User login
Treating Hepatitis C Virus Reinfection With 8 Weeks of Ledipasvir/Sofosbuvir Achieves Sustained Virologic Response
Three patients reinfected with hepatitis C virus after a sustained virologic response were considered treatment naïve and treated with a short-course direct acting antiviral regimen.
To decrease the incidence and prevalence of hepatitis C virus (HCV) in the United States, hepatology experts, public health officials, and patient advocates agree that linkage to care is essential for treatment of people who inject drugs (PWID). The most recent surveillance report from the Centers for Disease Control and Prevention (CDC) estimates that injection drug use accounts for the transmission of approximately 72% of new HCV infections.1,2
Although recent studies of direct-acting antiviral (DAA) agents have not been designed to investigate the long-term rates of reinfection in this population, various population-based studies in multiple countries have attempted to describe the rate of reinfection for this cohort.3-7 This rate varies widely based on the defined population of PWID, definition of reinfection, and the prevalence of HCV in a given PWID population. However, studies have consistently shown a relatively low historic rate of reinfection, which varies from 1 to 5 per 100 person-years in patients who have ever injected drugs, to 3 to 33 per 100 person-years in patients who continue injection drug use (IDU). Higher rates are found in those who engage in high-risk behaviors such as needle sharing.3-7 Yet, the US opioid crisis is attributable to a recent rise in both overall incidence and reinfections, highlighting the importance of determining the best treatment strategy for those who become reinfected.1
Current HCV guidelines from the American Association for the Study of Liver Diseases AASLD) and Infectious Diseases Society of America (IDSA) encourage access to retreatment for PWID who become reinfected, stating that new reinfections should follow treatment-naïve therapy recommendations.8 However, to date this recommendation has not been validated by published clinical trials or patient case reports. This is likely due in part both to the small number of reinfections among PWID requiring retreatment and barriers to payment for treatment, particularly for individuals with substance use disorders.9 While this recommendation can be found under the key population section for the “Identification and Management of HCV in People Who Inject Drugs,” health care providers (HCPs) may easily miss this statement if they alternatively refer to the “Treatment-Experienced” section that recommends escalation to either sofosbuvir/velpatasvir/voxilaprevir or glecaprevir/pibrentasvir in patients who are NS5A inhibitor DAA-experienced.8 Anecdotally, the first instinct for many HCPs when considering a treatment regimen for a reinfected patient is to refer to treatment-experienced regimen recommendations rather than appreciating the reinfected virus to be treatment naïve.
A treatment-escalation approach could have the consequence of limiting the number of times a patient could undergo treatment on successive reinfections. Additionally, these retreatment regimens often are more expensive, resulting in further cost barriers for payors approving retreatment for individuals with HCV reinfection. In contrast, demonstrating efficacy of a less costly short-course regimen would support increased access to initial and retreatment courses for PWID. The implications of enabling improved access to care is essential in the setting of the ongoing opioid epidemic in the United States.
Given the perspective that the virus should be considered treatment naïve for patients who become reinfected, we describe here 3 cases of patients previously achieving sustained virologic response (SVR) being retreated with the cost-effective 8-week regimen of ledipasvir/sofosbuvir following reinfection.
Case Reports
Case 1
A 59-year-old male presented for his third treatment course for HCV genotype 1a. The patient initially underwent 76 weeks of interferon-based HCV treatment in 2007 and 2008, from which he was determined to have achieved SVR in 24 weeks (SVR24) in April 2009. His viral load remained undetected through February 2010 but subsequently had detectable virus again in 2011 following relapsed use of alcohol, cocaine, and injection drugs. The patient elected to await approval of DAAs and eventually completed an 8-week regimen of ledipasvir/sofosbuvir from May to July 2016, achieving SVR24 in December 2016. The patient’s viral load was rechecked in October 2018 and he was again viremic following recent IDU, suggesting a second reinfection.
In preparation for his third HCV treatment, the patient was included in shared decision making to consider retreating his de novo infection as treatment naïve to provide a briefer (ie, 8 weeks) and more cost-effective treatment given his low likelihood of advanced fibrotic liver disease—his FibroScan score was 6.5 kPa, whereas scores ≥ 12.5 kPa in patients with chronic HCV suggest a higher likelihood of cirrhosis.10 At week 4, the patient’s viral load was undetected, he completed his 8-week regimen of ledipasvir/sofosbuvir as planned and achieved SVR12 (Table). He had reported excellent adherence throughout treatment with assistance of a pill box and validated by a reported pill count.
Case 2
A 32-year-old male presented with HCV genotype 1a. Like case 1, this patient had a low FibroScan score of 4.7 kPa. He was previously infected with genotype 3 and completed a 12-week course of sofosbuvir/velpatasvir in November 2016. He achieved SVR12 as evidenced by an undetected viral load in February 2017 despite questionable adherence throughout and relapsed use of heroin by the end of his regimen. He continued intermittent IDU and presented in October 2018 with a detectable viral load, now with genotype 1a. The patient similarly agreed to undergo an 8-week regimen of ledipasvir/sofosbuvir, considering his de novo infection to be treatment naïve. His viral load at treatment week 3 was quantitatively negative while qualitatively detectable at < 15 U/mL. He completed his treatment course in March 2019 and was determined to have achieved SVR24 in September 2019.
Case 3
A 51-year-old male presented with a history of HCV genotype 1a and a low FibroScan score (4.9 kPa ). The patient was previously infected with genotype 2 and had achieved SVR24 following a 12-week regimen of sofosbuvir/velpatasvir in 2017. The patient subsequently was reinfected with genotype 1a and completed an 8-week course of ledipasvir/sofosbuvir in May 2019. The patient had his SVR12 lab drawn 9 days early and was undetectable at that time. He reported 0 missed doses during treatment and achieved an undetected viral load by treatment week 4.
Discussion
We demonstrate that HCV reinfection after treatment with previous interferon and/or DAA-based regimens can be treated with less costly 8-week treatment regimens. Current guidelines include a statement allowing for reinfected patients to follow initial treatment guidelines, but this statement has previously lacked published evidence and may be overlooked by HCPs who refer to recommendations for treatment-experienced patients. Given the increasing likelihood of HCPs encountering patients who have become reinfected with HCV after achieving SVR from a DAA regimen, further delineation may be needed in the recommendations for treatment-experienced patients to highlight the important nuance of recognizing that reinfections should follow initial treatment guidance.
While all 3 of these cases met criteria for the least costly and simplest 1 pill once daily 8-week regimen of ledipasvir/sofosbuvir, patients requiring retreatment with alternative genotypes or evidence of advanced fibrotic liver disease could benefit from a similar approach of using the least expensive and/or shortest duration regimen for which they meet eligibility. With this approach, coverage could be further expanded to the PWID population to help limit HCV transmission amid the opioid crisis.1
Studies have established that PWID are able to achieve similar SVR efficacy rates similar to that of the general population when treated in the setting of an interdisciplinary treatment team that offers collaborative management of complex psychosocial comorbidities and harm reduction strategies.11,12 These integrative patient-centric strategies may include personalized behavioral health pretreatment evaluations, access to substance use treatment, harm reduction counseling, needle exchange programs, and close follow-up by a case manager.2,13 Current DAA regimens combined with 1 or more of these strategies have demonstrated SVR12 rates of 90 to 95% for initial treatment regimens.11 These high SVR12 rates were even achieved in a recent study in which 74% (76/103) of participants had self-reported IDU within 30 days of HCV treatment start and similar IDU rates throughout treatment.12 A meta-analysis, including real-world studies of DAA treatment outcomes yielded a pooled SVR of 88% (95% CI, 83‐92%) for recent PWID and 91% (95% CI, 88‐95%) for individuals using opiate substitution therapy (OST).14 Additionally, linking PWID with OST also reduces risk for reinfection.14,15
For any patient with detectable HCV after completing the initial DAA regimen, it is important to distinguish between relapse and reinfection. SVR12 is generally synonymous with a clinical cure. Patients with ongoing risk factors posttreatment should continue to have their HCV viral load monitored for evidence of reinfection. Patients without known risk factors may benefit from repeat viral load only if there is clinical concern for reinfection, for example, a rise in liver enzymes.
We have shown that patients with ongoing risk factors who are reinfected can be treated successfully with cost-effective 8-week regimens. For comparison this 8-week regimen of ledipasvir/sofosbuvir has an average wholesale price (AWP) of $28,800, while alternative regimens approved for treatment-naïve patients vary in AWP from $31,680 to $43,200, and regimens approved for retreatment of DAA failures have an AWP as high as $89,712.
An 8-week treatment regimen for both initial and reinfection regimens affords many advantages in medication adherence and both medication and provider resource cost-effectiveness. First, new HCV reinfections are disproportionally younger individuals often with complex psychosocial issues that impact retention in treatment. An 8-week course of treatment can be initiated concurrently with substance abuse treatment programs, including intensive outpatient programs and residential treatment programs that are usually at least 28 days. Many of these programs provide aftercare options that would extend the entire course of treatment. These opportunities afford individuals to receive HCV treatment in a setting that supports medication adherence, sobriety efforts, and education on harm reduction to reduce risk for reinfection.
Finally, statistical models indicate eradication of HCV will require scaling up the treatment of PWID in conjunction with harm reduction strategies such as OST and needle exchange programs.16 In contrast, there are low risks associated with retreatment given these medications are well-tolerated, treatment of PWID lowers the risk of further HCV transmission, and the understanding of these reinfections being treatment naïve disavows concerns of these patients having resistance to regimens that cleared their prior infections. The opportunity to provide retreatment without escalating regimen complexity or cost increases access to care for a vulnerable population while aiding in the eradication of HCV.
1. Centers for Disease Control and Prevention. Viral Hepatitis Surveillance - United States, 2018. Updated August 28, 2020. Accessed May 18, 2021. https://www.cdc.gov/hepatitis/statistics/2018surveillance/HepC.htm 2. Grebely J, Robaeys G, Bruggmann P, et al; International Network for Hepatitis in Substance Users. Recommendations for the management of hepatitis C virus infection among people who inject drugs. Int J Drug Policy. 2015;26(10):1028-1038. doi:10.1016/j.drugpo.2015.07.005
3. Marco A, Esteban JI, Solé C, et al. Hepatitis C virus reinfection among prisoners with sustained virological response after treatment for chronic hepatitis C. J Hepatol. 2013;59(1):45-51. doi:10.1016/j.jhep.2013.03.008
4. Midgard H, Bjøro B, Mæland A, et al. Hepatitis C reinfection after sustained virological response. J Hepatol. 2016;64(5):1020-1026. doi:10.1016/j.jhep.2016.01.001
5. Currie SL, Ryan JC, Tracy D, et al. A prospective study to examine persistent HCV reinfection in injection drug users who have previously cleared the virus [published correction appears in Drug Alcohol Depend. 2008 Jul;96(1-2):192]. Drug Alcohol Depend. 2008;93(1-2):148-154. doi:10.1016/j.drugalcdep.2007.09.011
6. Grady BP, Vanhommerig JW, Schinkel J, et al. Low incidence of reinfection with the hepatitis C virus following treatment in active drug users in Amsterdam. Eur J Gastroenterol Hepatol. 2012;24(11):1302-1307. doi:10.1097/MEG.0b013e32835702a8
7. Grebely J, Pham ST, Matthews GV, et al; ATAHC Study Group. Hepatitis C virus reinfection and superinfection among treated and untreated participants with recent infection. Hepatology. 2012;55(4):1058-1069. doi:10.1002/hep.24754
8. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Accessed May 26, 2021. https://www.hcvguidelines.org
9. National Viral Hepatitis Roundtable, Center for Health Law and Policy Innovation, Harvard Law School. Hepatitis C: The State of Medicaid Access. 2017 National Summary Report. Updated October 23, 2017. Accessed May 26, 2021. https://hepcstage.wpengine.com/wp-content/uploads/2017/10/State-of-HepC_2017_FINAL.pdf
10. Singh S, Muir AJ, Dieterich DT, Falck-Ytter YT. American Gastroenterological Association Institute technical review on the role of elastography in chronic liver diseases. Gastroenterology. 2017;152(6):1544-1577. doi:10.1053/j.gastro.2017.03.016
11. Dore GJ, Altice F, Litwin AH, et al; C-EDGE CO-STAR Study Group. Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial. Ann Intern Med. 2016;165(9):625-634. doi:10.7326/M16-0816
12. Grebely J, Dalgard O, Conway B, et al; SIMPLIFY Study Group. Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open-label, single-arm, phase 4, multicentre trial. Lancet Gastroenterol Hepatol. 2018;3(3):153-161. doi:10.1016/S2468-1253(17)30404-1
13. Cos TA, Bartholomew TS, Huynh, KJ. Role of behavioral health providers in treating hepatitis C. Professional Psychol Res Pract. 2019;50(4):246–254. doi:10.1037/pro0000243
14. Latham NH, Doyle JS, Palmer AY, et al. Staying hepatitis C negative: a systematic review and meta-analysis of cure and reinfection in people who inject drugs. Liver Int. 2019;39(12):2244-2260. doi:10.1111/liv.14152
15. Platt L, Minozzi S, Reed J, et al. Needle syringe programmes and opioid substitution therapy for preventing hepatitis C transmission in people who inject drugs. Cochrane Database Syst Rev. 2017;9(9):CD012021. Published 2017 Sep 18. doi:10.1002/14651858.CD012021.pub2
16. Fraser H, Martin NK, Brummer-Korvenkontio H, et al. Model projections on the impact of HCV treatment in the prevention of HCV transmission among people who inject drugs in Europe. J Hepatol. 2018;68(3):402-411. doi:10.1016/j.jhep.2017.10.010
Three patients reinfected with hepatitis C virus after a sustained virologic response were considered treatment naïve and treated with a short-course direct acting antiviral regimen.
Three patients reinfected with hepatitis C virus after a sustained virologic response were considered treatment naïve and treated with a short-course direct acting antiviral regimen.
To decrease the incidence and prevalence of hepatitis C virus (HCV) in the United States, hepatology experts, public health officials, and patient advocates agree that linkage to care is essential for treatment of people who inject drugs (PWID). The most recent surveillance report from the Centers for Disease Control and Prevention (CDC) estimates that injection drug use accounts for the transmission of approximately 72% of new HCV infections.1,2
Although recent studies of direct-acting antiviral (DAA) agents have not been designed to investigate the long-term rates of reinfection in this population, various population-based studies in multiple countries have attempted to describe the rate of reinfection for this cohort.3-7 This rate varies widely based on the defined population of PWID, definition of reinfection, and the prevalence of HCV in a given PWID population. However, studies have consistently shown a relatively low historic rate of reinfection, which varies from 1 to 5 per 100 person-years in patients who have ever injected drugs, to 3 to 33 per 100 person-years in patients who continue injection drug use (IDU). Higher rates are found in those who engage in high-risk behaviors such as needle sharing.3-7 Yet, the US opioid crisis is attributable to a recent rise in both overall incidence and reinfections, highlighting the importance of determining the best treatment strategy for those who become reinfected.1
Current HCV guidelines from the American Association for the Study of Liver Diseases AASLD) and Infectious Diseases Society of America (IDSA) encourage access to retreatment for PWID who become reinfected, stating that new reinfections should follow treatment-naïve therapy recommendations.8 However, to date this recommendation has not been validated by published clinical trials or patient case reports. This is likely due in part both to the small number of reinfections among PWID requiring retreatment and barriers to payment for treatment, particularly for individuals with substance use disorders.9 While this recommendation can be found under the key population section for the “Identification and Management of HCV in People Who Inject Drugs,” health care providers (HCPs) may easily miss this statement if they alternatively refer to the “Treatment-Experienced” section that recommends escalation to either sofosbuvir/velpatasvir/voxilaprevir or glecaprevir/pibrentasvir in patients who are NS5A inhibitor DAA-experienced.8 Anecdotally, the first instinct for many HCPs when considering a treatment regimen for a reinfected patient is to refer to treatment-experienced regimen recommendations rather than appreciating the reinfected virus to be treatment naïve.
A treatment-escalation approach could have the consequence of limiting the number of times a patient could undergo treatment on successive reinfections. Additionally, these retreatment regimens often are more expensive, resulting in further cost barriers for payors approving retreatment for individuals with HCV reinfection. In contrast, demonstrating efficacy of a less costly short-course regimen would support increased access to initial and retreatment courses for PWID. The implications of enabling improved access to care is essential in the setting of the ongoing opioid epidemic in the United States.
Given the perspective that the virus should be considered treatment naïve for patients who become reinfected, we describe here 3 cases of patients previously achieving sustained virologic response (SVR) being retreated with the cost-effective 8-week regimen of ledipasvir/sofosbuvir following reinfection.
Case Reports
Case 1
A 59-year-old male presented for his third treatment course for HCV genotype 1a. The patient initially underwent 76 weeks of interferon-based HCV treatment in 2007 and 2008, from which he was determined to have achieved SVR in 24 weeks (SVR24) in April 2009. His viral load remained undetected through February 2010 but subsequently had detectable virus again in 2011 following relapsed use of alcohol, cocaine, and injection drugs. The patient elected to await approval of DAAs and eventually completed an 8-week regimen of ledipasvir/sofosbuvir from May to July 2016, achieving SVR24 in December 2016. The patient’s viral load was rechecked in October 2018 and he was again viremic following recent IDU, suggesting a second reinfection.
In preparation for his third HCV treatment, the patient was included in shared decision making to consider retreating his de novo infection as treatment naïve to provide a briefer (ie, 8 weeks) and more cost-effective treatment given his low likelihood of advanced fibrotic liver disease—his FibroScan score was 6.5 kPa, whereas scores ≥ 12.5 kPa in patients with chronic HCV suggest a higher likelihood of cirrhosis.10 At week 4, the patient’s viral load was undetected, he completed his 8-week regimen of ledipasvir/sofosbuvir as planned and achieved SVR12 (Table). He had reported excellent adherence throughout treatment with assistance of a pill box and validated by a reported pill count.
Case 2
A 32-year-old male presented with HCV genotype 1a. Like case 1, this patient had a low FibroScan score of 4.7 kPa. He was previously infected with genotype 3 and completed a 12-week course of sofosbuvir/velpatasvir in November 2016. He achieved SVR12 as evidenced by an undetected viral load in February 2017 despite questionable adherence throughout and relapsed use of heroin by the end of his regimen. He continued intermittent IDU and presented in October 2018 with a detectable viral load, now with genotype 1a. The patient similarly agreed to undergo an 8-week regimen of ledipasvir/sofosbuvir, considering his de novo infection to be treatment naïve. His viral load at treatment week 3 was quantitatively negative while qualitatively detectable at < 15 U/mL. He completed his treatment course in March 2019 and was determined to have achieved SVR24 in September 2019.
Case 3
A 51-year-old male presented with a history of HCV genotype 1a and a low FibroScan score (4.9 kPa ). The patient was previously infected with genotype 2 and had achieved SVR24 following a 12-week regimen of sofosbuvir/velpatasvir in 2017. The patient subsequently was reinfected with genotype 1a and completed an 8-week course of ledipasvir/sofosbuvir in May 2019. The patient had his SVR12 lab drawn 9 days early and was undetectable at that time. He reported 0 missed doses during treatment and achieved an undetected viral load by treatment week 4.
Discussion
We demonstrate that HCV reinfection after treatment with previous interferon and/or DAA-based regimens can be treated with less costly 8-week treatment regimens. Current guidelines include a statement allowing for reinfected patients to follow initial treatment guidelines, but this statement has previously lacked published evidence and may be overlooked by HCPs who refer to recommendations for treatment-experienced patients. Given the increasing likelihood of HCPs encountering patients who have become reinfected with HCV after achieving SVR from a DAA regimen, further delineation may be needed in the recommendations for treatment-experienced patients to highlight the important nuance of recognizing that reinfections should follow initial treatment guidance.
While all 3 of these cases met criteria for the least costly and simplest 1 pill once daily 8-week regimen of ledipasvir/sofosbuvir, patients requiring retreatment with alternative genotypes or evidence of advanced fibrotic liver disease could benefit from a similar approach of using the least expensive and/or shortest duration regimen for which they meet eligibility. With this approach, coverage could be further expanded to the PWID population to help limit HCV transmission amid the opioid crisis.1
Studies have established that PWID are able to achieve similar SVR efficacy rates similar to that of the general population when treated in the setting of an interdisciplinary treatment team that offers collaborative management of complex psychosocial comorbidities and harm reduction strategies.11,12 These integrative patient-centric strategies may include personalized behavioral health pretreatment evaluations, access to substance use treatment, harm reduction counseling, needle exchange programs, and close follow-up by a case manager.2,13 Current DAA regimens combined with 1 or more of these strategies have demonstrated SVR12 rates of 90 to 95% for initial treatment regimens.11 These high SVR12 rates were even achieved in a recent study in which 74% (76/103) of participants had self-reported IDU within 30 days of HCV treatment start and similar IDU rates throughout treatment.12 A meta-analysis, including real-world studies of DAA treatment outcomes yielded a pooled SVR of 88% (95% CI, 83‐92%) for recent PWID and 91% (95% CI, 88‐95%) for individuals using opiate substitution therapy (OST).14 Additionally, linking PWID with OST also reduces risk for reinfection.14,15
For any patient with detectable HCV after completing the initial DAA regimen, it is important to distinguish between relapse and reinfection. SVR12 is generally synonymous with a clinical cure. Patients with ongoing risk factors posttreatment should continue to have their HCV viral load monitored for evidence of reinfection. Patients without known risk factors may benefit from repeat viral load only if there is clinical concern for reinfection, for example, a rise in liver enzymes.
We have shown that patients with ongoing risk factors who are reinfected can be treated successfully with cost-effective 8-week regimens. For comparison this 8-week regimen of ledipasvir/sofosbuvir has an average wholesale price (AWP) of $28,800, while alternative regimens approved for treatment-naïve patients vary in AWP from $31,680 to $43,200, and regimens approved for retreatment of DAA failures have an AWP as high as $89,712.
An 8-week treatment regimen for both initial and reinfection regimens affords many advantages in medication adherence and both medication and provider resource cost-effectiveness. First, new HCV reinfections are disproportionally younger individuals often with complex psychosocial issues that impact retention in treatment. An 8-week course of treatment can be initiated concurrently with substance abuse treatment programs, including intensive outpatient programs and residential treatment programs that are usually at least 28 days. Many of these programs provide aftercare options that would extend the entire course of treatment. These opportunities afford individuals to receive HCV treatment in a setting that supports medication adherence, sobriety efforts, and education on harm reduction to reduce risk for reinfection.
Finally, statistical models indicate eradication of HCV will require scaling up the treatment of PWID in conjunction with harm reduction strategies such as OST and needle exchange programs.16 In contrast, there are low risks associated with retreatment given these medications are well-tolerated, treatment of PWID lowers the risk of further HCV transmission, and the understanding of these reinfections being treatment naïve disavows concerns of these patients having resistance to regimens that cleared their prior infections. The opportunity to provide retreatment without escalating regimen complexity or cost increases access to care for a vulnerable population while aiding in the eradication of HCV.
To decrease the incidence and prevalence of hepatitis C virus (HCV) in the United States, hepatology experts, public health officials, and patient advocates agree that linkage to care is essential for treatment of people who inject drugs (PWID). The most recent surveillance report from the Centers for Disease Control and Prevention (CDC) estimates that injection drug use accounts for the transmission of approximately 72% of new HCV infections.1,2
Although recent studies of direct-acting antiviral (DAA) agents have not been designed to investigate the long-term rates of reinfection in this population, various population-based studies in multiple countries have attempted to describe the rate of reinfection for this cohort.3-7 This rate varies widely based on the defined population of PWID, definition of reinfection, and the prevalence of HCV in a given PWID population. However, studies have consistently shown a relatively low historic rate of reinfection, which varies from 1 to 5 per 100 person-years in patients who have ever injected drugs, to 3 to 33 per 100 person-years in patients who continue injection drug use (IDU). Higher rates are found in those who engage in high-risk behaviors such as needle sharing.3-7 Yet, the US opioid crisis is attributable to a recent rise in both overall incidence and reinfections, highlighting the importance of determining the best treatment strategy for those who become reinfected.1
Current HCV guidelines from the American Association for the Study of Liver Diseases AASLD) and Infectious Diseases Society of America (IDSA) encourage access to retreatment for PWID who become reinfected, stating that new reinfections should follow treatment-naïve therapy recommendations.8 However, to date this recommendation has not been validated by published clinical trials or patient case reports. This is likely due in part both to the small number of reinfections among PWID requiring retreatment and barriers to payment for treatment, particularly for individuals with substance use disorders.9 While this recommendation can be found under the key population section for the “Identification and Management of HCV in People Who Inject Drugs,” health care providers (HCPs) may easily miss this statement if they alternatively refer to the “Treatment-Experienced” section that recommends escalation to either sofosbuvir/velpatasvir/voxilaprevir or glecaprevir/pibrentasvir in patients who are NS5A inhibitor DAA-experienced.8 Anecdotally, the first instinct for many HCPs when considering a treatment regimen for a reinfected patient is to refer to treatment-experienced regimen recommendations rather than appreciating the reinfected virus to be treatment naïve.
A treatment-escalation approach could have the consequence of limiting the number of times a patient could undergo treatment on successive reinfections. Additionally, these retreatment regimens often are more expensive, resulting in further cost barriers for payors approving retreatment for individuals with HCV reinfection. In contrast, demonstrating efficacy of a less costly short-course regimen would support increased access to initial and retreatment courses for PWID. The implications of enabling improved access to care is essential in the setting of the ongoing opioid epidemic in the United States.
Given the perspective that the virus should be considered treatment naïve for patients who become reinfected, we describe here 3 cases of patients previously achieving sustained virologic response (SVR) being retreated with the cost-effective 8-week regimen of ledipasvir/sofosbuvir following reinfection.
Case Reports
Case 1
A 59-year-old male presented for his third treatment course for HCV genotype 1a. The patient initially underwent 76 weeks of interferon-based HCV treatment in 2007 and 2008, from which he was determined to have achieved SVR in 24 weeks (SVR24) in April 2009. His viral load remained undetected through February 2010 but subsequently had detectable virus again in 2011 following relapsed use of alcohol, cocaine, and injection drugs. The patient elected to await approval of DAAs and eventually completed an 8-week regimen of ledipasvir/sofosbuvir from May to July 2016, achieving SVR24 in December 2016. The patient’s viral load was rechecked in October 2018 and he was again viremic following recent IDU, suggesting a second reinfection.
In preparation for his third HCV treatment, the patient was included in shared decision making to consider retreating his de novo infection as treatment naïve to provide a briefer (ie, 8 weeks) and more cost-effective treatment given his low likelihood of advanced fibrotic liver disease—his FibroScan score was 6.5 kPa, whereas scores ≥ 12.5 kPa in patients with chronic HCV suggest a higher likelihood of cirrhosis.10 At week 4, the patient’s viral load was undetected, he completed his 8-week regimen of ledipasvir/sofosbuvir as planned and achieved SVR12 (Table). He had reported excellent adherence throughout treatment with assistance of a pill box and validated by a reported pill count.
Case 2
A 32-year-old male presented with HCV genotype 1a. Like case 1, this patient had a low FibroScan score of 4.7 kPa. He was previously infected with genotype 3 and completed a 12-week course of sofosbuvir/velpatasvir in November 2016. He achieved SVR12 as evidenced by an undetected viral load in February 2017 despite questionable adherence throughout and relapsed use of heroin by the end of his regimen. He continued intermittent IDU and presented in October 2018 with a detectable viral load, now with genotype 1a. The patient similarly agreed to undergo an 8-week regimen of ledipasvir/sofosbuvir, considering his de novo infection to be treatment naïve. His viral load at treatment week 3 was quantitatively negative while qualitatively detectable at < 15 U/mL. He completed his treatment course in March 2019 and was determined to have achieved SVR24 in September 2019.
Case 3
A 51-year-old male presented with a history of HCV genotype 1a and a low FibroScan score (4.9 kPa ). The patient was previously infected with genotype 2 and had achieved SVR24 following a 12-week regimen of sofosbuvir/velpatasvir in 2017. The patient subsequently was reinfected with genotype 1a and completed an 8-week course of ledipasvir/sofosbuvir in May 2019. The patient had his SVR12 lab drawn 9 days early and was undetectable at that time. He reported 0 missed doses during treatment and achieved an undetected viral load by treatment week 4.
Discussion
We demonstrate that HCV reinfection after treatment with previous interferon and/or DAA-based regimens can be treated with less costly 8-week treatment regimens. Current guidelines include a statement allowing for reinfected patients to follow initial treatment guidelines, but this statement has previously lacked published evidence and may be overlooked by HCPs who refer to recommendations for treatment-experienced patients. Given the increasing likelihood of HCPs encountering patients who have become reinfected with HCV after achieving SVR from a DAA regimen, further delineation may be needed in the recommendations for treatment-experienced patients to highlight the important nuance of recognizing that reinfections should follow initial treatment guidance.
While all 3 of these cases met criteria for the least costly and simplest 1 pill once daily 8-week regimen of ledipasvir/sofosbuvir, patients requiring retreatment with alternative genotypes or evidence of advanced fibrotic liver disease could benefit from a similar approach of using the least expensive and/or shortest duration regimen for which they meet eligibility. With this approach, coverage could be further expanded to the PWID population to help limit HCV transmission amid the opioid crisis.1
Studies have established that PWID are able to achieve similar SVR efficacy rates similar to that of the general population when treated in the setting of an interdisciplinary treatment team that offers collaborative management of complex psychosocial comorbidities and harm reduction strategies.11,12 These integrative patient-centric strategies may include personalized behavioral health pretreatment evaluations, access to substance use treatment, harm reduction counseling, needle exchange programs, and close follow-up by a case manager.2,13 Current DAA regimens combined with 1 or more of these strategies have demonstrated SVR12 rates of 90 to 95% for initial treatment regimens.11 These high SVR12 rates were even achieved in a recent study in which 74% (76/103) of participants had self-reported IDU within 30 days of HCV treatment start and similar IDU rates throughout treatment.12 A meta-analysis, including real-world studies of DAA treatment outcomes yielded a pooled SVR of 88% (95% CI, 83‐92%) for recent PWID and 91% (95% CI, 88‐95%) for individuals using opiate substitution therapy (OST).14 Additionally, linking PWID with OST also reduces risk for reinfection.14,15
For any patient with detectable HCV after completing the initial DAA regimen, it is important to distinguish between relapse and reinfection. SVR12 is generally synonymous with a clinical cure. Patients with ongoing risk factors posttreatment should continue to have their HCV viral load monitored for evidence of reinfection. Patients without known risk factors may benefit from repeat viral load only if there is clinical concern for reinfection, for example, a rise in liver enzymes.
We have shown that patients with ongoing risk factors who are reinfected can be treated successfully with cost-effective 8-week regimens. For comparison this 8-week regimen of ledipasvir/sofosbuvir has an average wholesale price (AWP) of $28,800, while alternative regimens approved for treatment-naïve patients vary in AWP from $31,680 to $43,200, and regimens approved for retreatment of DAA failures have an AWP as high as $89,712.
An 8-week treatment regimen for both initial and reinfection regimens affords many advantages in medication adherence and both medication and provider resource cost-effectiveness. First, new HCV reinfections are disproportionally younger individuals often with complex psychosocial issues that impact retention in treatment. An 8-week course of treatment can be initiated concurrently with substance abuse treatment programs, including intensive outpatient programs and residential treatment programs that are usually at least 28 days. Many of these programs provide aftercare options that would extend the entire course of treatment. These opportunities afford individuals to receive HCV treatment in a setting that supports medication adherence, sobriety efforts, and education on harm reduction to reduce risk for reinfection.
Finally, statistical models indicate eradication of HCV will require scaling up the treatment of PWID in conjunction with harm reduction strategies such as OST and needle exchange programs.16 In contrast, there are low risks associated with retreatment given these medications are well-tolerated, treatment of PWID lowers the risk of further HCV transmission, and the understanding of these reinfections being treatment naïve disavows concerns of these patients having resistance to regimens that cleared their prior infections. The opportunity to provide retreatment without escalating regimen complexity or cost increases access to care for a vulnerable population while aiding in the eradication of HCV.
1. Centers for Disease Control and Prevention. Viral Hepatitis Surveillance - United States, 2018. Updated August 28, 2020. Accessed May 18, 2021. https://www.cdc.gov/hepatitis/statistics/2018surveillance/HepC.htm 2. Grebely J, Robaeys G, Bruggmann P, et al; International Network for Hepatitis in Substance Users. Recommendations for the management of hepatitis C virus infection among people who inject drugs. Int J Drug Policy. 2015;26(10):1028-1038. doi:10.1016/j.drugpo.2015.07.005
3. Marco A, Esteban JI, Solé C, et al. Hepatitis C virus reinfection among prisoners with sustained virological response after treatment for chronic hepatitis C. J Hepatol. 2013;59(1):45-51. doi:10.1016/j.jhep.2013.03.008
4. Midgard H, Bjøro B, Mæland A, et al. Hepatitis C reinfection after sustained virological response. J Hepatol. 2016;64(5):1020-1026. doi:10.1016/j.jhep.2016.01.001
5. Currie SL, Ryan JC, Tracy D, et al. A prospective study to examine persistent HCV reinfection in injection drug users who have previously cleared the virus [published correction appears in Drug Alcohol Depend. 2008 Jul;96(1-2):192]. Drug Alcohol Depend. 2008;93(1-2):148-154. doi:10.1016/j.drugalcdep.2007.09.011
6. Grady BP, Vanhommerig JW, Schinkel J, et al. Low incidence of reinfection with the hepatitis C virus following treatment in active drug users in Amsterdam. Eur J Gastroenterol Hepatol. 2012;24(11):1302-1307. doi:10.1097/MEG.0b013e32835702a8
7. Grebely J, Pham ST, Matthews GV, et al; ATAHC Study Group. Hepatitis C virus reinfection and superinfection among treated and untreated participants with recent infection. Hepatology. 2012;55(4):1058-1069. doi:10.1002/hep.24754
8. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Accessed May 26, 2021. https://www.hcvguidelines.org
9. National Viral Hepatitis Roundtable, Center for Health Law and Policy Innovation, Harvard Law School. Hepatitis C: The State of Medicaid Access. 2017 National Summary Report. Updated October 23, 2017. Accessed May 26, 2021. https://hepcstage.wpengine.com/wp-content/uploads/2017/10/State-of-HepC_2017_FINAL.pdf
10. Singh S, Muir AJ, Dieterich DT, Falck-Ytter YT. American Gastroenterological Association Institute technical review on the role of elastography in chronic liver diseases. Gastroenterology. 2017;152(6):1544-1577. doi:10.1053/j.gastro.2017.03.016
11. Dore GJ, Altice F, Litwin AH, et al; C-EDGE CO-STAR Study Group. Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial. Ann Intern Med. 2016;165(9):625-634. doi:10.7326/M16-0816
12. Grebely J, Dalgard O, Conway B, et al; SIMPLIFY Study Group. Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open-label, single-arm, phase 4, multicentre trial. Lancet Gastroenterol Hepatol. 2018;3(3):153-161. doi:10.1016/S2468-1253(17)30404-1
13. Cos TA, Bartholomew TS, Huynh, KJ. Role of behavioral health providers in treating hepatitis C. Professional Psychol Res Pract. 2019;50(4):246–254. doi:10.1037/pro0000243
14. Latham NH, Doyle JS, Palmer AY, et al. Staying hepatitis C negative: a systematic review and meta-analysis of cure and reinfection in people who inject drugs. Liver Int. 2019;39(12):2244-2260. doi:10.1111/liv.14152
15. Platt L, Minozzi S, Reed J, et al. Needle syringe programmes and opioid substitution therapy for preventing hepatitis C transmission in people who inject drugs. Cochrane Database Syst Rev. 2017;9(9):CD012021. Published 2017 Sep 18. doi:10.1002/14651858.CD012021.pub2
16. Fraser H, Martin NK, Brummer-Korvenkontio H, et al. Model projections on the impact of HCV treatment in the prevention of HCV transmission among people who inject drugs in Europe. J Hepatol. 2018;68(3):402-411. doi:10.1016/j.jhep.2017.10.010
1. Centers for Disease Control and Prevention. Viral Hepatitis Surveillance - United States, 2018. Updated August 28, 2020. Accessed May 18, 2021. https://www.cdc.gov/hepatitis/statistics/2018surveillance/HepC.htm 2. Grebely J, Robaeys G, Bruggmann P, et al; International Network for Hepatitis in Substance Users. Recommendations for the management of hepatitis C virus infection among people who inject drugs. Int J Drug Policy. 2015;26(10):1028-1038. doi:10.1016/j.drugpo.2015.07.005
3. Marco A, Esteban JI, Solé C, et al. Hepatitis C virus reinfection among prisoners with sustained virological response after treatment for chronic hepatitis C. J Hepatol. 2013;59(1):45-51. doi:10.1016/j.jhep.2013.03.008
4. Midgard H, Bjøro B, Mæland A, et al. Hepatitis C reinfection after sustained virological response. J Hepatol. 2016;64(5):1020-1026. doi:10.1016/j.jhep.2016.01.001
5. Currie SL, Ryan JC, Tracy D, et al. A prospective study to examine persistent HCV reinfection in injection drug users who have previously cleared the virus [published correction appears in Drug Alcohol Depend. 2008 Jul;96(1-2):192]. Drug Alcohol Depend. 2008;93(1-2):148-154. doi:10.1016/j.drugalcdep.2007.09.011
6. Grady BP, Vanhommerig JW, Schinkel J, et al. Low incidence of reinfection with the hepatitis C virus following treatment in active drug users in Amsterdam. Eur J Gastroenterol Hepatol. 2012;24(11):1302-1307. doi:10.1097/MEG.0b013e32835702a8
7. Grebely J, Pham ST, Matthews GV, et al; ATAHC Study Group. Hepatitis C virus reinfection and superinfection among treated and untreated participants with recent infection. Hepatology. 2012;55(4):1058-1069. doi:10.1002/hep.24754
8. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Accessed May 26, 2021. https://www.hcvguidelines.org
9. National Viral Hepatitis Roundtable, Center for Health Law and Policy Innovation, Harvard Law School. Hepatitis C: The State of Medicaid Access. 2017 National Summary Report. Updated October 23, 2017. Accessed May 26, 2021. https://hepcstage.wpengine.com/wp-content/uploads/2017/10/State-of-HepC_2017_FINAL.pdf
10. Singh S, Muir AJ, Dieterich DT, Falck-Ytter YT. American Gastroenterological Association Institute technical review on the role of elastography in chronic liver diseases. Gastroenterology. 2017;152(6):1544-1577. doi:10.1053/j.gastro.2017.03.016
11. Dore GJ, Altice F, Litwin AH, et al; C-EDGE CO-STAR Study Group. Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial. Ann Intern Med. 2016;165(9):625-634. doi:10.7326/M16-0816
12. Grebely J, Dalgard O, Conway B, et al; SIMPLIFY Study Group. Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open-label, single-arm, phase 4, multicentre trial. Lancet Gastroenterol Hepatol. 2018;3(3):153-161. doi:10.1016/S2468-1253(17)30404-1
13. Cos TA, Bartholomew TS, Huynh, KJ. Role of behavioral health providers in treating hepatitis C. Professional Psychol Res Pract. 2019;50(4):246–254. doi:10.1037/pro0000243
14. Latham NH, Doyle JS, Palmer AY, et al. Staying hepatitis C negative: a systematic review and meta-analysis of cure and reinfection in people who inject drugs. Liver Int. 2019;39(12):2244-2260. doi:10.1111/liv.14152
15. Platt L, Minozzi S, Reed J, et al. Needle syringe programmes and opioid substitution therapy for preventing hepatitis C transmission in people who inject drugs. Cochrane Database Syst Rev. 2017;9(9):CD012021. Published 2017 Sep 18. doi:10.1002/14651858.CD012021.pub2
16. Fraser H, Martin NK, Brummer-Korvenkontio H, et al. Model projections on the impact of HCV treatment in the prevention of HCV transmission among people who inject drugs in Europe. J Hepatol. 2018;68(3):402-411. doi:10.1016/j.jhep.2017.10.010
Significant HbA1c Lowering in Patients Achieving a Hepatitis C Virus Cure (FULL)
The immediate clinically significant reduction in hemoglobin A1c following HCV treatment observed in this study contrasts with the expected rise seen with normal disease progression.
According to estimates, between 2.7 and 3.9 million people are infected with hepatitis C virus (HCV) in the US, with worldwide infection estimated to be about 185 million people.1-3 The majority of patients infected with HCV develop a chronic infection, which is the leading cause of liver-related complications in the Western world, including cirrhosis, hepatocellular carcinoma, and the need for liver transplantation.4 In addition to the direct effects HCV has on the liver, extrahepatic complications can occur, often related to the immune-mediated mechanism of cryoglobulinemia, such as vasculitis, renal disease, and palpable purpura. Additionally, > 70 studies globally have associated HCV with insulin resistance and worsening glycemic control.5,6
The prevalence of patients infected with HCV that have comorbid type 2 diabetes mellitus (T2DM) is estimated to be about 30%.7,8 The landmark cross-sectional National Health and Nutrition Examination Survey III study found the prevalence of T2DM among HCV patients in the US aged > 40 years to be about 3-fold higher than those without HCV.9 These findings were further supported by a Taiwanese prospective community-based cohort study that found a higher incidence of T2DM in HCV-positive patients compared with HCV negative patients (hazard ratio [HR], 1.7; 95% CI, 1.3-2.1).10 This relationship appears to be separate from the diabetogenic effect of cirrhosis itself as a significantly higher prevalence of DM has been observed in people with HCV when compared with people with cirrhosis due to other etiologies.11 Although the mechanism for this relationship is not fully understood and is likely multifactorial, it is believed to primarily be an effect of the HCV core protein increasing phosphorylation of insulin receptor substrate-1.6,12,13 The increased presence of the inflammatory cytokine, tumor necrosis factor-α, is also believed to play a role in the effects on insulinreceptor substrate-1 as well as mediating hepatic insulin resistance, stimulating lipolysis, down-regulating peroxisome proliferator-activated receptor-γ, and interfering with β-cell function.14-17
The relationship between HCV and T2DM has been further established by measured improvements in insulin resistance among patients undergoing HCV treatment with the pre-2011 standard of care—peginterferon and ribavirin.Kawaguchi and colleagues found sustained treatment responders to have a significant decrease in both the homeostatic model assessment-insulin resistance (HOMA-IR) score, representing insulin resistance, and the HOMA-β score, representing β-cell function.18 Improvements in the HOMA-IR score were further validated by Kim and colleagues and a nested cohort within the Hepatitis C Long-term Treatment against Cirrhosis (HALT-C) trial.19,20 Furthermore, Romero-Gómez and colleagues found that patients achieving a cure from HCV treatment defined as a sustained virologic response (SVR) had a nearly 50% reduced risk of impaired fasting glucose or T2DM over a mean posttreatment follow-up of 27 months.21
The recent development of direct-acting antivirals (DAAs) has marked significant HCV treatment advances in terms of efficacy and tolerability, leading current guidelines to emphasize that nearly all patients with HCV would benefit from treatment.22 Despite these guidelines, issues have been documented throughout the US with payors often limiting this costly treatment to only those with advanced fibrotic disease.23 Although the benefits of HCV treatment on reducing liver-related morbidity and mortality may be most appreciated in individuals with advanced fibrotic liver disease, improvements in insulin resistance would suggest potential morbidity and mortality benefits beyond the liver in many more at-risk individuals.24
Increasingly, cases are being reported of new DAA regimens having a significant impact on reducing insulin resistance as demonstrated by marked decreases in antihyperglycemic requirements, fasting blood glucose, and hemoglobin A1c (HbA1c).25-30 One striking case describes a patient being able to de-escalate his regimen from 42 daily units of insulin to a single oral dipeptidyl peptidase-4 inhibitor while maintaining goal HbA1c level over a 2-year time period.31 A database-driven study of veterans found a mean HbA1c drop of 0.37% in its overall included cohort of patients with T2DM who achieved SVR from HCV DAA treatment.32
Despite these data, the individual predictability and variable magnitude of improved insulin resistance based on baseline HbA1c remains unknown. The objective of this study was to assess the impact of HCV treatment with short course DAAs on glucose control in veteran patients with T2DM at a single center.
Methods
This retrospective cohort study was performed at the Department of Veterans Affairs (VA) Northeast Ohio Healthcare System (VANEOHS) in Cleveland. This study received approval from the VANEOHS Institutional Review Board. Retrospective patient data were collected from the Veterans Health Administration (VHA) Computerized Patient Record System (CPRS) electronic health record. Collectively, the VHA has treated > 100,000 patients with DAAs, making it the largest provider of HCV treatment in the US. VANEOHS has treated nearly 2,000 patients with DAAs, rendering it one of the largest single-institution cohorts to be able to examine the effects of HCV treatment on subpopulations, such as patients with T2DM.
Patient Population
Patients were identified using ICD-9/10 codes for T2DM and medication dispense history of hepatitis C DAAs. Patients were included if they had a diagnosis of T2DM, were initiated on a hepatitis C DAA between February 1, 2014 to September 26, 2016. To be eligible, patients were required to have both a baseline HbA1c within 6 months prior to starting HCV treatment as well as a HbA1c within 4 months posttreatment. The HCV treatment included were new short-course DAAs, including sofosbuvir, simeprevir, ombitasvir/paritaprevir/ritonavir ± dasabuvir, ledipasvir/sofosbuvir, elbasvir/grazoprevir, and sofosbuvir/velpatasvir. Patients were excluded if they were not on any antihyperglycemic medications at the start of HCV treatment or did not complete a full HCV treatment course.
Baseline Characteristics
Pertinent demographic data collected at baseline included patient age, gender, HCV genotype, and presence of advanced fibrotic liver disease (defined as a Metavir fibrosis stage 4 on liver biopsy, transient elastography > 12.5 kPa, or radiologic evidence of cirrhosis). HCV treatment initiation and completion dates were collected along with treatment response at 12 weeks posttreatment. Patients were considered to have achieved SVR12 if their hepatitis C viral load remained undetectable at posttreatment day 77 or thereafter. Treatment relapse was defined as a patient who achieved an undetectable HCV RNA by the end of treatment but subsequently had detectable HCV RNA following treatment cessation.
Outcome Measures
Baseline HbA1c was defined as the HbA1c drawn closest to the date of HCV treatment initiation, at least 6 months prior to treatment. Immediate posttreatment HbA1c was defined as HbA1c drawn up to 4 months posttreatment, and sustained HbA1c was captured up to 18 months posttreatment. Antihyperglycemic medication regimens and doses were collected at baseline, the end of treatment, and 3 months posttreatment via medication dispense history as well as provider notes documented in CPRS.
The primary endpoint was the change in HbA1c up to 4 months posttreatment in patients achieving SVR12. Secondary endpoints included the sustained change in HbA1c up to 12- and 18-months posttreatment, as well as change in antihyperglycemic medications from baseline to the end of HCV treatment and from baseline to 3 months posttreatment in patients achieving SVR12.
Statistical Analysis
The anticipated sample size after inclusion and exclusion for this study was 160 patients. As HbA1c is a continuous variable and tested prior to treatment and up to 18-months posttreatment, a paired dependent 2-sided t test was used for this study. For a paired dependent t test with an α of 0.05 and a power of 80%, a sample size of 160 would be able to detect a moderately small, but clinically relevant effect size of 0.22. Descriptive statistics were used for secondary outcomes. For categorical data, frequencies and percentages are provided.
Results
A total of 437 patients were identified as having a diagnosis of T2DM and being prescribed a HCV DAA, of which 157 patients met inclusion criteria. The 280 excluded patients included 127 who were not on antihyperglycemics at the start of HCV treatment, 147 who did not have HbA1c data within the specified time frame, 4 were excluded due to delayed treatment initiation outside of the study time period, and 2 self-discontinued HCV treatment due to adverse drug reactions.
Baseline Demographics
The majority of patients were male (96%), primarily African American (56%), with a mean age of 62 years (Table 1). 
Metformin was the most commonly prescribed antihyperglycemic medication (62%), followed by insulin (54%), and sulfonylureas (40%) (Table 2). 
Primary and Secondary Endpoints
There was a significant immediate HbA1c lowering of 0.67% (from 7.67% to 7.00%; P < .001) in patients who achieved SVR12 over a mean of 2-months posttreatment (Figure 1). 
In the overall cohort of patients achieving SVR12, the HbA1c lowering was not sustained at 18 months posttreatment. However, a subanalysis demonstrated that patients with baseline HbA1c ≥ 8%, ≥ 9%, and ≥ 10% had an increasingly larger HbA1c Δ upon HCV treatment completion; the change in HbA1c for these subcohorts did remain significant at sustained time points. Patients with a baseline HbA1c ≥ 8%, ≥ 9%, and ≥ 10%, showed 18-month posttreatment HbA1c decreases of 1.65% (P < .001), 2.28% (P = .004), and 3.63% (P = .003), respectively (Figure 3). 
Of the 8 patients who relapsed, there was a significant decrease in HbA1c of 0.90% from 7.54% to 6.64% (P = .024) at 4 months posttreatment. Of the relapsers who had HbA1c values up to 12 months and 18-months posttreatment, the observed change in HbA1c was 0.61% and 0.2%, respectively. However, the data are limited by its small numbers. One (13%) of the HCV treatment relapsers had an escalation of their antihyperglycemic regimen, while 1 (13%) had a de-escalation, and the remaining 6 (75%) had no change.
Discussion
The immediate reduction in HbA1c following HCV treatment observed in this study of -0.67% is clinically significant and contrasts with the expected rise in HbA1c seen with normal disease progression. The results from this study are comparable to HbA1c reductions seen with certain oral, antihyperglycemic medications, such as DPP-4 inhibitors, meglitinides, and SGLT-2 inhibitors that have an average HbA1c lowering of 0.5% to 1%. This effect was increasingly magnified in patients with a higher baseline HbA1c.
The sustained effect on HbA1c may have not been seen in the overall cohort achieving SVR12 due to the fairly well-controlled mean baseline HbA1c for this older patient cohort. In addition to improvements in HbA1c, one-third of patients achieving SVR12 required de-escalation of concomitant antihyperglycemic medications. The de-escalation of antihyperglycemics may have made the sustained HbA1c impact underappreciated in the overall cohort. There were also limited sustained HbA1c data to evaluate at the time the review was completed.
Despite the clinically significant magnitude of HbA1c change, this study suggests that this effect is not predictable for all patients with DM achieving SVR12 from HCV treatment. Nineteen percent (28/147) of these patients neither had a decrease in their HbA1c nor a de-escalation of their antihyperglycemic treatment. Patients whose T2DM onset preceded or was independent of the diabetogenic effects of HCV may be more likely to have insulin resistance unaffected by hepatitis C viral clearance. Notably, the small number of treatment relapses in this study limits this group’s ability to serve as a comparator. However, one may expect a treatment relapse to have an initial decrease in insulin resistance while the hepatitis C viral load decreases below the level of detectability, yet the effects not be sustained once the HCV relapses.
Of the 35 patients who had their HbA1c decrease to < 6% following HCV treatment, concerningly 29 (83%) had either no change or even had an escalation in their antihyperglycemic regimen. This lack of de-escalation occurred despite 45% (13/29) of these patients continuing insulin posttreatment. These patients may be at a particularly high risk for hypoglycemia. Given the mean age of patients was 62 years, extremely tight glycemic control typically is not the goal for this older patient population with numerous comorbidities and high potential for hypoglycemia unawareness.
This raises concerns that patients with T2DM undergoing HCV treatment experience a new heightened risk of hypoglycemia, particularly if neither patients or providers managing DM are aware of the high potential for decreased antihyperglycemic needs upon achieving hepatitis C virologic response. It is important that these providers are aware of the mean decreased insulin resistance achieved from hepatitis C viral clearance. Providers managing DM should advise frequent serum blood glucose monitoring with close follow-up to allow for medication adjustments to prevent hypoglycemic episodes occurring during and after HCV treatment.
Limitations
The limitations of this study included small sample sizes in subgroups, and the retrospective design prohibited the ability to quantify and describe hypoglycemic events that may have occurred as a result of HCV treatment. In addition, the documentation of medication changes in CPRS may not have fully accounted for adjustments or self-discontinuations of DM medications. An alternative definition for change in antihyperglycemic medications may have accounted for the variable HbA1c-lowering between oral antihyperglycemic medications.
Finally, hemoglobin was not collected to account for any impact ribavirin-associated anemia may have had on the immediate posttreatment HbA1c values. Phase 3 DAA trials have demonstrated that between 7% and 9% of patients on ribavirin-containing DAA regimens are expected to have a hemoglobin < 10 g/dL during the HCV treatment course.33-36 Ribavirin-containing regimens may minimally impact the immediate posttreatment HbA1c result, but not necessarily the 12- or 18-month posttreatment HbA1c levels due to the reversible nature of this adverse effect (AE) following discontinuation of ribavirin.
Future studies may be strengthened by controlling for possible confounders such as concomitant ribavirin, adherence to antihyperglycemic medications, comorbidities, years since initial DM diagnosis, and lifestyle modifications, including a decrease of alcohol consumption. A prospective study also may include data on hypoglycemic events and further determine the sustained response by including an 18- or 24-month posttreatment HbA1c in the protocol.
Conclusion
The findings of this study validate the significant HbA1c changes post-HCV treatment described in the recent veteran database study.32 However, the current study’s validated patient chart data provide a better understanding of the changes made to antihyperglycemic regimens. This also is the first study describing this phenomenon of improved insulin resistance to only be observed in approximately 80% of patients infected with HCV and comorbid T2DM. Furthermore, the variable magnitude of HbA1c impact reliant on baseline HbA1c is informative for individual patient management. In addition to the direct benefits for the liver on hepatitis C viral eradication, improvements in HbA1c and the de-escalation of antihyperglycemic regimens may be a benefit of receiving HCV treatment.
The improved DM control achieved with hepatitis C viral eradication may represent an opportunity to prevent progressive DM and cardiovascular AEs. Additionally, HCV treatment may be able to prevent the onset of T2DM in patients at risk. Arguably HCV treatment has significant benefits in terms of health outcomes, quality of life, and long-term cost avoidance to patients beyond the well-described value of decreasing liver-related morbidity and mortality. This may be an incentive for payers to improve access to HCV DAAs by expanding eligibility criteria beyond those with advanced fibrotic liver disease.
Acknowledgments
This material is the result of work supported with the resources and the use of facilities at the VA Northeast Ohio Healthcare System.
1. Backus LI, Belperio PS, Loomis TP, Yip GH, Mole LA. Hepatitis C virus screening and prevalence among US veterans in Department of Veterans Affairs care. JAMA Intern Med. 2013;173(16):1549-1552.
2. Edlin BR, Eckhardt BJ, Shu MA, Holmberg SD, Swan T. Toward a more accurate estimate of the prevalence of hepatitis C in the United States. Hepatology. 2015;62(5):1353-1363.
3. World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. http://www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/. Published April 2014. Accessed January 24, 2019.
4. Antonelli A, Ferri C, Galeazzi C, et al. HCV infection: pathogenesis, clinical manifestations and therapy. Clin Exp Rheumatol. 2008;26(1)(suppl 48):S39-S47.
5. Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond the liver. Clin Gastroenterol Hepatol. 2010;8(12):1017-1029.
6. Antonelli A, Ferrari SM, Giuggioli D, et al. Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. World J Diabetes. 2014;5(5):586-600.
7. Knobler H, Schihmanter R, Zifroni A, Fenakel G, Schattner A. Increased risk of type 2 diabetes mellitus in non-cirrhotic patients with hepatitis C. Mayo Clin Proc. 2000;75(4):355-359.
8. Hammerstad SS, Grock SF, Lee HJ, Hasham A, Sundaram N, Tomer Y. Diabetes and hepatitis C: a two-way association. Front Endocrinol (Lausanne). 2015;6:134.
9. Mehta SH, Brancati FI, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Interns Med. 2000;133(8):592-599.
10. Wang CS, Wang ST, Yao WJ, Chang TT, Chou P. Hepatitis C virus infection and the development of type 2 diabetes in a community-based longitudinal study. Am J Epidemiol. 2007;166(2):196-203.
11. Allison ME, Wreghitt T, Palmer CR, Alexander GJ. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol. 1994;21(6):1135-1139.
12. Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165(5):1499-1508.
13. Negro F, Alaei M. Hepatitis C virus and type 2 diabetes. World J Gastroenterol. 2009;15(13):1537-1547.
14. Knobler H, Schattner A. TNF-α, chronic hepatitis C and diabetes: a novel triad. QJM. 2005;98(1):1-6.
15. Greenberg AS, McDaniel ML. Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes. Eur J Clin Invest. 2002;32(suppl 3):24-34.
16. Ruan H, Lodish HF. Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev. 2003;14(5):447-455.
17. Kralj D, Virovic´ Jukic´ L, Stojsavljevic´ S, Duvnjak M, Smolic´ M, C˘urc˘ic´ IB. Hepatitis C virus, insulin resistance, and steatosis. J Clin Transl Hepatol. 2016;4(1):66-75.
18. Kawaguchi T, Ide T, Taniguchi E, et al. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 2007;102(3):570-576.
19. Kim HJ, Park JH, Park DI, et al. Clearance of HCV by combination therapy of pegylated interferon alpha-2a and ribavirin improves insulin resistance. Gut Liver. 2009;3(2):108-115.
20. Delgado-Borrego A, Jordan SH, Negre B, et al; Halt-C Trial Group. Reduction of insulin resistance with effective clearance of hepatitis C infection: results from the HALT-C trial. Clin Gastroenterol Hepatol. 2010;8(5):458-462.
21. Romero-Gómez M, Fernández-Rodríguez CM, Andrade RJ, et al. Effect of sustained virologic response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol. 2008;48(5):721-727.
22. American Association for the Study of Liver Disease, Infectious Disease Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Updated May 24, 20187. Accessed January 24, 2019.
23. Barua S, Greenwald R, Grebely J, Dore GJ, Swan T, Taylor LE. Restrictions for Medicaid reimbursement of sofosbuvir for the treatment of hepatitis C virus infection in the United States. Ann Intern Med. 2015;163(3):215-223.
24. Smith-Palmer J, Cerri K, Valentine W. Achieving sustained virologic response in hepatitis C: a systematic review of clinical, economic, and quality of life benefits. BMC Infect Dis. 2015;15:19.
25. Moucari R, Forestier N, Larrey D, et al. Danoprevir, an HCV NS3/4A protease inhibitor, improves insulin sensitivity in patients with genotype 1 chronic hepatitis C. Gut. 2010;59(12):1694-1698.
26. Pedersen MR, Backstedt D, Kakati BR, et al. Sustained virologic response to direct acting antiviral therapy improves components is associated with improvements in the metabolic syndrome. Abstract 1043. Presented at: The 66th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting, October 2015; San Francisco, CA.
27. Doyle MA, Curtis C. Successful hepatitis C antiviral therapy induces remission of type 2 diabetes: a case report. Am J Case Rep. 2015;16:745-750.
28. Pavone P, Tieghi T, d’Ettore G, et al. Rapid decline of fasting glucose in HCV diabetic patients treated with direct-acting antiviral agents. Clin Microbiol Infect. 2016;22(5):462.e1-e3.
29. Pashun RA, Shen NT, Jesudian A. Markedly improved glycemic control in poorly controlled type 2 diabetes following direct acting antiviral treatment of genotype 1 hepatitis C. Case Reports Hepatol. 2016:7807921.
30. Stine JG, Wynter JA, Niccum B, Kelly V, Caldwell SH, Shah NL. Effect of treatment with direct acting antiviral on glycemic control in patients with diabetes mellitus and chronic hepatitis C. Ann Hepatol. 2017;16(2):215-220.
31. Davis TME, Davis WA, Jeffrey G. Successful withdrawal of insulin therapy after post-treatment clearance of hepatitis C virus in a man with type 2 diabetes. Am J Case Rep. 2017;18:414-417.
32. Hum J, Jou JH, Green PK, et al. Improvement in glycemic control of type 2 diabetes after successful treatment of hepatitis C virus. Diabetes Care. 2017;40(9):1173-1180.
33. Afdhal N, Zeuzem S, Kwo P, et al; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-1898.
34. Afdhal N, Reddy R, Nelson DR, et al; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014:370 (16):1483-1493.
35. Ferenci P, Bernstein D, Lalezari J, et al; PEARL-III Study; PEARL-IV Study. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370(21):1983-1992.
36. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370(21):1973-1982.
The immediate clinically significant reduction in hemoglobin A1c following HCV treatment observed in this study contrasts with the expected rise seen with normal disease progression.
The immediate clinically significant reduction in hemoglobin A1c following HCV treatment observed in this study contrasts with the expected rise seen with normal disease progression.
According to estimates, between 2.7 and 3.9 million people are infected with hepatitis C virus (HCV) in the US, with worldwide infection estimated to be about 185 million people.1-3 The majority of patients infected with HCV develop a chronic infection, which is the leading cause of liver-related complications in the Western world, including cirrhosis, hepatocellular carcinoma, and the need for liver transplantation.4 In addition to the direct effects HCV has on the liver, extrahepatic complications can occur, often related to the immune-mediated mechanism of cryoglobulinemia, such as vasculitis, renal disease, and palpable purpura. Additionally, > 70 studies globally have associated HCV with insulin resistance and worsening glycemic control.5,6
The prevalence of patients infected with HCV that have comorbid type 2 diabetes mellitus (T2DM) is estimated to be about 30%.7,8 The landmark cross-sectional National Health and Nutrition Examination Survey III study found the prevalence of T2DM among HCV patients in the US aged > 40 years to be about 3-fold higher than those without HCV.9 These findings were further supported by a Taiwanese prospective community-based cohort study that found a higher incidence of T2DM in HCV-positive patients compared with HCV negative patients (hazard ratio [HR], 1.7; 95% CI, 1.3-2.1).10 This relationship appears to be separate from the diabetogenic effect of cirrhosis itself as a significantly higher prevalence of DM has been observed in people with HCV when compared with people with cirrhosis due to other etiologies.11 Although the mechanism for this relationship is not fully understood and is likely multifactorial, it is believed to primarily be an effect of the HCV core protein increasing phosphorylation of insulin receptor substrate-1.6,12,13 The increased presence of the inflammatory cytokine, tumor necrosis factor-α, is also believed to play a role in the effects on insulinreceptor substrate-1 as well as mediating hepatic insulin resistance, stimulating lipolysis, down-regulating peroxisome proliferator-activated receptor-γ, and interfering with β-cell function.14-17
The relationship between HCV and T2DM has been further established by measured improvements in insulin resistance among patients undergoing HCV treatment with the pre-2011 standard of care—peginterferon and ribavirin.Kawaguchi and colleagues found sustained treatment responders to have a significant decrease in both the homeostatic model assessment-insulin resistance (HOMA-IR) score, representing insulin resistance, and the HOMA-β score, representing β-cell function.18 Improvements in the HOMA-IR score were further validated by Kim and colleagues and a nested cohort within the Hepatitis C Long-term Treatment against Cirrhosis (HALT-C) trial.19,20 Furthermore, Romero-Gómez and colleagues found that patients achieving a cure from HCV treatment defined as a sustained virologic response (SVR) had a nearly 50% reduced risk of impaired fasting glucose or T2DM over a mean posttreatment follow-up of 27 months.21
The recent development of direct-acting antivirals (DAAs) has marked significant HCV treatment advances in terms of efficacy and tolerability, leading current guidelines to emphasize that nearly all patients with HCV would benefit from treatment.22 Despite these guidelines, issues have been documented throughout the US with payors often limiting this costly treatment to only those with advanced fibrotic disease.23 Although the benefits of HCV treatment on reducing liver-related morbidity and mortality may be most appreciated in individuals with advanced fibrotic liver disease, improvements in insulin resistance would suggest potential morbidity and mortality benefits beyond the liver in many more at-risk individuals.24
Increasingly, cases are being reported of new DAA regimens having a significant impact on reducing insulin resistance as demonstrated by marked decreases in antihyperglycemic requirements, fasting blood glucose, and hemoglobin A1c (HbA1c).25-30 One striking case describes a patient being able to de-escalate his regimen from 42 daily units of insulin to a single oral dipeptidyl peptidase-4 inhibitor while maintaining goal HbA1c level over a 2-year time period.31 A database-driven study of veterans found a mean HbA1c drop of 0.37% in its overall included cohort of patients with T2DM who achieved SVR from HCV DAA treatment.32
Despite these data, the individual predictability and variable magnitude of improved insulin resistance based on baseline HbA1c remains unknown. The objective of this study was to assess the impact of HCV treatment with short course DAAs on glucose control in veteran patients with T2DM at a single center.
Methods
This retrospective cohort study was performed at the Department of Veterans Affairs (VA) Northeast Ohio Healthcare System (VANEOHS) in Cleveland. This study received approval from the VANEOHS Institutional Review Board. Retrospective patient data were collected from the Veterans Health Administration (VHA) Computerized Patient Record System (CPRS) electronic health record. Collectively, the VHA has treated > 100,000 patients with DAAs, making it the largest provider of HCV treatment in the US. VANEOHS has treated nearly 2,000 patients with DAAs, rendering it one of the largest single-institution cohorts to be able to examine the effects of HCV treatment on subpopulations, such as patients with T2DM.
Patient Population
Patients were identified using ICD-9/10 codes for T2DM and medication dispense history of hepatitis C DAAs. Patients were included if they had a diagnosis of T2DM, were initiated on a hepatitis C DAA between February 1, 2014 to September 26, 2016. To be eligible, patients were required to have both a baseline HbA1c within 6 months prior to starting HCV treatment as well as a HbA1c within 4 months posttreatment. The HCV treatment included were new short-course DAAs, including sofosbuvir, simeprevir, ombitasvir/paritaprevir/ritonavir ± dasabuvir, ledipasvir/sofosbuvir, elbasvir/grazoprevir, and sofosbuvir/velpatasvir. Patients were excluded if they were not on any antihyperglycemic medications at the start of HCV treatment or did not complete a full HCV treatment course.
Baseline Characteristics
Pertinent demographic data collected at baseline included patient age, gender, HCV genotype, and presence of advanced fibrotic liver disease (defined as a Metavir fibrosis stage 4 on liver biopsy, transient elastography > 12.5 kPa, or radiologic evidence of cirrhosis). HCV treatment initiation and completion dates were collected along with treatment response at 12 weeks posttreatment. Patients were considered to have achieved SVR12 if their hepatitis C viral load remained undetectable at posttreatment day 77 or thereafter. Treatment relapse was defined as a patient who achieved an undetectable HCV RNA by the end of treatment but subsequently had detectable HCV RNA following treatment cessation.
Outcome Measures
Baseline HbA1c was defined as the HbA1c drawn closest to the date of HCV treatment initiation, at least 6 months prior to treatment. Immediate posttreatment HbA1c was defined as HbA1c drawn up to 4 months posttreatment, and sustained HbA1c was captured up to 18 months posttreatment. Antihyperglycemic medication regimens and doses were collected at baseline, the end of treatment, and 3 months posttreatment via medication dispense history as well as provider notes documented in CPRS.
The primary endpoint was the change in HbA1c up to 4 months posttreatment in patients achieving SVR12. Secondary endpoints included the sustained change in HbA1c up to 12- and 18-months posttreatment, as well as change in antihyperglycemic medications from baseline to the end of HCV treatment and from baseline to 3 months posttreatment in patients achieving SVR12.
Statistical Analysis
The anticipated sample size after inclusion and exclusion for this study was 160 patients. As HbA1c is a continuous variable and tested prior to treatment and up to 18-months posttreatment, a paired dependent 2-sided t test was used for this study. For a paired dependent t test with an α of 0.05 and a power of 80%, a sample size of 160 would be able to detect a moderately small, but clinically relevant effect size of 0.22. Descriptive statistics were used for secondary outcomes. For categorical data, frequencies and percentages are provided.
Results
A total of 437 patients were identified as having a diagnosis of T2DM and being prescribed a HCV DAA, of which 157 patients met inclusion criteria. The 280 excluded patients included 127 who were not on antihyperglycemics at the start of HCV treatment, 147 who did not have HbA1c data within the specified time frame, 4 were excluded due to delayed treatment initiation outside of the study time period, and 2 self-discontinued HCV treatment due to adverse drug reactions.
Baseline Demographics
The majority of patients were male (96%), primarily African American (56%), with a mean age of 62 years (Table 1).
Metformin was the most commonly prescribed antihyperglycemic medication (62%), followed by insulin (54%), and sulfonylureas (40%) (Table 2).
Primary and Secondary Endpoints
There was a significant immediate HbA1c lowering of 0.67% (from 7.67% to 7.00%; P < .001) in patients who achieved SVR12 over a mean of 2-months posttreatment (Figure 1).
In the overall cohort of patients achieving SVR12, the HbA1c lowering was not sustained at 18 months posttreatment. However, a subanalysis demonstrated that patients with baseline HbA1c ≥ 8%, ≥ 9%, and ≥ 10% had an increasingly larger HbA1c Δ upon HCV treatment completion; the change in HbA1c for these subcohorts did remain significant at sustained time points. Patients with a baseline HbA1c ≥ 8%, ≥ 9%, and ≥ 10%, showed 18-month posttreatment HbA1c decreases of 1.65% (P < .001), 2.28% (P = .004), and 3.63% (P = .003), respectively (Figure 3).
Of the 8 patients who relapsed, there was a significant decrease in HbA1c of 0.90% from 7.54% to 6.64% (P = .024) at 4 months posttreatment. Of the relapsers who had HbA1c values up to 12 months and 18-months posttreatment, the observed change in HbA1c was 0.61% and 0.2%, respectively. However, the data are limited by its small numbers. One (13%) of the HCV treatment relapsers had an escalation of their antihyperglycemic regimen, while 1 (13%) had a de-escalation, and the remaining 6 (75%) had no change.
Discussion
The immediate reduction in HbA1c following HCV treatment observed in this study of -0.67% is clinically significant and contrasts with the expected rise in HbA1c seen with normal disease progression. The results from this study are comparable to HbA1c reductions seen with certain oral, antihyperglycemic medications, such as DPP-4 inhibitors, meglitinides, and SGLT-2 inhibitors that have an average HbA1c lowering of 0.5% to 1%. This effect was increasingly magnified in patients with a higher baseline HbA1c.
The sustained effect on HbA1c may have not been seen in the overall cohort achieving SVR12 due to the fairly well-controlled mean baseline HbA1c for this older patient cohort. In addition to improvements in HbA1c, one-third of patients achieving SVR12 required de-escalation of concomitant antihyperglycemic medications. The de-escalation of antihyperglycemics may have made the sustained HbA1c impact underappreciated in the overall cohort. There were also limited sustained HbA1c data to evaluate at the time the review was completed.
Despite the clinically significant magnitude of HbA1c change, this study suggests that this effect is not predictable for all patients with DM achieving SVR12 from HCV treatment. Nineteen percent (28/147) of these patients neither had a decrease in their HbA1c nor a de-escalation of their antihyperglycemic treatment. Patients whose T2DM onset preceded or was independent of the diabetogenic effects of HCV may be more likely to have insulin resistance unaffected by hepatitis C viral clearance. Notably, the small number of treatment relapses in this study limits this group’s ability to serve as a comparator. However, one may expect a treatment relapse to have an initial decrease in insulin resistance while the hepatitis C viral load decreases below the level of detectability, yet the effects not be sustained once the HCV relapses.
Of the 35 patients who had their HbA1c decrease to < 6% following HCV treatment, concerningly 29 (83%) had either no change or even had an escalation in their antihyperglycemic regimen. This lack of de-escalation occurred despite 45% (13/29) of these patients continuing insulin posttreatment. These patients may be at a particularly high risk for hypoglycemia. Given the mean age of patients was 62 years, extremely tight glycemic control typically is not the goal for this older patient population with numerous comorbidities and high potential for hypoglycemia unawareness.
This raises concerns that patients with T2DM undergoing HCV treatment experience a new heightened risk of hypoglycemia, particularly if neither patients or providers managing DM are aware of the high potential for decreased antihyperglycemic needs upon achieving hepatitis C virologic response. It is important that these providers are aware of the mean decreased insulin resistance achieved from hepatitis C viral clearance. Providers managing DM should advise frequent serum blood glucose monitoring with close follow-up to allow for medication adjustments to prevent hypoglycemic episodes occurring during and after HCV treatment.
Limitations
The limitations of this study included small sample sizes in subgroups, and the retrospective design prohibited the ability to quantify and describe hypoglycemic events that may have occurred as a result of HCV treatment. In addition, the documentation of medication changes in CPRS may not have fully accounted for adjustments or self-discontinuations of DM medications. An alternative definition for change in antihyperglycemic medications may have accounted for the variable HbA1c-lowering between oral antihyperglycemic medications.
Finally, hemoglobin was not collected to account for any impact ribavirin-associated anemia may have had on the immediate posttreatment HbA1c values. Phase 3 DAA trials have demonstrated that between 7% and 9% of patients on ribavirin-containing DAA regimens are expected to have a hemoglobin < 10 g/dL during the HCV treatment course.33-36 Ribavirin-containing regimens may minimally impact the immediate posttreatment HbA1c result, but not necessarily the 12- or 18-month posttreatment HbA1c levels due to the reversible nature of this adverse effect (AE) following discontinuation of ribavirin.
Future studies may be strengthened by controlling for possible confounders such as concomitant ribavirin, adherence to antihyperglycemic medications, comorbidities, years since initial DM diagnosis, and lifestyle modifications, including a decrease of alcohol consumption. A prospective study also may include data on hypoglycemic events and further determine the sustained response by including an 18- or 24-month posttreatment HbA1c in the protocol.
Conclusion
The findings of this study validate the significant HbA1c changes post-HCV treatment described in the recent veteran database study.32 However, the current study’s validated patient chart data provide a better understanding of the changes made to antihyperglycemic regimens. This also is the first study describing this phenomenon of improved insulin resistance to only be observed in approximately 80% of patients infected with HCV and comorbid T2DM. Furthermore, the variable magnitude of HbA1c impact reliant on baseline HbA1c is informative for individual patient management. In addition to the direct benefits for the liver on hepatitis C viral eradication, improvements in HbA1c and the de-escalation of antihyperglycemic regimens may be a benefit of receiving HCV treatment.
The improved DM control achieved with hepatitis C viral eradication may represent an opportunity to prevent progressive DM and cardiovascular AEs. Additionally, HCV treatment may be able to prevent the onset of T2DM in patients at risk. Arguably HCV treatment has significant benefits in terms of health outcomes, quality of life, and long-term cost avoidance to patients beyond the well-described value of decreasing liver-related morbidity and mortality. This may be an incentive for payers to improve access to HCV DAAs by expanding eligibility criteria beyond those with advanced fibrotic liver disease.
Acknowledgments
This material is the result of work supported with the resources and the use of facilities at the VA Northeast Ohio Healthcare System.
According to estimates, between 2.7 and 3.9 million people are infected with hepatitis C virus (HCV) in the US, with worldwide infection estimated to be about 185 million people.1-3 The majority of patients infected with HCV develop a chronic infection, which is the leading cause of liver-related complications in the Western world, including cirrhosis, hepatocellular carcinoma, and the need for liver transplantation.4 In addition to the direct effects HCV has on the liver, extrahepatic complications can occur, often related to the immune-mediated mechanism of cryoglobulinemia, such as vasculitis, renal disease, and palpable purpura. Additionally, > 70 studies globally have associated HCV with insulin resistance and worsening glycemic control.5,6
The prevalence of patients infected with HCV that have comorbid type 2 diabetes mellitus (T2DM) is estimated to be about 30%.7,8 The landmark cross-sectional National Health and Nutrition Examination Survey III study found the prevalence of T2DM among HCV patients in the US aged > 40 years to be about 3-fold higher than those without HCV.9 These findings were further supported by a Taiwanese prospective community-based cohort study that found a higher incidence of T2DM in HCV-positive patients compared with HCV negative patients (hazard ratio [HR], 1.7; 95% CI, 1.3-2.1).10 This relationship appears to be separate from the diabetogenic effect of cirrhosis itself as a significantly higher prevalence of DM has been observed in people with HCV when compared with people with cirrhosis due to other etiologies.11 Although the mechanism for this relationship is not fully understood and is likely multifactorial, it is believed to primarily be an effect of the HCV core protein increasing phosphorylation of insulin receptor substrate-1.6,12,13 The increased presence of the inflammatory cytokine, tumor necrosis factor-α, is also believed to play a role in the effects on insulinreceptor substrate-1 as well as mediating hepatic insulin resistance, stimulating lipolysis, down-regulating peroxisome proliferator-activated receptor-γ, and interfering with β-cell function.14-17
The relationship between HCV and T2DM has been further established by measured improvements in insulin resistance among patients undergoing HCV treatment with the pre-2011 standard of care—peginterferon and ribavirin.Kawaguchi and colleagues found sustained treatment responders to have a significant decrease in both the homeostatic model assessment-insulin resistance (HOMA-IR) score, representing insulin resistance, and the HOMA-β score, representing β-cell function.18 Improvements in the HOMA-IR score were further validated by Kim and colleagues and a nested cohort within the Hepatitis C Long-term Treatment against Cirrhosis (HALT-C) trial.19,20 Furthermore, Romero-Gómez and colleagues found that patients achieving a cure from HCV treatment defined as a sustained virologic response (SVR) had a nearly 50% reduced risk of impaired fasting glucose or T2DM over a mean posttreatment follow-up of 27 months.21
The recent development of direct-acting antivirals (DAAs) has marked significant HCV treatment advances in terms of efficacy and tolerability, leading current guidelines to emphasize that nearly all patients with HCV would benefit from treatment.22 Despite these guidelines, issues have been documented throughout the US with payors often limiting this costly treatment to only those with advanced fibrotic disease.23 Although the benefits of HCV treatment on reducing liver-related morbidity and mortality may be most appreciated in individuals with advanced fibrotic liver disease, improvements in insulin resistance would suggest potential morbidity and mortality benefits beyond the liver in many more at-risk individuals.24
Increasingly, cases are being reported of new DAA regimens having a significant impact on reducing insulin resistance as demonstrated by marked decreases in antihyperglycemic requirements, fasting blood glucose, and hemoglobin A1c (HbA1c).25-30 One striking case describes a patient being able to de-escalate his regimen from 42 daily units of insulin to a single oral dipeptidyl peptidase-4 inhibitor while maintaining goal HbA1c level over a 2-year time period.31 A database-driven study of veterans found a mean HbA1c drop of 0.37% in its overall included cohort of patients with T2DM who achieved SVR from HCV DAA treatment.32
Despite these data, the individual predictability and variable magnitude of improved insulin resistance based on baseline HbA1c remains unknown. The objective of this study was to assess the impact of HCV treatment with short course DAAs on glucose control in veteran patients with T2DM at a single center.
Methods
This retrospective cohort study was performed at the Department of Veterans Affairs (VA) Northeast Ohio Healthcare System (VANEOHS) in Cleveland. This study received approval from the VANEOHS Institutional Review Board. Retrospective patient data were collected from the Veterans Health Administration (VHA) Computerized Patient Record System (CPRS) electronic health record. Collectively, the VHA has treated > 100,000 patients with DAAs, making it the largest provider of HCV treatment in the US. VANEOHS has treated nearly 2,000 patients with DAAs, rendering it one of the largest single-institution cohorts to be able to examine the effects of HCV treatment on subpopulations, such as patients with T2DM.
Patient Population
Patients were identified using ICD-9/10 codes for T2DM and medication dispense history of hepatitis C DAAs. Patients were included if they had a diagnosis of T2DM, were initiated on a hepatitis C DAA between February 1, 2014 to September 26, 2016. To be eligible, patients were required to have both a baseline HbA1c within 6 months prior to starting HCV treatment as well as a HbA1c within 4 months posttreatment. The HCV treatment included were new short-course DAAs, including sofosbuvir, simeprevir, ombitasvir/paritaprevir/ritonavir ± dasabuvir, ledipasvir/sofosbuvir, elbasvir/grazoprevir, and sofosbuvir/velpatasvir. Patients were excluded if they were not on any antihyperglycemic medications at the start of HCV treatment or did not complete a full HCV treatment course.
Baseline Characteristics
Pertinent demographic data collected at baseline included patient age, gender, HCV genotype, and presence of advanced fibrotic liver disease (defined as a Metavir fibrosis stage 4 on liver biopsy, transient elastography > 12.5 kPa, or radiologic evidence of cirrhosis). HCV treatment initiation and completion dates were collected along with treatment response at 12 weeks posttreatment. Patients were considered to have achieved SVR12 if their hepatitis C viral load remained undetectable at posttreatment day 77 or thereafter. Treatment relapse was defined as a patient who achieved an undetectable HCV RNA by the end of treatment but subsequently had detectable HCV RNA following treatment cessation.
Outcome Measures
Baseline HbA1c was defined as the HbA1c drawn closest to the date of HCV treatment initiation, at least 6 months prior to treatment. Immediate posttreatment HbA1c was defined as HbA1c drawn up to 4 months posttreatment, and sustained HbA1c was captured up to 18 months posttreatment. Antihyperglycemic medication regimens and doses were collected at baseline, the end of treatment, and 3 months posttreatment via medication dispense history as well as provider notes documented in CPRS.
The primary endpoint was the change in HbA1c up to 4 months posttreatment in patients achieving SVR12. Secondary endpoints included the sustained change in HbA1c up to 12- and 18-months posttreatment, as well as change in antihyperglycemic medications from baseline to the end of HCV treatment and from baseline to 3 months posttreatment in patients achieving SVR12.
Statistical Analysis
The anticipated sample size after inclusion and exclusion for this study was 160 patients. As HbA1c is a continuous variable and tested prior to treatment and up to 18-months posttreatment, a paired dependent 2-sided t test was used for this study. For a paired dependent t test with an α of 0.05 and a power of 80%, a sample size of 160 would be able to detect a moderately small, but clinically relevant effect size of 0.22. Descriptive statistics were used for secondary outcomes. For categorical data, frequencies and percentages are provided.
Results
A total of 437 patients were identified as having a diagnosis of T2DM and being prescribed a HCV DAA, of which 157 patients met inclusion criteria. The 280 excluded patients included 127 who were not on antihyperglycemics at the start of HCV treatment, 147 who did not have HbA1c data within the specified time frame, 4 were excluded due to delayed treatment initiation outside of the study time period, and 2 self-discontinued HCV treatment due to adverse drug reactions.
Baseline Demographics
The majority of patients were male (96%), primarily African American (56%), with a mean age of 62 years (Table 1).
Metformin was the most commonly prescribed antihyperglycemic medication (62%), followed by insulin (54%), and sulfonylureas (40%) (Table 2).
Primary and Secondary Endpoints
There was a significant immediate HbA1c lowering of 0.67% (from 7.67% to 7.00%; P < .001) in patients who achieved SVR12 over a mean of 2-months posttreatment (Figure 1).
In the overall cohort of patients achieving SVR12, the HbA1c lowering was not sustained at 18 months posttreatment. However, a subanalysis demonstrated that patients with baseline HbA1c ≥ 8%, ≥ 9%, and ≥ 10% had an increasingly larger HbA1c Δ upon HCV treatment completion; the change in HbA1c for these subcohorts did remain significant at sustained time points. Patients with a baseline HbA1c ≥ 8%, ≥ 9%, and ≥ 10%, showed 18-month posttreatment HbA1c decreases of 1.65% (P < .001), 2.28% (P = .004), and 3.63% (P = .003), respectively (Figure 3).
Of the 8 patients who relapsed, there was a significant decrease in HbA1c of 0.90% from 7.54% to 6.64% (P = .024) at 4 months posttreatment. Of the relapsers who had HbA1c values up to 12 months and 18-months posttreatment, the observed change in HbA1c was 0.61% and 0.2%, respectively. However, the data are limited by its small numbers. One (13%) of the HCV treatment relapsers had an escalation of their antihyperglycemic regimen, while 1 (13%) had a de-escalation, and the remaining 6 (75%) had no change.
Discussion
The immediate reduction in HbA1c following HCV treatment observed in this study of -0.67% is clinically significant and contrasts with the expected rise in HbA1c seen with normal disease progression. The results from this study are comparable to HbA1c reductions seen with certain oral, antihyperglycemic medications, such as DPP-4 inhibitors, meglitinides, and SGLT-2 inhibitors that have an average HbA1c lowering of 0.5% to 1%. This effect was increasingly magnified in patients with a higher baseline HbA1c.
The sustained effect on HbA1c may have not been seen in the overall cohort achieving SVR12 due to the fairly well-controlled mean baseline HbA1c for this older patient cohort. In addition to improvements in HbA1c, one-third of patients achieving SVR12 required de-escalation of concomitant antihyperglycemic medications. The de-escalation of antihyperglycemics may have made the sustained HbA1c impact underappreciated in the overall cohort. There were also limited sustained HbA1c data to evaluate at the time the review was completed.
Despite the clinically significant magnitude of HbA1c change, this study suggests that this effect is not predictable for all patients with DM achieving SVR12 from HCV treatment. Nineteen percent (28/147) of these patients neither had a decrease in their HbA1c nor a de-escalation of their antihyperglycemic treatment. Patients whose T2DM onset preceded or was independent of the diabetogenic effects of HCV may be more likely to have insulin resistance unaffected by hepatitis C viral clearance. Notably, the small number of treatment relapses in this study limits this group’s ability to serve as a comparator. However, one may expect a treatment relapse to have an initial decrease in insulin resistance while the hepatitis C viral load decreases below the level of detectability, yet the effects not be sustained once the HCV relapses.
Of the 35 patients who had their HbA1c decrease to < 6% following HCV treatment, concerningly 29 (83%) had either no change or even had an escalation in their antihyperglycemic regimen. This lack of de-escalation occurred despite 45% (13/29) of these patients continuing insulin posttreatment. These patients may be at a particularly high risk for hypoglycemia. Given the mean age of patients was 62 years, extremely tight glycemic control typically is not the goal for this older patient population with numerous comorbidities and high potential for hypoglycemia unawareness.
This raises concerns that patients with T2DM undergoing HCV treatment experience a new heightened risk of hypoglycemia, particularly if neither patients or providers managing DM are aware of the high potential for decreased antihyperglycemic needs upon achieving hepatitis C virologic response. It is important that these providers are aware of the mean decreased insulin resistance achieved from hepatitis C viral clearance. Providers managing DM should advise frequent serum blood glucose monitoring with close follow-up to allow for medication adjustments to prevent hypoglycemic episodes occurring during and after HCV treatment.
Limitations
The limitations of this study included small sample sizes in subgroups, and the retrospective design prohibited the ability to quantify and describe hypoglycemic events that may have occurred as a result of HCV treatment. In addition, the documentation of medication changes in CPRS may not have fully accounted for adjustments or self-discontinuations of DM medications. An alternative definition for change in antihyperglycemic medications may have accounted for the variable HbA1c-lowering between oral antihyperglycemic medications.
Finally, hemoglobin was not collected to account for any impact ribavirin-associated anemia may have had on the immediate posttreatment HbA1c values. Phase 3 DAA trials have demonstrated that between 7% and 9% of patients on ribavirin-containing DAA regimens are expected to have a hemoglobin < 10 g/dL during the HCV treatment course.33-36 Ribavirin-containing regimens may minimally impact the immediate posttreatment HbA1c result, but not necessarily the 12- or 18-month posttreatment HbA1c levels due to the reversible nature of this adverse effect (AE) following discontinuation of ribavirin.
Future studies may be strengthened by controlling for possible confounders such as concomitant ribavirin, adherence to antihyperglycemic medications, comorbidities, years since initial DM diagnosis, and lifestyle modifications, including a decrease of alcohol consumption. A prospective study also may include data on hypoglycemic events and further determine the sustained response by including an 18- or 24-month posttreatment HbA1c in the protocol.
Conclusion
The findings of this study validate the significant HbA1c changes post-HCV treatment described in the recent veteran database study.32 However, the current study’s validated patient chart data provide a better understanding of the changes made to antihyperglycemic regimens. This also is the first study describing this phenomenon of improved insulin resistance to only be observed in approximately 80% of patients infected with HCV and comorbid T2DM. Furthermore, the variable magnitude of HbA1c impact reliant on baseline HbA1c is informative for individual patient management. In addition to the direct benefits for the liver on hepatitis C viral eradication, improvements in HbA1c and the de-escalation of antihyperglycemic regimens may be a benefit of receiving HCV treatment.
The improved DM control achieved with hepatitis C viral eradication may represent an opportunity to prevent progressive DM and cardiovascular AEs. Additionally, HCV treatment may be able to prevent the onset of T2DM in patients at risk. Arguably HCV treatment has significant benefits in terms of health outcomes, quality of life, and long-term cost avoidance to patients beyond the well-described value of decreasing liver-related morbidity and mortality. This may be an incentive for payers to improve access to HCV DAAs by expanding eligibility criteria beyond those with advanced fibrotic liver disease.
Acknowledgments
This material is the result of work supported with the resources and the use of facilities at the VA Northeast Ohio Healthcare System.
1. Backus LI, Belperio PS, Loomis TP, Yip GH, Mole LA. Hepatitis C virus screening and prevalence among US veterans in Department of Veterans Affairs care. JAMA Intern Med. 2013;173(16):1549-1552.
2. Edlin BR, Eckhardt BJ, Shu MA, Holmberg SD, Swan T. Toward a more accurate estimate of the prevalence of hepatitis C in the United States. Hepatology. 2015;62(5):1353-1363.
3. World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. http://www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/. Published April 2014. Accessed January 24, 2019.
4. Antonelli A, Ferri C, Galeazzi C, et al. HCV infection: pathogenesis, clinical manifestations and therapy. Clin Exp Rheumatol. 2008;26(1)(suppl 48):S39-S47.
5. Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond the liver. Clin Gastroenterol Hepatol. 2010;8(12):1017-1029.
6. Antonelli A, Ferrari SM, Giuggioli D, et al. Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. World J Diabetes. 2014;5(5):586-600.
7. Knobler H, Schihmanter R, Zifroni A, Fenakel G, Schattner A. Increased risk of type 2 diabetes mellitus in non-cirrhotic patients with hepatitis C. Mayo Clin Proc. 2000;75(4):355-359.
8. Hammerstad SS, Grock SF, Lee HJ, Hasham A, Sundaram N, Tomer Y. Diabetes and hepatitis C: a two-way association. Front Endocrinol (Lausanne). 2015;6:134.
9. Mehta SH, Brancati FI, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Interns Med. 2000;133(8):592-599.
10. Wang CS, Wang ST, Yao WJ, Chang TT, Chou P. Hepatitis C virus infection and the development of type 2 diabetes in a community-based longitudinal study. Am J Epidemiol. 2007;166(2):196-203.
11. Allison ME, Wreghitt T, Palmer CR, Alexander GJ. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol. 1994;21(6):1135-1139.
12. Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165(5):1499-1508.
13. Negro F, Alaei M. Hepatitis C virus and type 2 diabetes. World J Gastroenterol. 2009;15(13):1537-1547.
14. Knobler H, Schattner A. TNF-α, chronic hepatitis C and diabetes: a novel triad. QJM. 2005;98(1):1-6.
15. Greenberg AS, McDaniel ML. Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes. Eur J Clin Invest. 2002;32(suppl 3):24-34.
16. Ruan H, Lodish HF. Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev. 2003;14(5):447-455.
17. Kralj D, Virovic´ Jukic´ L, Stojsavljevic´ S, Duvnjak M, Smolic´ M, C˘urc˘ic´ IB. Hepatitis C virus, insulin resistance, and steatosis. J Clin Transl Hepatol. 2016;4(1):66-75.
18. Kawaguchi T, Ide T, Taniguchi E, et al. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 2007;102(3):570-576.
19. Kim HJ, Park JH, Park DI, et al. Clearance of HCV by combination therapy of pegylated interferon alpha-2a and ribavirin improves insulin resistance. Gut Liver. 2009;3(2):108-115.
20. Delgado-Borrego A, Jordan SH, Negre B, et al; Halt-C Trial Group. Reduction of insulin resistance with effective clearance of hepatitis C infection: results from the HALT-C trial. Clin Gastroenterol Hepatol. 2010;8(5):458-462.
21. Romero-Gómez M, Fernández-Rodríguez CM, Andrade RJ, et al. Effect of sustained virologic response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol. 2008;48(5):721-727.
22. American Association for the Study of Liver Disease, Infectious Disease Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Updated May 24, 20187. Accessed January 24, 2019.
23. Barua S, Greenwald R, Grebely J, Dore GJ, Swan T, Taylor LE. Restrictions for Medicaid reimbursement of sofosbuvir for the treatment of hepatitis C virus infection in the United States. Ann Intern Med. 2015;163(3):215-223.
24. Smith-Palmer J, Cerri K, Valentine W. Achieving sustained virologic response in hepatitis C: a systematic review of clinical, economic, and quality of life benefits. BMC Infect Dis. 2015;15:19.
25. Moucari R, Forestier N, Larrey D, et al. Danoprevir, an HCV NS3/4A protease inhibitor, improves insulin sensitivity in patients with genotype 1 chronic hepatitis C. Gut. 2010;59(12):1694-1698.
26. Pedersen MR, Backstedt D, Kakati BR, et al. Sustained virologic response to direct acting antiviral therapy improves components is associated with improvements in the metabolic syndrome. Abstract 1043. Presented at: The 66th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting, October 2015; San Francisco, CA.
27. Doyle MA, Curtis C. Successful hepatitis C antiviral therapy induces remission of type 2 diabetes: a case report. Am J Case Rep. 2015;16:745-750.
28. Pavone P, Tieghi T, d’Ettore G, et al. Rapid decline of fasting glucose in HCV diabetic patients treated with direct-acting antiviral agents. Clin Microbiol Infect. 2016;22(5):462.e1-e3.
29. Pashun RA, Shen NT, Jesudian A. Markedly improved glycemic control in poorly controlled type 2 diabetes following direct acting antiviral treatment of genotype 1 hepatitis C. Case Reports Hepatol. 2016:7807921.
30. Stine JG, Wynter JA, Niccum B, Kelly V, Caldwell SH, Shah NL. Effect of treatment with direct acting antiviral on glycemic control in patients with diabetes mellitus and chronic hepatitis C. Ann Hepatol. 2017;16(2):215-220.
31. Davis TME, Davis WA, Jeffrey G. Successful withdrawal of insulin therapy after post-treatment clearance of hepatitis C virus in a man with type 2 diabetes. Am J Case Rep. 2017;18:414-417.
32. Hum J, Jou JH, Green PK, et al. Improvement in glycemic control of type 2 diabetes after successful treatment of hepatitis C virus. Diabetes Care. 2017;40(9):1173-1180.
33. Afdhal N, Zeuzem S, Kwo P, et al; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-1898.
34. Afdhal N, Reddy R, Nelson DR, et al; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014:370 (16):1483-1493.
35. Ferenci P, Bernstein D, Lalezari J, et al; PEARL-III Study; PEARL-IV Study. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370(21):1983-1992.
36. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370(21):1973-1982.
1. Backus LI, Belperio PS, Loomis TP, Yip GH, Mole LA. Hepatitis C virus screening and prevalence among US veterans in Department of Veterans Affairs care. JAMA Intern Med. 2013;173(16):1549-1552.
2. Edlin BR, Eckhardt BJ, Shu MA, Holmberg SD, Swan T. Toward a more accurate estimate of the prevalence of hepatitis C in the United States. Hepatology. 2015;62(5):1353-1363.
3. World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. http://www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/. Published April 2014. Accessed January 24, 2019.
4. Antonelli A, Ferri C, Galeazzi C, et al. HCV infection: pathogenesis, clinical manifestations and therapy. Clin Exp Rheumatol. 2008;26(1)(suppl 48):S39-S47.
5. Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond the liver. Clin Gastroenterol Hepatol. 2010;8(12):1017-1029.
6. Antonelli A, Ferrari SM, Giuggioli D, et al. Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. World J Diabetes. 2014;5(5):586-600.
7. Knobler H, Schihmanter R, Zifroni A, Fenakel G, Schattner A. Increased risk of type 2 diabetes mellitus in non-cirrhotic patients with hepatitis C. Mayo Clin Proc. 2000;75(4):355-359.
8. Hammerstad SS, Grock SF, Lee HJ, Hasham A, Sundaram N, Tomer Y. Diabetes and hepatitis C: a two-way association. Front Endocrinol (Lausanne). 2015;6:134.
9. Mehta SH, Brancati FI, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Interns Med. 2000;133(8):592-599.
10. Wang CS, Wang ST, Yao WJ, Chang TT, Chou P. Hepatitis C virus infection and the development of type 2 diabetes in a community-based longitudinal study. Am J Epidemiol. 2007;166(2):196-203.
11. Allison ME, Wreghitt T, Palmer CR, Alexander GJ. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol. 1994;21(6):1135-1139.
12. Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165(5):1499-1508.
13. Negro F, Alaei M. Hepatitis C virus and type 2 diabetes. World J Gastroenterol. 2009;15(13):1537-1547.
14. Knobler H, Schattner A. TNF-α, chronic hepatitis C and diabetes: a novel triad. QJM. 2005;98(1):1-6.
15. Greenberg AS, McDaniel ML. Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes. Eur J Clin Invest. 2002;32(suppl 3):24-34.
16. Ruan H, Lodish HF. Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev. 2003;14(5):447-455.
17. Kralj D, Virovic´ Jukic´ L, Stojsavljevic´ S, Duvnjak M, Smolic´ M, C˘urc˘ic´ IB. Hepatitis C virus, insulin resistance, and steatosis. J Clin Transl Hepatol. 2016;4(1):66-75.
18. Kawaguchi T, Ide T, Taniguchi E, et al. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 2007;102(3):570-576.
19. Kim HJ, Park JH, Park DI, et al. Clearance of HCV by combination therapy of pegylated interferon alpha-2a and ribavirin improves insulin resistance. Gut Liver. 2009;3(2):108-115.
20. Delgado-Borrego A, Jordan SH, Negre B, et al; Halt-C Trial Group. Reduction of insulin resistance with effective clearance of hepatitis C infection: results from the HALT-C trial. Clin Gastroenterol Hepatol. 2010;8(5):458-462.
21. Romero-Gómez M, Fernández-Rodríguez CM, Andrade RJ, et al. Effect of sustained virologic response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol. 2008;48(5):721-727.
22. American Association for the Study of Liver Disease, Infectious Disease Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Updated May 24, 20187. Accessed January 24, 2019.
23. Barua S, Greenwald R, Grebely J, Dore GJ, Swan T, Taylor LE. Restrictions for Medicaid reimbursement of sofosbuvir for the treatment of hepatitis C virus infection in the United States. Ann Intern Med. 2015;163(3):215-223.
24. Smith-Palmer J, Cerri K, Valentine W. Achieving sustained virologic response in hepatitis C: a systematic review of clinical, economic, and quality of life benefits. BMC Infect Dis. 2015;15:19.
25. Moucari R, Forestier N, Larrey D, et al. Danoprevir, an HCV NS3/4A protease inhibitor, improves insulin sensitivity in patients with genotype 1 chronic hepatitis C. Gut. 2010;59(12):1694-1698.
26. Pedersen MR, Backstedt D, Kakati BR, et al. Sustained virologic response to direct acting antiviral therapy improves components is associated with improvements in the metabolic syndrome. Abstract 1043. Presented at: The 66th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting, October 2015; San Francisco, CA.
27. Doyle MA, Curtis C. Successful hepatitis C antiviral therapy induces remission of type 2 diabetes: a case report. Am J Case Rep. 2015;16:745-750.
28. Pavone P, Tieghi T, d’Ettore G, et al. Rapid decline of fasting glucose in HCV diabetic patients treated with direct-acting antiviral agents. Clin Microbiol Infect. 2016;22(5):462.e1-e3.
29. Pashun RA, Shen NT, Jesudian A. Markedly improved glycemic control in poorly controlled type 2 diabetes following direct acting antiviral treatment of genotype 1 hepatitis C. Case Reports Hepatol. 2016:7807921.
30. Stine JG, Wynter JA, Niccum B, Kelly V, Caldwell SH, Shah NL. Effect of treatment with direct acting antiviral on glycemic control in patients with diabetes mellitus and chronic hepatitis C. Ann Hepatol. 2017;16(2):215-220.
31. Davis TME, Davis WA, Jeffrey G. Successful withdrawal of insulin therapy after post-treatment clearance of hepatitis C virus in a man with type 2 diabetes. Am J Case Rep. 2017;18:414-417.
32. Hum J, Jou JH, Green PK, et al. Improvement in glycemic control of type 2 diabetes after successful treatment of hepatitis C virus. Diabetes Care. 2017;40(9):1173-1180.
33. Afdhal N, Zeuzem S, Kwo P, et al; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-1898.
34. Afdhal N, Reddy R, Nelson DR, et al; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014:370 (16):1483-1493.
35. Ferenci P, Bernstein D, Lalezari J, et al; PEARL-III Study; PEARL-IV Study. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370(21):1983-1992.
36. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370(21):1973-1982.