalence of HBV in the general U.S. population, outcome of infection, who should be screened and vaccinated against HBV, appropriate methods for screening and interpretation of serologic tests for HBV, and proper treatment of persons with chronic infection. As a consequence, the IOM recommended educational programs for HCPs on the prevalence of HBV infection in the general U.S. population and at-risk populations, particularly foreign-born persons. In addition, these educational programs should target all levels of HCPs, including undergraduates and postgraduates, and include information on screening and prevention, testing, and interpretation of tests.¹⁴

Need to Treat

The global HBV disease burden remains high despite the existence of an effective vaccine. Worldwide, there are an estimated 4.5 million new infections and 780,000 HBVrelated deaths each year.¹⁵ In the U.S., the highest rates of mortality are seen in Asians and Pacific Islanders and among persons aged 55 to 64 years. Asians and Pacific Islanders also have the highest rate of liver cancer deaths.^16,17

The natural history of chronic hepatitis B is highly variable and dependent on a complex interplay between the virus and the host immune response. It is estimated that between 25% and 40% of persons with chronic hepatitis B will be at risk for progression to cirrhosis.^7,18,19 In a study among persons with cirrhosis, the 5-year cumulative risk of developing hepatocellular carcinoma was 17% in Asian patients and 10% in white Americans and Europeans. The 5-year liver-related death rate was 14% among East Asians and 15% among white Europeans.¹⁸

A significant proportion of individuals infected with HBV are unaware of their diagnosis, not enrolled in care, or not receiving therapy.^7,12,20-24 Data from several prospective and retrospective cohort studies have demonstrated that prolonged viral suppression achieved with therapy is associated with regression of fibrosis and reversal of cirrhosis in a substantial proportion of individuals.^25,26 Treatment has also been associated with a reduction in rates of liver decompensation, HCC, liverrelated, and all-cause mortality among patients with liver cirrhosis.²⁷

Given the risk of serious complications and the availability of safe and effective therapy, it is imperative that persons identified as having chronic hepatitis B be referred for evaluation to determine whether therapy is warranted. However, it is also important to recognize that a cure for HBV infection is currently not available, and most patients who initiate therapy will require longterm treatment. In addition, persons who are not currently treatment candidates may become candidates due to changes in disease activity. This underscores the point that patients with chronic hepatitis B require lifelong monitoring regardless of whether they are receiving treatment.

Conclusions

The primary reasons to screen for HBV are to reduce morbidity and mortality related to liver disease and to prevent transmission. Significant barriers remain to screening and referral for care for HBV in the U.S. Educational programs to increase knowledge and awareness among HCPs and the public together with improved access to care are critical to improve disease outcomes and prevent transmission. Despite the availability of an effective vaccine for 3 decades, the global prevalence of HBV has not substantially declined. Further research is needed to explore strategies to overcome screening barriers, improve vaccination rates, and to develop new models of health care delivery to reduce the burden of disease-related to HBV.

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