Pharmacology

A class of drugs long used to treat HIV and hepatitis B viral infections appears to prevent the development of diabetes in a substantial proportion of patients who take these agents, an analysis of multiple databases has shown.

“Nucleoside reverse transcriptase inhibitors [NRTIs], drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation,” Jayakrishna Ambati, MD, University of Virginia, Charlottesville, and colleagues wrote in Nature Communications.

“[We showed that] the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure. ... These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes,” they wrote.

The researchers made a small chemical modification to NRTIs that led to their developing a new class of drugs, which they have termed “kamuvudines.” Kamuvudines are nontoxic derivatives of NRTIs, Dr. Ambati said in an interview.

“People take NRTIs because they need to live with HIV, but giving them to the general population is not a great idea because of the toxicities associated with long-term NRTI use. So our focus is not to go forward specifically with NRTIs but rather with these new molecules that are far less toxic, and that is how we envision a clinical trial going forward,” Dr. Ambati noted.
 

Researchers screened five databases of >100,000 patients

Dr. Ambati and colleagues analyzed information from five databases in which patients who had been exposed to an NRTI but who had not previously been diagnosed with type 2 diabetes were assessed for the subsequent development of diabetes over varying time intervals. In one, the Veterans Health Administration database – from the largest integrated health care system in the United States – the analysis spanned a period of 17 years.

Of 79,744 patients with a confirmed diagnosis of HIV or hepatitis B in the Veterans Health Administration database, the risk for type 2 diabetes was reduced by 34% among NRTI users, compared with nonusers after adjusting for potential confounders (P < .0001).

The reduction in diabetes risk was similar among HIV-positive and hepatitis B–positive patients.

These results were reaffirmed by further analyses of four other databases, the investigators reported. One of these, the employer-based health insurance Truven database, had data on 23,634 patients who had been diagnosed with HIV or hepatitis B. After adjusting for potential confounders, NRTI users had a 39% lower risk of developing type 2 diabetes, compared with nonusers (P < .0001).

The risk of developing type 2 diabetes was somewhat lower among NRTI users in the Pearl Diver database, which includes predominantly private health insurance claims. Of 16,045 patients diagnosed with HIV or hepatitis B included in this database, the risk for type 2 diabetes was 26% lower among NRTI users, compared with nonusers (P = .004).

A similar magnitude of risk reduction was seen in the analysis of the Clinformatics dataset. Among 6,341 users of NRTIs, the risk for type 2 diabetes was 27% lower than it was for nonusers (P = .009).

The least reduction in diabetes risk was in the Medicare database, in which only 3,097 patients had been diagnosed with either HIV or hepatitis B. Among these patients, the risk for diabetes was 17% lower among NRTI users than it was for nonusers (P = .137).
 

One-third reduction across multiple databases enhances confidence

“Collectively, among 128,861 patients with HIV-1 or hepatitis B, users of NRTIs had a 33% reduced hazard of developing type 2 diabetes,” Dr. Ambati and colleagues emphasize.

“The fact that the protective effect against the development of diabetes was replicated in multiple databases in studies from multiple institutions enhances confidence in the results,” Dr. Ambati noted in a statement from the University of Virginia.

Dr. Ambati and colleagues also showed that the NRTI lamivudine restores insulin sensitivity in human cells from type 2 diabetes patients.

That drug prevented induction of insulin resistance in human cells from people who did not have diabetes. It also prevented inflammasome activation in mice fed a high-fat diet.

“These investigations of human cell, mouse and population database systems collectively suggest a potential beneficial effect of NRTIs in forestalling diabetes onset,” they stressed.
 

Trial assessing kamuvudines slated to begin next year

In the interview, Dr. Ambati explained that inflammasomes are protein complexes that form a large superstructure within the cell. “When activated, they lead to the production of some very powerful inflammatory cytokines, including interleukin-1 beta and IL-18.”

Although there are many different types of inflammasomes, the one implicated in type 2 diabetes, as well as many other chronic diseases, including macular degeneration, is the NLRP3 inflammasome.

Activation of this molecule promotes insulin resistance, a key driver of type 2 diabetes, he explained.

Importantly, previous research showed that the way the NRTIs block this inflammasome has nothing to do with their anti-HIV activity.

After making a small chemical modification in the NRTIs, Dr. Ambati and colleagues were able to show that the resulting agents, which they have dubbed “kamuvudines,” are able to block inflammasome activation independently of their antiviral effects.

They hope that this modification will reduce the toxicities associated with the agents. This would be necessary if kamuvudines were to be more widely used in a noninfected, healthier population, Ambati stressed.

Dr. Ambati and his colleague, Paul Ashton, PhD, cofounder of Inflammasone Therapeutics, plan a clinical trial with one of these kamuvudines in macular degeneration, which they hope will begin early next year.

“We are trying to pick a disease where we can show efficacy fairly quickly in a small number of people,” Dr. Ashton explained in an interview. “We’re very enthusiastic about this as it looks really, really promising.”

Dr. Ambati and Dr. Ashton cofounded Inflammasone Therapeutics, located in Boston. Dr. Ashton is the CEO of the company.

A version of this article originally appeared on Medscape.com.

A class of drugs long used to treat HIV and hepatitis B viral infections appears to prevent the development of diabetes in a substantial proportion of patients who take these agents, an analysis of multiple databases has shown.

“Nucleoside reverse transcriptase inhibitors [NRTIs], drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation,” Jayakrishna Ambati, MD, University of Virginia, Charlottesville, and colleagues wrote in Nature Communications.

“[We showed that] the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure. ... These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes,” they wrote.

The researchers made a small chemical modification to NRTIs that led to their developing a new class of drugs, which they have termed “kamuvudines.” Kamuvudines are nontoxic derivatives of NRTIs, Dr. Ambati said in an interview.

“People take NRTIs because they need to live with HIV, but giving them to the general population is not a great idea because of the toxicities associated with long-term NRTI use. So our focus is not to go forward specifically with NRTIs but rather with these new molecules that are far less toxic, and that is how we envision a clinical trial going forward,” Dr. Ambati noted.
 

Researchers screened five databases of >100,000 patients

Dr. Ambati and colleagues analyzed information from five databases in which patients who had been exposed to an NRTI but who had not previously been diagnosed with type 2 diabetes were assessed for the subsequent development of diabetes over varying time intervals. In one, the Veterans Health Administration database – from the largest integrated health care system in the United States – the analysis spanned a period of 17 years.

Of 79,744 patients with a confirmed diagnosis of HIV or hepatitis B in the Veterans Health Administration database, the risk for type 2 diabetes was reduced by 34% among NRTI users, compared with nonusers after adjusting for potential confounders (P < .0001).

The reduction in diabetes risk was similar among HIV-positive and hepatitis B–positive patients.

These results were reaffirmed by further analyses of four other databases, the investigators reported. One of these, the employer-based health insurance Truven database, had data on 23,634 patients who had been diagnosed with HIV or hepatitis B. After adjusting for potential confounders, NRTI users had a 39% lower risk of developing type 2 diabetes, compared with nonusers (P < .0001).

The risk of developing type 2 diabetes was somewhat lower among NRTI users in the Pearl Diver database, which includes predominantly private health insurance claims. Of 16,045 patients diagnosed with HIV or hepatitis B included in this database, the risk for type 2 diabetes was 26% lower among NRTI users, compared with nonusers (P = .004).

A similar magnitude of risk reduction was seen in the analysis of the Clinformatics dataset. Among 6,341 users of NRTIs, the risk for type 2 diabetes was 27% lower than it was for nonusers (P = .009).

The least reduction in diabetes risk was in the Medicare database, in which only 3,097 patients had been diagnosed with either HIV or hepatitis B. Among these patients, the risk for diabetes was 17% lower among NRTI users than it was for nonusers (P = .137).
 

One-third reduction across multiple databases enhances confidence

“Collectively, among 128,861 patients with HIV-1 or hepatitis B, users of NRTIs had a 33% reduced hazard of developing type 2 diabetes,” Dr. Ambati and colleagues emphasize.

“The fact that the protective effect against the development of diabetes was replicated in multiple databases in studies from multiple institutions enhances confidence in the results,” Dr. Ambati noted in a statement from the University of Virginia.

Dr. Ambati and colleagues also showed that the NRTI lamivudine restores insulin sensitivity in human cells from type 2 diabetes patients.

That drug prevented induction of insulin resistance in human cells from people who did not have diabetes. It also prevented inflammasome activation in mice fed a high-fat diet.

“These investigations of human cell, mouse and population database systems collectively suggest a potential beneficial effect of NRTIs in forestalling diabetes onset,” they stressed.
 

Trial assessing kamuvudines slated to begin next year

In the interview, Dr. Ambati explained that inflammasomes are protein complexes that form a large superstructure within the cell. “When activated, they lead to the production of some very powerful inflammatory cytokines, including interleukin-1 beta and IL-18.”

Although there are many different types of inflammasomes, the one implicated in type 2 diabetes, as well as many other chronic diseases, including macular degeneration, is the NLRP3 inflammasome.

Activation of this molecule promotes insulin resistance, a key driver of type 2 diabetes, he explained.

Importantly, previous research showed that the way the NRTIs block this inflammasome has nothing to do with their anti-HIV activity.

After making a small chemical modification in the NRTIs, Dr. Ambati and colleagues were able to show that the resulting agents, which they have dubbed “kamuvudines,” are able to block inflammasome activation independently of their antiviral effects.

They hope that this modification will reduce the toxicities associated with the agents. This would be necessary if kamuvudines were to be more widely used in a noninfected, healthier population, Ambati stressed.

Dr. Ambati and his colleague, Paul Ashton, PhD, cofounder of Inflammasone Therapeutics, plan a clinical trial with one of these kamuvudines in macular degeneration, which they hope will begin early next year.

“We are trying to pick a disease where we can show efficacy fairly quickly in a small number of people,” Dr. Ashton explained in an interview. “We’re very enthusiastic about this as it looks really, really promising.”

Dr. Ambati and Dr. Ashton cofounded Inflammasone Therapeutics, located in Boston. Dr. Ashton is the CEO of the company.

A version of this article originally appeared on Medscape.com.

A class of drugs long used to treat HIV and hepatitis B viral infections appears to prevent the development of diabetes in a substantial proportion of patients who take these agents, an analysis of multiple databases has shown.

“Nucleoside reverse transcriptase inhibitors [NRTIs], drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation,” Jayakrishna Ambati, MD, University of Virginia, Charlottesville, and colleagues wrote in Nature Communications.

“[We showed that] the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure. ... These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes,” they wrote.

The researchers made a small chemical modification to NRTIs that led to their developing a new class of drugs, which they have termed “kamuvudines.” Kamuvudines are nontoxic derivatives of NRTIs, Dr. Ambati said in an interview.

“People take NRTIs because they need to live with HIV, but giving them to the general population is not a great idea because of the toxicities associated with long-term NRTI use. So our focus is not to go forward specifically with NRTIs but rather with these new molecules that are far less toxic, and that is how we envision a clinical trial going forward,” Dr. Ambati noted.
 

Researchers screened five databases of >100,000 patients

Dr. Ambati and colleagues analyzed information from five databases in which patients who had been exposed to an NRTI but who had not previously been diagnosed with type 2 diabetes were assessed for the subsequent development of diabetes over varying time intervals. In one, the Veterans Health Administration database – from the largest integrated health care system in the United States – the analysis spanned a period of 17 years.

Of 79,744 patients with a confirmed diagnosis of HIV or hepatitis B in the Veterans Health Administration database, the risk for type 2 diabetes was reduced by 34% among NRTI users, compared with nonusers after adjusting for potential confounders (P < .0001).

The reduction in diabetes risk was similar among HIV-positive and hepatitis B–positive patients.

These results were reaffirmed by further analyses of four other databases, the investigators reported. One of these, the employer-based health insurance Truven database, had data on 23,634 patients who had been diagnosed with HIV or hepatitis B. After adjusting for potential confounders, NRTI users had a 39% lower risk of developing type 2 diabetes, compared with nonusers (P < .0001).

The risk of developing type 2 diabetes was somewhat lower among NRTI users in the Pearl Diver database, which includes predominantly private health insurance claims. Of 16,045 patients diagnosed with HIV or hepatitis B included in this database, the risk for type 2 diabetes was 26% lower among NRTI users, compared with nonusers (P = .004).

A similar magnitude of risk reduction was seen in the analysis of the Clinformatics dataset. Among 6,341 users of NRTIs, the risk for type 2 diabetes was 27% lower than it was for nonusers (P = .009).

The least reduction in diabetes risk was in the Medicare database, in which only 3,097 patients had been diagnosed with either HIV or hepatitis B. Among these patients, the risk for diabetes was 17% lower among NRTI users than it was for nonusers (P = .137).
 

One-third reduction across multiple databases enhances confidence

“Collectively, among 128,861 patients with HIV-1 or hepatitis B, users of NRTIs had a 33% reduced hazard of developing type 2 diabetes,” Dr. Ambati and colleagues emphasize.

“The fact that the protective effect against the development of diabetes was replicated in multiple databases in studies from multiple institutions enhances confidence in the results,” Dr. Ambati noted in a statement from the University of Virginia.

Dr. Ambati and colleagues also showed that the NRTI lamivudine restores insulin sensitivity in human cells from type 2 diabetes patients.

That drug prevented induction of insulin resistance in human cells from people who did not have diabetes. It also prevented inflammasome activation in mice fed a high-fat diet.

“These investigations of human cell, mouse and population database systems collectively suggest a potential beneficial effect of NRTIs in forestalling diabetes onset,” they stressed.
 

Trial assessing kamuvudines slated to begin next year

In the interview, Dr. Ambati explained that inflammasomes are protein complexes that form a large superstructure within the cell. “When activated, they lead to the production of some very powerful inflammatory cytokines, including interleukin-1 beta and IL-18.”

Although there are many different types of inflammasomes, the one implicated in type 2 diabetes, as well as many other chronic diseases, including macular degeneration, is the NLRP3 inflammasome.

Activation of this molecule promotes insulin resistance, a key driver of type 2 diabetes, he explained.

Importantly, previous research showed that the way the NRTIs block this inflammasome has nothing to do with their anti-HIV activity.

After making a small chemical modification in the NRTIs, Dr. Ambati and colleagues were able to show that the resulting agents, which they have dubbed “kamuvudines,” are able to block inflammasome activation independently of their antiviral effects.

They hope that this modification will reduce the toxicities associated with the agents. This would be necessary if kamuvudines were to be more widely used in a noninfected, healthier population, Ambati stressed.

Dr. Ambati and his colleague, Paul Ashton, PhD, cofounder of Inflammasone Therapeutics, plan a clinical trial with one of these kamuvudines in macular degeneration, which they hope will begin early next year.

“We are trying to pick a disease where we can show efficacy fairly quickly in a small number of people,” Dr. Ashton explained in an interview. “We’re very enthusiastic about this as it looks really, really promising.”

Dr. Ambati and Dr. Ashton cofounded Inflammasone Therapeutics, located in Boston. Dr. Ashton is the CEO of the company.

A version of this article originally appeared on Medscape.com.

A new, large study has confirmed that different types of hormone replacement therapy (HRT) are associated with an increased risk for breast cancer and has provided additional information on factors associated with that increased risk.

The study was published online on October 28 in The BMJ.

“The study confirms increased risk of breast cancer in patients taking HRT but shows that the magnitude of risk depends on a number of factors,” first author Yana Vinogradova, PhD, said in an interview. Dr. Vinogradova is a medical statistician at the University of Nottingham (England).

The study also suggests the risk may be lower than was estimated in a large meta-analysis of 24 trials that was published in 2019 in The Lancet. In that study, researchers suggested the risk for breast cancer with HRT was higher and persisted longer than had been thought.

This conclusion from the meta-analysis was widely reported in the lay press and led to the UK Medicine and Healthcare Products Regulatory Agency issuing a safety alert for HRT regarding breast cancer. Experts in the field questioned the alert and said it caused undue anxiety. The European Medicines Agency also issued a safety alert because of the study.

This new study was begun before publication of the meta-analysis. Although the results are broadly similar in suggesting increased risk for breast cancer with HRT use, findings from the new study suggest the risk is lower than had been estimated in the meta-analysis and that the risk diminishes more rapidly after stopping HRT than was suggested by the meta-analysis.

“The publicity surrounding publication of the meta-analysis highlighted unexpectedly high risks and led to a heightened level of concern in some quarters,” Dr. Vinogradova commented. “Our study, based on general population data, has not confirmed any such findings. In general, it showed lower levels of risk and clarified the variability of magnitude within them.”

Dr. Vinogradova said the discrepancy could be related to the fact that the studies were designed differently. The meta-analysis relied on results from 24 studies that were conducted around the world at different periods and included women of different ages and backgrounds. The studies in the meta-analysis used different methods, including questionnaires that relied on women’s memories and therefore could have been biased, she said.

In contrast, the new study analyzed EMR data collected prospectively by general practices in the United Kingdom. The data came from the QResearch and from the Clinical Practice Research Datalink (CPRD) databases, the two largest primary care databases in the United Kingdom, which were linked to hospital, mortality, and cancer registries.

Because this study used a “consistent design” and “consistent data sources,” these new results “are likely to be more accurate and reliable for assessing risks among HRT users,” Dr. Vinogradova commented.

This study used an observational design, so it cannot prove that HRT causes breast cancer. These results may better represent women in the general U.K. population, compared with the earlier meta-analysis, she added.

Commenting on the new study, Michael Jones, PhD, senior staff scientist in genetics and epidemiology at the Institute of Cancer Research, London, also emphasized that it was large and its data came from general practitioner medical records, “so the strong statistical associations are unlikely to be due to chance.

“The results of this study generally confirm what has been seen before and is well established – that the use of combined estrogen plus progestogen HRT is associated with increased risk of breast cancer, and this risk increases with duration of use. But reassuringly, after stopping HRT, the raised risk of breast cancer mostly returns to that seen in nonusers of HRT,” he said.

“It’s important to note that no one study should be considered in isolation,” he added. “Even though some risks were found to be slightly smaller than those reported in another meta-analysis of the worldwide epidemiological evidence recently published in 2019, women considering use of HRT should still follow advice given to them by their [general practitioners].”
 

Study details

In the study, researchers evaluated all types of HRT commonly prescribed in the United Kingdom over the past 20 years, including topical estrogen, vaginal pessaries, and creams. They grouped HRT use by recent (within the past 5 years) and past (5 or more years ago) and HRT duration as short term (less than 5 years) and long term (5 years or longer). Results were adjusted for a range of factors that could affect breast cancer risk, including lifestyle, smoking, alcohol consumption, other medical conditions, family history, and use of other prescribed drugs.

The analysis included 98,611 women aged 50-79 years who were first diagnosed with breast cancer between 1998 and 2019. These women were matched by age and general practice to 457,498 women who were not diagnosed with breast cancer over these years. HRT use was reported in 34% (33,703) of women with breast cancer and in 31% (134,391) of women without breast cancer.

Overall, the risk for breast cancer was increased with use of most HRT drugs (adjusted odds ratio, 1.21; 95% confidence, 1.19-1.23), compared with not using HRT drugs. The highest risk was tied to combined estrogen/progestogen HRT (adjusted OR, 1.26; 95% CI, 1.24-1.29). The lowest risk was tied to estrogen-only HRT (adjusted OR, 1.06; 95% CI, 1.03-1.10). Estrogen cream and vaginal estrogen were not associated with increased breast cancer risk.

In general, breast cancer risk was higher among recent HRT users and those receiving long-term therapy. HRT-associated breast cancer risk increased with age and declined after discontinuing treatment. Therapy of less than 1 year was not associated with increased breast cancer risk.

Women who had recently been receiving long-term combined estrogen/progestogen HRT had a 79% increased risk for breast cancer (adjusted OR, 1.79; 95% CI, 1.73-1.85), compared with never-users. Among recent long-term users of combined HRT, breast cancer risk was highest for norethisterone (adjusted OR, 1.88; 95% CI, 1.79-1.99) and lowest for dydrogesterone (adjusted OR, 1.24; 95% CI, 1.03-1.48). Women who had recently been receiving long-term estrogen-only HRT had a 15% increased risk for breast cancer compared to never-users (adjusted OR, 1.15; 95% CI, 1.09-1.21).

Among women who discontinued HRT 5 or more years ago, risk for breast cancer was no longer increased for long-term estrogen-only therapy and short-term estrogen/progestogen therapy. However, breast cancer risk remained elevated 5 years after discontinuing long-term estrogen/progestogen (adjusted OR, 1.16; 95% CI, 1.11-1.21).

HRT-associated risk for breast cancer increased with age across all durations of therapy.

Compared with never-use, recent long-term estrogen-only therapy was associated with zero extra breast cancer cases per 10,000 women-years among women aged 50-59 years and eight extra cases per 10,000 women-years among women aged 70-79.

Recent long-term estrogen/progestogen use was associated with 15 extra breast cancer cases among women aged 50-59 and 36 extra cases among women aged 70-79 per 10,000 women-years.

Past long-term estrogen/progestogen use was associated with zero extra breast cancer cases among women aged 50-59 and eight extra cases among women aged 70-79 per 10,000 women-years.

Summarizing, Dr. Vinogradova said the increased risk for breast cancer with HRT appears to be “relatively small, particularly for younger women and for any women who use HRT only for a restricted period.”

Decisions about whether to use HRT and which type to use should depend on symptom severity, patient factors, and suitability of other treatment options, she commented.

“Particularly for those women who our study has shown to be most at risk, these decisions should be made through discussions between the patient and her doctor,” she concluded. “We hope that the new and more detailed information provided by our study will facilitate such prescribing decisions.”

The study was partially funded by the School for Primary Care Research of the National Institute for Health Research, by Cancer Research UK, and by the Cancer Research UK Oxford Center. Dr. Vinogradova has disclosed no relevant financial relationships. Senior author Julia Hippisley-Cox is an unpaid director of QResearch and was a paid director of ClinRisk until 2019. The other authors have disclosed no relevant financial relationships.
 

A version of this story originally appeared on Medscape.com.

A new, large study has confirmed that different types of hormone replacement therapy (HRT) are associated with an increased risk for breast cancer and has provided additional information on factors associated with that increased risk.

The study was published online on October 28 in The BMJ.

“The study confirms increased risk of breast cancer in patients taking HRT but shows that the magnitude of risk depends on a number of factors,” first author Yana Vinogradova, PhD, said in an interview. Dr. Vinogradova is a medical statistician at the University of Nottingham (England).

The study also suggests the risk may be lower than was estimated in a large meta-analysis of 24 trials that was published in 2019 in The Lancet. In that study, researchers suggested the risk for breast cancer with HRT was higher and persisted longer than had been thought.

This conclusion from the meta-analysis was widely reported in the lay press and led to the UK Medicine and Healthcare Products Regulatory Agency issuing a safety alert for HRT regarding breast cancer. Experts in the field questioned the alert and said it caused undue anxiety. The European Medicines Agency also issued a safety alert because of the study.

This new study was begun before publication of the meta-analysis. Although the results are broadly similar in suggesting increased risk for breast cancer with HRT use, findings from the new study suggest the risk is lower than had been estimated in the meta-analysis and that the risk diminishes more rapidly after stopping HRT than was suggested by the meta-analysis.

“The publicity surrounding publication of the meta-analysis highlighted unexpectedly high risks and led to a heightened level of concern in some quarters,” Dr. Vinogradova commented. “Our study, based on general population data, has not confirmed any such findings. In general, it showed lower levels of risk and clarified the variability of magnitude within them.”

Dr. Vinogradova said the discrepancy could be related to the fact that the studies were designed differently. The meta-analysis relied on results from 24 studies that were conducted around the world at different periods and included women of different ages and backgrounds. The studies in the meta-analysis used different methods, including questionnaires that relied on women’s memories and therefore could have been biased, she said.

In contrast, the new study analyzed EMR data collected prospectively by general practices in the United Kingdom. The data came from the QResearch and from the Clinical Practice Research Datalink (CPRD) databases, the two largest primary care databases in the United Kingdom, which were linked to hospital, mortality, and cancer registries.

Because this study used a “consistent design” and “consistent data sources,” these new results “are likely to be more accurate and reliable for assessing risks among HRT users,” Dr. Vinogradova commented.

This study used an observational design, so it cannot prove that HRT causes breast cancer. These results may better represent women in the general U.K. population, compared with the earlier meta-analysis, she added.

Commenting on the new study, Michael Jones, PhD, senior staff scientist in genetics and epidemiology at the Institute of Cancer Research, London, also emphasized that it was large and its data came from general practitioner medical records, “so the strong statistical associations are unlikely to be due to chance.

“The results of this study generally confirm what has been seen before and is well established – that the use of combined estrogen plus progestogen HRT is associated with increased risk of breast cancer, and this risk increases with duration of use. But reassuringly, after stopping HRT, the raised risk of breast cancer mostly returns to that seen in nonusers of HRT,” he said.

“It’s important to note that no one study should be considered in isolation,” he added. “Even though some risks were found to be slightly smaller than those reported in another meta-analysis of the worldwide epidemiological evidence recently published in 2019, women considering use of HRT should still follow advice given to them by their [general practitioners].”
 

Study details

In the study, researchers evaluated all types of HRT commonly prescribed in the United Kingdom over the past 20 years, including topical estrogen, vaginal pessaries, and creams. They grouped HRT use by recent (within the past 5 years) and past (5 or more years ago) and HRT duration as short term (less than 5 years) and long term (5 years or longer). Results were adjusted for a range of factors that could affect breast cancer risk, including lifestyle, smoking, alcohol consumption, other medical conditions, family history, and use of other prescribed drugs.

The analysis included 98,611 women aged 50-79 years who were first diagnosed with breast cancer between 1998 and 2019. These women were matched by age and general practice to 457,498 women who were not diagnosed with breast cancer over these years. HRT use was reported in 34% (33,703) of women with breast cancer and in 31% (134,391) of women without breast cancer.

Overall, the risk for breast cancer was increased with use of most HRT drugs (adjusted odds ratio, 1.21; 95% confidence, 1.19-1.23), compared with not using HRT drugs. The highest risk was tied to combined estrogen/progestogen HRT (adjusted OR, 1.26; 95% CI, 1.24-1.29). The lowest risk was tied to estrogen-only HRT (adjusted OR, 1.06; 95% CI, 1.03-1.10). Estrogen cream and vaginal estrogen were not associated with increased breast cancer risk.

In general, breast cancer risk was higher among recent HRT users and those receiving long-term therapy. HRT-associated breast cancer risk increased with age and declined after discontinuing treatment. Therapy of less than 1 year was not associated with increased breast cancer risk.

Women who had recently been receiving long-term combined estrogen/progestogen HRT had a 79% increased risk for breast cancer (adjusted OR, 1.79; 95% CI, 1.73-1.85), compared with never-users. Among recent long-term users of combined HRT, breast cancer risk was highest for norethisterone (adjusted OR, 1.88; 95% CI, 1.79-1.99) and lowest for dydrogesterone (adjusted OR, 1.24; 95% CI, 1.03-1.48). Women who had recently been receiving long-term estrogen-only HRT had a 15% increased risk for breast cancer compared to never-users (adjusted OR, 1.15; 95% CI, 1.09-1.21).

Among women who discontinued HRT 5 or more years ago, risk for breast cancer was no longer increased for long-term estrogen-only therapy and short-term estrogen/progestogen therapy. However, breast cancer risk remained elevated 5 years after discontinuing long-term estrogen/progestogen (adjusted OR, 1.16; 95% CI, 1.11-1.21).

HRT-associated risk for breast cancer increased with age across all durations of therapy.

Compared with never-use, recent long-term estrogen-only therapy was associated with zero extra breast cancer cases per 10,000 women-years among women aged 50-59 years and eight extra cases per 10,000 women-years among women aged 70-79.

Recent long-term estrogen/progestogen use was associated with 15 extra breast cancer cases among women aged 50-59 and 36 extra cases among women aged 70-79 per 10,000 women-years.

Past long-term estrogen/progestogen use was associated with zero extra breast cancer cases among women aged 50-59 and eight extra cases among women aged 70-79 per 10,000 women-years.

Summarizing, Dr. Vinogradova said the increased risk for breast cancer with HRT appears to be “relatively small, particularly for younger women and for any women who use HRT only for a restricted period.”

Decisions about whether to use HRT and which type to use should depend on symptom severity, patient factors, and suitability of other treatment options, she commented.

“Particularly for those women who our study has shown to be most at risk, these decisions should be made through discussions between the patient and her doctor,” she concluded. “We hope that the new and more detailed information provided by our study will facilitate such prescribing decisions.”

The study was partially funded by the School for Primary Care Research of the National Institute for Health Research, by Cancer Research UK, and by the Cancer Research UK Oxford Center. Dr. Vinogradova has disclosed no relevant financial relationships. Senior author Julia Hippisley-Cox is an unpaid director of QResearch and was a paid director of ClinRisk until 2019. The other authors have disclosed no relevant financial relationships.
 

A version of this story originally appeared on Medscape.com.

A new, large study has confirmed that different types of hormone replacement therapy (HRT) are associated with an increased risk for breast cancer and has provided additional information on factors associated with that increased risk.

The study was published online on October 28 in The BMJ.

“The study confirms increased risk of breast cancer in patients taking HRT but shows that the magnitude of risk depends on a number of factors,” first author Yana Vinogradova, PhD, said in an interview. Dr. Vinogradova is a medical statistician at the University of Nottingham (England).

The study also suggests the risk may be lower than was estimated in a large meta-analysis of 24 trials that was published in 2019 in The Lancet. In that study, researchers suggested the risk for breast cancer with HRT was higher and persisted longer than had been thought.

This conclusion from the meta-analysis was widely reported in the lay press and led to the UK Medicine and Healthcare Products Regulatory Agency issuing a safety alert for HRT regarding breast cancer. Experts in the field questioned the alert and said it caused undue anxiety. The European Medicines Agency also issued a safety alert because of the study.

This new study was begun before publication of the meta-analysis. Although the results are broadly similar in suggesting increased risk for breast cancer with HRT use, findings from the new study suggest the risk is lower than had been estimated in the meta-analysis and that the risk diminishes more rapidly after stopping HRT than was suggested by the meta-analysis.

“The publicity surrounding publication of the meta-analysis highlighted unexpectedly high risks and led to a heightened level of concern in some quarters,” Dr. Vinogradova commented. “Our study, based on general population data, has not confirmed any such findings. In general, it showed lower levels of risk and clarified the variability of magnitude within them.”

Dr. Vinogradova said the discrepancy could be related to the fact that the studies were designed differently. The meta-analysis relied on results from 24 studies that were conducted around the world at different periods and included women of different ages and backgrounds. The studies in the meta-analysis used different methods, including questionnaires that relied on women’s memories and therefore could have been biased, she said.

In contrast, the new study analyzed EMR data collected prospectively by general practices in the United Kingdom. The data came from the QResearch and from the Clinical Practice Research Datalink (CPRD) databases, the two largest primary care databases in the United Kingdom, which were linked to hospital, mortality, and cancer registries.

Because this study used a “consistent design” and “consistent data sources,” these new results “are likely to be more accurate and reliable for assessing risks among HRT users,” Dr. Vinogradova commented.

This study used an observational design, so it cannot prove that HRT causes breast cancer. These results may better represent women in the general U.K. population, compared with the earlier meta-analysis, she added.

Commenting on the new study, Michael Jones, PhD, senior staff scientist in genetics and epidemiology at the Institute of Cancer Research, London, also emphasized that it was large and its data came from general practitioner medical records, “so the strong statistical associations are unlikely to be due to chance.

“The results of this study generally confirm what has been seen before and is well established – that the use of combined estrogen plus progestogen HRT is associated with increased risk of breast cancer, and this risk increases with duration of use. But reassuringly, after stopping HRT, the raised risk of breast cancer mostly returns to that seen in nonusers of HRT,” he said.

“It’s important to note that no one study should be considered in isolation,” he added. “Even though some risks were found to be slightly smaller than those reported in another meta-analysis of the worldwide epidemiological evidence recently published in 2019, women considering use of HRT should still follow advice given to them by their [general practitioners].”
 

Study details

In the study, researchers evaluated all types of HRT commonly prescribed in the United Kingdom over the past 20 years, including topical estrogen, vaginal pessaries, and creams. They grouped HRT use by recent (within the past 5 years) and past (5 or more years ago) and HRT duration as short term (less than 5 years) and long term (5 years or longer). Results were adjusted for a range of factors that could affect breast cancer risk, including lifestyle, smoking, alcohol consumption, other medical conditions, family history, and use of other prescribed drugs.

The analysis included 98,611 women aged 50-79 years who were first diagnosed with breast cancer between 1998 and 2019. These women were matched by age and general practice to 457,498 women who were not diagnosed with breast cancer over these years. HRT use was reported in 34% (33,703) of women with breast cancer and in 31% (134,391) of women without breast cancer.

Overall, the risk for breast cancer was increased with use of most HRT drugs (adjusted odds ratio, 1.21; 95% confidence, 1.19-1.23), compared with not using HRT drugs. The highest risk was tied to combined estrogen/progestogen HRT (adjusted OR, 1.26; 95% CI, 1.24-1.29). The lowest risk was tied to estrogen-only HRT (adjusted OR, 1.06; 95% CI, 1.03-1.10). Estrogen cream and vaginal estrogen were not associated with increased breast cancer risk.

In general, breast cancer risk was higher among recent HRT users and those receiving long-term therapy. HRT-associated breast cancer risk increased with age and declined after discontinuing treatment. Therapy of less than 1 year was not associated with increased breast cancer risk.

Women who had recently been receiving long-term combined estrogen/progestogen HRT had a 79% increased risk for breast cancer (adjusted OR, 1.79; 95% CI, 1.73-1.85), compared with never-users. Among recent long-term users of combined HRT, breast cancer risk was highest for norethisterone (adjusted OR, 1.88; 95% CI, 1.79-1.99) and lowest for dydrogesterone (adjusted OR, 1.24; 95% CI, 1.03-1.48). Women who had recently been receiving long-term estrogen-only HRT had a 15% increased risk for breast cancer compared to never-users (adjusted OR, 1.15; 95% CI, 1.09-1.21).

Among women who discontinued HRT 5 or more years ago, risk for breast cancer was no longer increased for long-term estrogen-only therapy and short-term estrogen/progestogen therapy. However, breast cancer risk remained elevated 5 years after discontinuing long-term estrogen/progestogen (adjusted OR, 1.16; 95% CI, 1.11-1.21).

HRT-associated risk for breast cancer increased with age across all durations of therapy.

Compared with never-use, recent long-term estrogen-only therapy was associated with zero extra breast cancer cases per 10,000 women-years among women aged 50-59 years and eight extra cases per 10,000 women-years among women aged 70-79.

Recent long-term estrogen/progestogen use was associated with 15 extra breast cancer cases among women aged 50-59 and 36 extra cases among women aged 70-79 per 10,000 women-years.

Past long-term estrogen/progestogen use was associated with zero extra breast cancer cases among women aged 50-59 and eight extra cases among women aged 70-79 per 10,000 women-years.

Summarizing, Dr. Vinogradova said the increased risk for breast cancer with HRT appears to be “relatively small, particularly for younger women and for any women who use HRT only for a restricted period.”

Decisions about whether to use HRT and which type to use should depend on symptom severity, patient factors, and suitability of other treatment options, she commented.

“Particularly for those women who our study has shown to be most at risk, these decisions should be made through discussions between the patient and her doctor,” she concluded. “We hope that the new and more detailed information provided by our study will facilitate such prescribing decisions.”

The study was partially funded by the School for Primary Care Research of the National Institute for Health Research, by Cancer Research UK, and by the Cancer Research UK Oxford Center. Dr. Vinogradova has disclosed no relevant financial relationships. Senior author Julia Hippisley-Cox is an unpaid director of QResearch and was a paid director of ClinRisk until 2019. The other authors have disclosed no relevant financial relationships.
 

A version of this story originally appeared on Medscape.com.

Sexual dysfunction is a common treatment-related problem observed across numerous cancer diagnoses, and a new survey finds that 87% of cancer survivors have had such problems.

However, most of them also reported that their oncologist had not formally discussed the topic, and female patients were particularly unlikely to be asked about sexual dysfunction.

“The main takeaway from our study is that sexual side effects following treatment are very common,” said lead author James Taylor, MD, MPH, chief resident in radiation oncology at the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, Pennsylvania.

“Nearly 9 in 10 patients reported some change after cancer treatment that negatively affected their sexual health,” he said.

Taylor was speaking at the American Society for Radiation Oncology (ASTRO) Annual Meeting, held virtually this year because of the pandemic.

“Negative effects on sexual health after cancer treatment are unfortunately very common,” he said. “This is not just patients treated with radiation but this includes chemotherapy, hormonal therapy, surgery, and other treatment modalities.”

Potential issues include physical complications such as erectile dysfunction with prostate cancer treatment or vaginal dryness with gynecological cancer treatment. One recent study found that one-third of men who had undergone treatment for prostate cancer reported that a subsequent lack of sexual function has had the greatest impact on their quality of life. Another study reported that nearly all patients with breast cancer taking endocrine therapy experience a high degree of sexual dysfunction, including vulvovaginal dryness and severe dyspareunia.
 

Not discussed, not warned

Taylor and colleagues developed a questionnaire with input from radiation oncologists, medical oncologists, and surgeons, which consisted of more than 25 questions and was specifically targeted at cancer survivors.

A total of 405 adults completed the electronic survey about their experiences with sexual side effects after cancer treatment (391 responses were eligible for analysis). Most of the respondents were women (81%), and the most common cancer types were breast (67%), prostate (16%), and endometrial (6%). Treatments included chemotherapy (78%), radiation therapy (54%), and hormone therapy (47%).

“The questionnaires were distributed at Thomas Jefferson and throughout social media,” said Taylor. “The responses from social media are important because it shows a broad representation of patients who are treated in multiple clinics across the United States.”

Most of the survivors who responded (n = 337, 87%) stated cancer treatment had impacted sexual function or desire, with 53.8% reporting body image distortion, 73.4% with dyspareunia, and 42.3% unable to achieve orgasm.

Only about one-quarter (27.9%) said they had been formally asked about their sexual health by their clinician.

“Only about 40% said that they have been preemptively warned that their sexual health may be affected by treatment,” said Taylor.

Women were far less likely to be asked about their sexual health by their provider. The survey showed that male respondents were twice as likely to say they had been asked about sexual health and counseled about the potential toxicity (53% vs 22%; P < .001), and a substantially higher percentage of men reported receiving a formal assessment tool such as a survey (32% vs 5%; P = .001) compared with female respondents.

Taylor noted that the survey demonstrated several things. “One is that sexual toxicity is exceedingly common, and number two, it identified a gender disparity,” he said. “But number 3, and I think that this is an important aspect of our study, is that the majority of respondents felt that they would like a standard questionnaire to initiate and guide a discussion on sexual health with their provider.”

The reason that aspect is very important, he emphasized, is that “we know metrics and questionnaires already exist, so this gives us an actionable intervention that we can distribute and help mitigate some of these disparities.”
 

Importance of being holistic

The results of the survey “highlight the importance of being holistic in our approach to patient survivorship,” commented Karen Winkfield, MD, PhD, associate professor of radiation oncology at Wake Forest University, Winston-Salem, North Carolina, and executive director of the Meharry-Vanderbilt Alliance, Nashville, Tennessee.

“We need to ask patients about all parts of their well-being, including sexual health,” Winkfield said. “Body dysmorphism can impact anyone, but especially patients who have had surgery or radiation,” she said, while chemotherapy can impact energy and libido and have other toxicities that impact sexual health.

“I encourage all oncologists to ask patients about their sexual health, and a standardized form that can be used across all sites will make this much easier,” Winkfield commented. “We owe it to our patients to treat them holistically.”

The authors have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Sexual dysfunction is a common treatment-related problem observed across numerous cancer diagnoses, and a new survey finds that 87% of cancer survivors have had such problems.

However, most of them also reported that their oncologist had not formally discussed the topic, and female patients were particularly unlikely to be asked about sexual dysfunction.

“The main takeaway from our study is that sexual side effects following treatment are very common,” said lead author James Taylor, MD, MPH, chief resident in radiation oncology at the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, Pennsylvania.

“Nearly 9 in 10 patients reported some change after cancer treatment that negatively affected their sexual health,” he said.

Taylor was speaking at the American Society for Radiation Oncology (ASTRO) Annual Meeting, held virtually this year because of the pandemic.

“Negative effects on sexual health after cancer treatment are unfortunately very common,” he said. “This is not just patients treated with radiation but this includes chemotherapy, hormonal therapy, surgery, and other treatment modalities.”

Potential issues include physical complications such as erectile dysfunction with prostate cancer treatment or vaginal dryness with gynecological cancer treatment. One recent study found that one-third of men who had undergone treatment for prostate cancer reported that a subsequent lack of sexual function has had the greatest impact on their quality of life. Another study reported that nearly all patients with breast cancer taking endocrine therapy experience a high degree of sexual dysfunction, including vulvovaginal dryness and severe dyspareunia.
 

Not discussed, not warned

Taylor and colleagues developed a questionnaire with input from radiation oncologists, medical oncologists, and surgeons, which consisted of more than 25 questions and was specifically targeted at cancer survivors.

A total of 405 adults completed the electronic survey about their experiences with sexual side effects after cancer treatment (391 responses were eligible for analysis). Most of the respondents were women (81%), and the most common cancer types were breast (67%), prostate (16%), and endometrial (6%). Treatments included chemotherapy (78%), radiation therapy (54%), and hormone therapy (47%).

“The questionnaires were distributed at Thomas Jefferson and throughout social media,” said Taylor. “The responses from social media are important because it shows a broad representation of patients who are treated in multiple clinics across the United States.”

Most of the survivors who responded (n = 337, 87%) stated cancer treatment had impacted sexual function or desire, with 53.8% reporting body image distortion, 73.4% with dyspareunia, and 42.3% unable to achieve orgasm.

Only about one-quarter (27.9%) said they had been formally asked about their sexual health by their clinician.

“Only about 40% said that they have been preemptively warned that their sexual health may be affected by treatment,” said Taylor.

Women were far less likely to be asked about their sexual health by their provider. The survey showed that male respondents were twice as likely to say they had been asked about sexual health and counseled about the potential toxicity (53% vs 22%; P < .001), and a substantially higher percentage of men reported receiving a formal assessment tool such as a survey (32% vs 5%; P = .001) compared with female respondents.

Taylor noted that the survey demonstrated several things. “One is that sexual toxicity is exceedingly common, and number two, it identified a gender disparity,” he said. “But number 3, and I think that this is an important aspect of our study, is that the majority of respondents felt that they would like a standard questionnaire to initiate and guide a discussion on sexual health with their provider.”

The reason that aspect is very important, he emphasized, is that “we know metrics and questionnaires already exist, so this gives us an actionable intervention that we can distribute and help mitigate some of these disparities.”
 

Importance of being holistic

The results of the survey “highlight the importance of being holistic in our approach to patient survivorship,” commented Karen Winkfield, MD, PhD, associate professor of radiation oncology at Wake Forest University, Winston-Salem, North Carolina, and executive director of the Meharry-Vanderbilt Alliance, Nashville, Tennessee.

“We need to ask patients about all parts of their well-being, including sexual health,” Winkfield said. “Body dysmorphism can impact anyone, but especially patients who have had surgery or radiation,” she said, while chemotherapy can impact energy and libido and have other toxicities that impact sexual health.

“I encourage all oncologists to ask patients about their sexual health, and a standardized form that can be used across all sites will make this much easier,” Winkfield commented. “We owe it to our patients to treat them holistically.”

The authors have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Sexual dysfunction is a common treatment-related problem observed across numerous cancer diagnoses, and a new survey finds that 87% of cancer survivors have had such problems.

However, most of them also reported that their oncologist had not formally discussed the topic, and female patients were particularly unlikely to be asked about sexual dysfunction.

“The main takeaway from our study is that sexual side effects following treatment are very common,” said lead author James Taylor, MD, MPH, chief resident in radiation oncology at the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, Pennsylvania.

“Nearly 9 in 10 patients reported some change after cancer treatment that negatively affected their sexual health,” he said.

Taylor was speaking at the American Society for Radiation Oncology (ASTRO) Annual Meeting, held virtually this year because of the pandemic.

“Negative effects on sexual health after cancer treatment are unfortunately very common,” he said. “This is not just patients treated with radiation but this includes chemotherapy, hormonal therapy, surgery, and other treatment modalities.”

Potential issues include physical complications such as erectile dysfunction with prostate cancer treatment or vaginal dryness with gynecological cancer treatment. One recent study found that one-third of men who had undergone treatment for prostate cancer reported that a subsequent lack of sexual function has had the greatest impact on their quality of life. Another study reported that nearly all patients with breast cancer taking endocrine therapy experience a high degree of sexual dysfunction, including vulvovaginal dryness and severe dyspareunia.
 

Not discussed, not warned

Taylor and colleagues developed a questionnaire with input from radiation oncologists, medical oncologists, and surgeons, which consisted of more than 25 questions and was specifically targeted at cancer survivors.

A total of 405 adults completed the electronic survey about their experiences with sexual side effects after cancer treatment (391 responses were eligible for analysis). Most of the respondents were women (81%), and the most common cancer types were breast (67%), prostate (16%), and endometrial (6%). Treatments included chemotherapy (78%), radiation therapy (54%), and hormone therapy (47%).

“The questionnaires were distributed at Thomas Jefferson and throughout social media,” said Taylor. “The responses from social media are important because it shows a broad representation of patients who are treated in multiple clinics across the United States.”

Most of the survivors who responded (n = 337, 87%) stated cancer treatment had impacted sexual function or desire, with 53.8% reporting body image distortion, 73.4% with dyspareunia, and 42.3% unable to achieve orgasm.

Only about one-quarter (27.9%) said they had been formally asked about their sexual health by their clinician.

“Only about 40% said that they have been preemptively warned that their sexual health may be affected by treatment,” said Taylor.

Women were far less likely to be asked about their sexual health by their provider. The survey showed that male respondents were twice as likely to say they had been asked about sexual health and counseled about the potential toxicity (53% vs 22%; P < .001), and a substantially higher percentage of men reported receiving a formal assessment tool such as a survey (32% vs 5%; P = .001) compared with female respondents.

Taylor noted that the survey demonstrated several things. “One is that sexual toxicity is exceedingly common, and number two, it identified a gender disparity,” he said. “But number 3, and I think that this is an important aspect of our study, is that the majority of respondents felt that they would like a standard questionnaire to initiate and guide a discussion on sexual health with their provider.”

The reason that aspect is very important, he emphasized, is that “we know metrics and questionnaires already exist, so this gives us an actionable intervention that we can distribute and help mitigate some of these disparities.”
 

Importance of being holistic

The results of the survey “highlight the importance of being holistic in our approach to patient survivorship,” commented Karen Winkfield, MD, PhD, associate professor of radiation oncology at Wake Forest University, Winston-Salem, North Carolina, and executive director of the Meharry-Vanderbilt Alliance, Nashville, Tennessee.

“We need to ask patients about all parts of their well-being, including sexual health,” Winkfield said. “Body dysmorphism can impact anyone, but especially patients who have had surgery or radiation,” she said, while chemotherapy can impact energy and libido and have other toxicities that impact sexual health.

“I encourage all oncologists to ask patients about their sexual health, and a standardized form that can be used across all sites will make this much easier,” Winkfield commented. “We owe it to our patients to treat them holistically.”

The authors have reported no relevant financial relationships.

This article first appeared on Medscape.com.

For patients with diabetic kidney disease, finerenone, an agent from a new class of selective, nonsteroidal mineralocorticoid receptor antagonists, led to significant reductions in combined adverse renal outcomes and in combined adverse cardiovascular outcomes in the pivotal FIDELIO-DKD trial.

And the safety results showed a good level of tolerability. The rate of hyperkalemia was higher with finerenone than with placebo, but the rate of drug discontinuations for elevated potassium was lower than that seen with spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA).

“An ideal drug would cause no hyperkalemia, but the absolute risk we saw is a fraction of what we see with spironolactone in this vulnerable patient population,” said Rajiv Agarwal, MD, from Indiana in Indianapolis, during a press briefing.

After a median follow-up of 2.6 years, finerenone was associated with a 3.4% absolute reduction in the rate of combined adverse renal events, the study’s primary end point, which comprised kidney failure, renal death, and a drop in estimated glomerular filtration rate (eGFR) of at least 40% from baseline. This produced a significant relative risk reduction of 18%, with a number needed to treat of 32 to prevent one of these events, Dr. Agarwal reported at Kidney Week 2020. Findings from the FIDELIO-DKD trial were published simultaneously in the New England Journal of Medicine.

Finerenone was also associated with an absolute 2.4% reduction in the rate of combined adverse cardiovascular events, the study’s “key secondary end point,” which included cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure. This translated into a significant relative risk reduction of 14% and a number needed to treat of 42 to prevent one of these events.

FIDELIO-DKD assessed 5,734 patients with type 2 diabetes and chronic kidney disease from more than 1,000 sites in 48 countries, including the United States, from 2015 to 2018. In the study cohort, average age was slightly more than 65 years, average baseline systolic blood pressure was 138 mm Hg, average duration of diabetes was nearly 17 years, average baseline glycated hemoglobin (A1c) was 7.7%, and fewer than 5% of patients were Black, 25% were Asian, and about 63% were White.
 

A suggestion of less severe hyperkalemia

Finerenone was well tolerated by the participants, and the findings suggest that it caused less clinically meaningful hyperkalemia than spironolactone, the most established and widely used MRA.

Like all MRA drugs, finerenone led to an increase in serum potassium in all patient subgroups – in this case 0.2 mmol/L – unlike placebo, said Dr. Agarwal.

The overall incidence of hyperkalemia was 16% in the 2,827 evaluable patients in the finerenone group and 8% in the 2,831 evaluable patients in the placebo group. Fewer than 10% of patients in the trial received a potassium-binding agent.

The rate of hyperkalemia leading to treatment discontinuation was higher in the finerenone group than in the placebo group (2.3% vs. 0.9%).

That 2.3% rate is 10 times lower than the 23.0% rate of hyperkalemia-related treatment discontinuation in patients who received spironolactone and no potassium-binding agent, said Dr. Agarwal, citing a previous study he was involved with.

He hypothesized that finerenone might cause less clinically meaningful hyperkalemia because it creates no active metabolites that linger in the body, whereas spironolactone produces active metabolites with a half life of about 1 week.

“The risk for hyperkalemia is clearly increased with finerenone compared with placebo, and in the absence of head-to-head studies, it’s hard to know how it compares with spironolactone or eplerenone [Inspra],” the other agents in the MRA class, said Mikhail N. Kosiborod, MD, from the University of Missouri–Kansas City.

“The rates of hyperkalemia observed in FIDELIO-DKD were overall comparable to what we would expect from eplerenone. But the rate of serious hyperkalemia was quite low with finerenone, which is reassuring,” Dr. Kosiborod said in an interview.

And the adverse-effect profile showed that finerenone “is as safe as you could expect from an MRA,” said Janani Rangaswami, MD, from the Einstein Medical Center in Philadelphia.

The rate of hyperkalemia should be interpreted in the context of the high risk the enrolled patients faced, given that they all had moderate to severe diabetic kidney disease with albuminuria and, in some cases, eGFR rates as low as 25 mL/min per 1.73m², she explained. In addition, all patients were on maximally tolerated treatment with either an angiotensin-converting–enzyme inhibitor or an angiotensin receptor blocker to inhibit the renin angiotensin system (RAS).

“Considering this background, it’s a very acceptable adverse-event profile,” Dr. Rangaswami said in an interview.
 

Renal drugs that could work together

More than 99% of patients in FIDELIO-DKD were on an RAS inhibitor, but fewer than 5% were on a sodium glucose cotransporter 2 (SGLT2) inhibitor at baseline, and fewer than 10% started on this drug class during the course of the study.

Despite that, both Dr. Kosiborod and Dr. Rangaswami are enthusiastic about the prospect of using the three drugs in combination to maximize renal and cardiovascular benefits in FIDELIO-DKD–type patients. Recent results from the CREDENCE study of canagliflozin (Invokana) and from the DAPA-CKD study of dapagluflozin (Farxiga) have established SGLT2 inhibitors – at least those two – as key agents for patients with chronic kidney disease.

Dual treatment with an RAS inhibitor and an SGLT2 inhibitor is “clearly established” for patients with diabetic kidney disease, said Dr. Agarwal.

“After CREDENCE, DAPA-CKD, and now FIDELIO-DKD, we need to seriously consider triple therapy as the future of treatment for diabetic kidney disease to prevent both cardiovascular and kidney complications,” said Dr. Kosiborod. The approach will mimic the multidrug therapy that’s now standard for patients with heart failure with reduced ejection fraction (HFrEF). But he cautioned that this triple combination needs further testing.

“Triple therapy will be the standard of care” for patients with diabetic kidney disease, Dr. Rangaswami agreed, but she cautioned that she would not currently expand the target population for finerenone to patients without type 2 diabetes or to patients without the level of albuminuria required for entry into FIDELIO-DKD: at least 30 mg/g of creatinine per day. And patients with HFrEF were excluded from FIDELIO-DKD, so that limitation on finerenone use should remain for the time being, she added.

Dr. Rangaswami said she is optimistic about the potential efficacy of finerenone added to an SGLT2 inhibitor because of the likelihood that the two drug classes work in different but complementary ways. SGLT2 inhibitors seem to exert their renal protective effects largely through hemodynamic effects, whereas it is likely that finerenone exerts its effects largely as an anti-inflammatory and antifibrotic agent, she speculated. The FIDELIO-DKD results appear to rule out any major effect of finerenone on blood pressure lowering because average systolic pressure fell by only about 2 mm Hg in the treatment group.

“The benefits of finerenone for cardiorenal outcomes are substantial and clinically meaningful,” Dr. Kosiborod said. “We cannot assume that other MRAs, such as spironolactone, provide similar benefits,” he cautioned, but the results are “very good news for patients with type 2 diabetes and chronic kidney disease. We now have another effective intervention with a different mechanism of action.”

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone (BAY 94-8862). Dr. Agarwal has been a consultant to and has received honoraria from Bayer and from several other companies. Dr. Kosiborod has been a consultant to Bayer and to AstraZeneca, Boehringer Ingelheim, Jansse, Merck, and Vifor and has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Rangaswami has disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

For patients with diabetic kidney disease, finerenone, an agent from a new class of selective, nonsteroidal mineralocorticoid receptor antagonists, led to significant reductions in combined adverse renal outcomes and in combined adverse cardiovascular outcomes in the pivotal FIDELIO-DKD trial.

And the safety results showed a good level of tolerability. The rate of hyperkalemia was higher with finerenone than with placebo, but the rate of drug discontinuations for elevated potassium was lower than that seen with spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA).

“An ideal drug would cause no hyperkalemia, but the absolute risk we saw is a fraction of what we see with spironolactone in this vulnerable patient population,” said Rajiv Agarwal, MD, from Indiana in Indianapolis, during a press briefing.

After a median follow-up of 2.6 years, finerenone was associated with a 3.4% absolute reduction in the rate of combined adverse renal events, the study’s primary end point, which comprised kidney failure, renal death, and a drop in estimated glomerular filtration rate (eGFR) of at least 40% from baseline. This produced a significant relative risk reduction of 18%, with a number needed to treat of 32 to prevent one of these events, Dr. Agarwal reported at Kidney Week 2020. Findings from the FIDELIO-DKD trial were published simultaneously in the New England Journal of Medicine.

Finerenone was also associated with an absolute 2.4% reduction in the rate of combined adverse cardiovascular events, the study’s “key secondary end point,” which included cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure. This translated into a significant relative risk reduction of 14% and a number needed to treat of 42 to prevent one of these events.

FIDELIO-DKD assessed 5,734 patients with type 2 diabetes and chronic kidney disease from more than 1,000 sites in 48 countries, including the United States, from 2015 to 2018. In the study cohort, average age was slightly more than 65 years, average baseline systolic blood pressure was 138 mm Hg, average duration of diabetes was nearly 17 years, average baseline glycated hemoglobin (A1c) was 7.7%, and fewer than 5% of patients were Black, 25% were Asian, and about 63% were White.
 

A suggestion of less severe hyperkalemia

Finerenone was well tolerated by the participants, and the findings suggest that it caused less clinically meaningful hyperkalemia than spironolactone, the most established and widely used MRA.

Like all MRA drugs, finerenone led to an increase in serum potassium in all patient subgroups – in this case 0.2 mmol/L – unlike placebo, said Dr. Agarwal.

The overall incidence of hyperkalemia was 16% in the 2,827 evaluable patients in the finerenone group and 8% in the 2,831 evaluable patients in the placebo group. Fewer than 10% of patients in the trial received a potassium-binding agent.

The rate of hyperkalemia leading to treatment discontinuation was higher in the finerenone group than in the placebo group (2.3% vs. 0.9%).

That 2.3% rate is 10 times lower than the 23.0% rate of hyperkalemia-related treatment discontinuation in patients who received spironolactone and no potassium-binding agent, said Dr. Agarwal, citing a previous study he was involved with.

He hypothesized that finerenone might cause less clinically meaningful hyperkalemia because it creates no active metabolites that linger in the body, whereas spironolactone produces active metabolites with a half life of about 1 week.

“The risk for hyperkalemia is clearly increased with finerenone compared with placebo, and in the absence of head-to-head studies, it’s hard to know how it compares with spironolactone or eplerenone [Inspra],” the other agents in the MRA class, said Mikhail N. Kosiborod, MD, from the University of Missouri–Kansas City.

“The rates of hyperkalemia observed in FIDELIO-DKD were overall comparable to what we would expect from eplerenone. But the rate of serious hyperkalemia was quite low with finerenone, which is reassuring,” Dr. Kosiborod said in an interview.

And the adverse-effect profile showed that finerenone “is as safe as you could expect from an MRA,” said Janani Rangaswami, MD, from the Einstein Medical Center in Philadelphia.

The rate of hyperkalemia should be interpreted in the context of the high risk the enrolled patients faced, given that they all had moderate to severe diabetic kidney disease with albuminuria and, in some cases, eGFR rates as low as 25 mL/min per 1.73m², she explained. In addition, all patients were on maximally tolerated treatment with either an angiotensin-converting–enzyme inhibitor or an angiotensin receptor blocker to inhibit the renin angiotensin system (RAS).

“Considering this background, it’s a very acceptable adverse-event profile,” Dr. Rangaswami said in an interview.
 

Renal drugs that could work together

More than 99% of patients in FIDELIO-DKD were on an RAS inhibitor, but fewer than 5% were on a sodium glucose cotransporter 2 (SGLT2) inhibitor at baseline, and fewer than 10% started on this drug class during the course of the study.

Despite that, both Dr. Kosiborod and Dr. Rangaswami are enthusiastic about the prospect of using the three drugs in combination to maximize renal and cardiovascular benefits in FIDELIO-DKD–type patients. Recent results from the CREDENCE study of canagliflozin (Invokana) and from the DAPA-CKD study of dapagluflozin (Farxiga) have established SGLT2 inhibitors – at least those two – as key agents for patients with chronic kidney disease.

Dual treatment with an RAS inhibitor and an SGLT2 inhibitor is “clearly established” for patients with diabetic kidney disease, said Dr. Agarwal.

“After CREDENCE, DAPA-CKD, and now FIDELIO-DKD, we need to seriously consider triple therapy as the future of treatment for diabetic kidney disease to prevent both cardiovascular and kidney complications,” said Dr. Kosiborod. The approach will mimic the multidrug therapy that’s now standard for patients with heart failure with reduced ejection fraction (HFrEF). But he cautioned that this triple combination needs further testing.

“Triple therapy will be the standard of care” for patients with diabetic kidney disease, Dr. Rangaswami agreed, but she cautioned that she would not currently expand the target population for finerenone to patients without type 2 diabetes or to patients without the level of albuminuria required for entry into FIDELIO-DKD: at least 30 mg/g of creatinine per day. And patients with HFrEF were excluded from FIDELIO-DKD, so that limitation on finerenone use should remain for the time being, she added.

Dr. Rangaswami said she is optimistic about the potential efficacy of finerenone added to an SGLT2 inhibitor because of the likelihood that the two drug classes work in different but complementary ways. SGLT2 inhibitors seem to exert their renal protective effects largely through hemodynamic effects, whereas it is likely that finerenone exerts its effects largely as an anti-inflammatory and antifibrotic agent, she speculated. The FIDELIO-DKD results appear to rule out any major effect of finerenone on blood pressure lowering because average systolic pressure fell by only about 2 mm Hg in the treatment group.

“The benefits of finerenone for cardiorenal outcomes are substantial and clinically meaningful,” Dr. Kosiborod said. “We cannot assume that other MRAs, such as spironolactone, provide similar benefits,” he cautioned, but the results are “very good news for patients with type 2 diabetes and chronic kidney disease. We now have another effective intervention with a different mechanism of action.”

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone (BAY 94-8862). Dr. Agarwal has been a consultant to and has received honoraria from Bayer and from several other companies. Dr. Kosiborod has been a consultant to Bayer and to AstraZeneca, Boehringer Ingelheim, Jansse, Merck, and Vifor and has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Rangaswami has disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

For patients with diabetic kidney disease, finerenone, an agent from a new class of selective, nonsteroidal mineralocorticoid receptor antagonists, led to significant reductions in combined adverse renal outcomes and in combined adverse cardiovascular outcomes in the pivotal FIDELIO-DKD trial.

And the safety results showed a good level of tolerability. The rate of hyperkalemia was higher with finerenone than with placebo, but the rate of drug discontinuations for elevated potassium was lower than that seen with spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA).

“An ideal drug would cause no hyperkalemia, but the absolute risk we saw is a fraction of what we see with spironolactone in this vulnerable patient population,” said Rajiv Agarwal, MD, from Indiana in Indianapolis, during a press briefing.

After a median follow-up of 2.6 years, finerenone was associated with a 3.4% absolute reduction in the rate of combined adverse renal events, the study’s primary end point, which comprised kidney failure, renal death, and a drop in estimated glomerular filtration rate (eGFR) of at least 40% from baseline. This produced a significant relative risk reduction of 18%, with a number needed to treat of 32 to prevent one of these events, Dr. Agarwal reported at Kidney Week 2020. Findings from the FIDELIO-DKD trial were published simultaneously in the New England Journal of Medicine.

Finerenone was also associated with an absolute 2.4% reduction in the rate of combined adverse cardiovascular events, the study’s “key secondary end point,” which included cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure. This translated into a significant relative risk reduction of 14% and a number needed to treat of 42 to prevent one of these events.

FIDELIO-DKD assessed 5,734 patients with type 2 diabetes and chronic kidney disease from more than 1,000 sites in 48 countries, including the United States, from 2015 to 2018. In the study cohort, average age was slightly more than 65 years, average baseline systolic blood pressure was 138 mm Hg, average duration of diabetes was nearly 17 years, average baseline glycated hemoglobin (A1c) was 7.7%, and fewer than 5% of patients were Black, 25% were Asian, and about 63% were White.
 

A suggestion of less severe hyperkalemia

Finerenone was well tolerated by the participants, and the findings suggest that it caused less clinically meaningful hyperkalemia than spironolactone, the most established and widely used MRA.

Like all MRA drugs, finerenone led to an increase in serum potassium in all patient subgroups – in this case 0.2 mmol/L – unlike placebo, said Dr. Agarwal.

The overall incidence of hyperkalemia was 16% in the 2,827 evaluable patients in the finerenone group and 8% in the 2,831 evaluable patients in the placebo group. Fewer than 10% of patients in the trial received a potassium-binding agent.

The rate of hyperkalemia leading to treatment discontinuation was higher in the finerenone group than in the placebo group (2.3% vs. 0.9%).

That 2.3% rate is 10 times lower than the 23.0% rate of hyperkalemia-related treatment discontinuation in patients who received spironolactone and no potassium-binding agent, said Dr. Agarwal, citing a previous study he was involved with.

He hypothesized that finerenone might cause less clinically meaningful hyperkalemia because it creates no active metabolites that linger in the body, whereas spironolactone produces active metabolites with a half life of about 1 week.

“The risk for hyperkalemia is clearly increased with finerenone compared with placebo, and in the absence of head-to-head studies, it’s hard to know how it compares with spironolactone or eplerenone [Inspra],” the other agents in the MRA class, said Mikhail N. Kosiborod, MD, from the University of Missouri–Kansas City.

“The rates of hyperkalemia observed in FIDELIO-DKD were overall comparable to what we would expect from eplerenone. But the rate of serious hyperkalemia was quite low with finerenone, which is reassuring,” Dr. Kosiborod said in an interview.

And the adverse-effect profile showed that finerenone “is as safe as you could expect from an MRA,” said Janani Rangaswami, MD, from the Einstein Medical Center in Philadelphia.

The rate of hyperkalemia should be interpreted in the context of the high risk the enrolled patients faced, given that they all had moderate to severe diabetic kidney disease with albuminuria and, in some cases, eGFR rates as low as 25 mL/min per 1.73m², she explained. In addition, all patients were on maximally tolerated treatment with either an angiotensin-converting–enzyme inhibitor or an angiotensin receptor blocker to inhibit the renin angiotensin system (RAS).

“Considering this background, it’s a very acceptable adverse-event profile,” Dr. Rangaswami said in an interview.
 

Renal drugs that could work together

More than 99% of patients in FIDELIO-DKD were on an RAS inhibitor, but fewer than 5% were on a sodium glucose cotransporter 2 (SGLT2) inhibitor at baseline, and fewer than 10% started on this drug class during the course of the study.

Despite that, both Dr. Kosiborod and Dr. Rangaswami are enthusiastic about the prospect of using the three drugs in combination to maximize renal and cardiovascular benefits in FIDELIO-DKD–type patients. Recent results from the CREDENCE study of canagliflozin (Invokana) and from the DAPA-CKD study of dapagluflozin (Farxiga) have established SGLT2 inhibitors – at least those two – as key agents for patients with chronic kidney disease.

Dual treatment with an RAS inhibitor and an SGLT2 inhibitor is “clearly established” for patients with diabetic kidney disease, said Dr. Agarwal.

“After CREDENCE, DAPA-CKD, and now FIDELIO-DKD, we need to seriously consider triple therapy as the future of treatment for diabetic kidney disease to prevent both cardiovascular and kidney complications,” said Dr. Kosiborod. The approach will mimic the multidrug therapy that’s now standard for patients with heart failure with reduced ejection fraction (HFrEF). But he cautioned that this triple combination needs further testing.

“Triple therapy will be the standard of care” for patients with diabetic kidney disease, Dr. Rangaswami agreed, but she cautioned that she would not currently expand the target population for finerenone to patients without type 2 diabetes or to patients without the level of albuminuria required for entry into FIDELIO-DKD: at least 30 mg/g of creatinine per day. And patients with HFrEF were excluded from FIDELIO-DKD, so that limitation on finerenone use should remain for the time being, she added.

Dr. Rangaswami said she is optimistic about the potential efficacy of finerenone added to an SGLT2 inhibitor because of the likelihood that the two drug classes work in different but complementary ways. SGLT2 inhibitors seem to exert their renal protective effects largely through hemodynamic effects, whereas it is likely that finerenone exerts its effects largely as an anti-inflammatory and antifibrotic agent, she speculated. The FIDELIO-DKD results appear to rule out any major effect of finerenone on blood pressure lowering because average systolic pressure fell by only about 2 mm Hg in the treatment group.

“The benefits of finerenone for cardiorenal outcomes are substantial and clinically meaningful,” Dr. Kosiborod said. “We cannot assume that other MRAs, such as spironolactone, provide similar benefits,” he cautioned, but the results are “very good news for patients with type 2 diabetes and chronic kidney disease. We now have another effective intervention with a different mechanism of action.”

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone (BAY 94-8862). Dr. Agarwal has been a consultant to and has received honoraria from Bayer and from several other companies. Dr. Kosiborod has been a consultant to Bayer and to AstraZeneca, Boehringer Ingelheim, Jansse, Merck, and Vifor and has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Rangaswami has disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

Tocilizumab (Actemra/RoActemra) was not found to have any clear role as a treatment for COVID-19 in four new studies.

Three randomized controlled trials showed that the drug either had no benefit or only a modest one, contradicting a large retrospective study that had hinted at a more robust effect.

“This is not a blockbuster,” said David Cennimo, MD, an infectious disease expert at Rutgers New Jersey Medical School, Newark, New Jersey. “This is not something that’s going to revolutionize our treatment of COVID-19.”

But some researchers still regard these studies as showing evidence that the drug benefits certain patients with severe inflammation.

The immune response to SARS-CoV-2 includes elevated levels of the cytokine interleukin-6 (IL-6). In some patients, this response becomes a nonspecific inflammation, a “cytokine storm,” involving edema and inflammatory cell infiltration in the lungs. These cases are among the most severe.

Dexamethasone has proved effective in controlling this inflammation in some patients. Researchers have theorized that a more targeted suppression of IL-6 could be even more effective or work in cases that don’t respond to dexamethasone.

A recombinant monoclonal antibody, tocilizumab blocks IL-6 receptors. It is approved by the US Food and Drug Administration for use in patients with rheumatologic disorders and cytokine release syndrome induced by chimeric antigen receptor T-cell therapy.

Current National Institutes of Health (NIH) guidelines recommend against the use of tocilizumab as a treatment for COVID-19, despite earlier observational studies that suggested the drug might help patients with moderate to severe disease. Controlled trials were lacking until now.

The most hopeful results in this batch came from the CORIMUNO-19 platform of open-label, randomized controlled trials of immune modulatory treatments for moderate or severe COVID-19 in France.

Published in JAMA Internal Medicine , the trial recruited patients from nine French hospitals. Patients were eligible if they required at least 3 L/min of oxygen without ventilation or admission to the intensive care unit.

The investigators randomly assigned 64 patients to receive tocilizumab 8 mg/kg body weight intravenously plus usual care and 67 patients to usual care alone. Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.

After 4 days, the investigators scored patients on the World Health Organization 10-point Clinical Progression Scale. Twelve of the patients who received tocilizumab scored higher than 5 vs 19 of the patients in the usual care group, with higher scores indicating clinical deterioration.

After 14 days, 24% of the patients taking tocilizumab required either noninvasive ventilation or mechanical ventilation or had died, vs 36% in the usual care group (median posterior hazard ratio [HR], 0.58; 90% credible interval, 0.33 – 1.00).

“We reduced the risk of dying or requiring mechanical ventilation, so for me, the study was positive,” said Olivier Hermine, MD, PhD, a professor of hematology at Paris Descartes University in Paris, France.

However, there was no difference in mortality at 28 days. Hermine hopes to have longer-term outcomes soon, he told Medscape Medical News.

A second randomized controlled trial, also published in JAMA Internal Medicine , provided less hope. In this RCT-TCZ-COVID-19 Study Group trial, conducted at 24 Italian centers, patients were enrolled if their partial pressure of arterial oxygen to fraction of inspired oxygen (PaO₂/FiO₂) ratios were between 200 and 300 mm Hg and if their inflammatory phenotypes were defined by fever and elevated C-reactive protein level.

The investigators randomly assigned 60 patients to receive tocilizumab 8 mg/kg up to a maximum of 800 mg within 8 hours of randomization, followed by a second dose after 12 hours. They assigned 66 patients to a control group that received supportive care until clinical worsening, at which point patients could receive tocilizumab as a rescue therapy.

Of the patients who received tocilizumab, 28.3% showed clinical worsening within 14 days, compared to 27.0% in the control group (rate ratio, 1.05; 95% CI, 0.59 – 1.86). There was no significant difference between the groups in terms of the proportion admitted to intensive care. The researchers stopped the trial prematurely because tocilizumab did not seem to be making a difference.

The BACC Bay Tocilizumab Trial was conducted at seven Boston hospitals. The results, which were published in The New England Journal of Medicine, were also discouraging.

In that trial, enrolled patients met two sets of parameters. First, the patients had at least one of the following signs: C-reactive protein level higher than 50 mg/L, ferritin level higher than 500 ng/mL, D-dimer level higher than 1000 ng/mL, or a lactate dehydrogenase level higher than 250 U/L. Second, the patients had to have at least two of the following signs: body temperature >38° C, pulmonary infiltrates, or the need for supplemental oxygen to maintain an oxygen saturation greater than 92%.

The investigators randomly assigned 161 patients to receive intravenous tocilizumab 8 mg/kg up to 800 mg and 81 to receive a placebo.

They didn’t find a statistically significant difference between the groups. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% CI, 0.38 – 1.81; P = .64). The hazard ratio for disease worsening was 1.11 (95% CI, 0.59 – 2.10; P = .73). At 14 days, the conditions of 18.0% of the patients who received tocilizumab and 14.9% of the patients who received the placebo worsened.

In contrast to these randomized trials, STOP-COVID, a retrospective analysis of 3924 patients, also published in JAMA Internal Medicine, found that the risk for death was lower for patients treated with tocilizumab compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56 – 0.92) over a median follow-up period of 27 days.

Also on the bright side, none of the new studies showed significant adverse reactions to tocilizumab.

More randomized clinical trials are underway. In press releases announcing topline data, Roche reported mostly negative results in its phase 3 COVACTA trial but noted a 44% reduction in the risk for progression to death or ventilation in its phase 3 IMPACTA trial. Roche did not comment on the ethnicity of its COVACTA patients; it said IMPACTA enrolled a majority of Hispanic patients and included large representations of Native American and Black patients.
 

Results don’t support routine use

Commenting on the new studies, editorialists in both JAMA Internal Medicine and The New England Journal of Medicine concluded that the tocilizumab results were not strong enough to support routine use.

“My take-home point from looking at all of these together is that, even if it does help, it’s most likely in a small subset of the population and/or a small effect,” Cennimo told Medscape Medical News.

But the NIH recommendation against tocilizumab goes too far, argued Cristina Mussini, MD, a professor of infectious diseases at the University of Modena and Reggio Emilia in Italy, who is a coauthor of a cohort study of tocilizumab and served on the CORIMUNO-19 Data Safety and Monitoring Board.

“I really think it’s too early to recommend against it because at least two clinical trials showed protection against mechanical ventilation and death,” she said.

She prescribes tocilizumab for patients who have not been helped by dexamethasone. “It’s just a rescue drug,” she told Medscape Medical News. “It’s not something you use for everybody, but it’s the only weapon we have now when the patient is really going to the intensive care unit.”

The BACC Bay Tocilizumab Trial was funded by Genentech/Roche. Genentech/Roche provided the drug for the CORIMUNO and RCT-TCZ-COVID-19 trials. The STOP-COVID study was supported by grants from the NIH and by the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor. Cennimo, Hermine, and Mussini have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Tocilizumab (Actemra/RoActemra) was not found to have any clear role as a treatment for COVID-19 in four new studies.

Three randomized controlled trials showed that the drug either had no benefit or only a modest one, contradicting a large retrospective study that had hinted at a more robust effect.

“This is not a blockbuster,” said David Cennimo, MD, an infectious disease expert at Rutgers New Jersey Medical School, Newark, New Jersey. “This is not something that’s going to revolutionize our treatment of COVID-19.”

But some researchers still regard these studies as showing evidence that the drug benefits certain patients with severe inflammation.

The immune response to SARS-CoV-2 includes elevated levels of the cytokine interleukin-6 (IL-6). In some patients, this response becomes a nonspecific inflammation, a “cytokine storm,” involving edema and inflammatory cell infiltration in the lungs. These cases are among the most severe.

Dexamethasone has proved effective in controlling this inflammation in some patients. Researchers have theorized that a more targeted suppression of IL-6 could be even more effective or work in cases that don’t respond to dexamethasone.

A recombinant monoclonal antibody, tocilizumab blocks IL-6 receptors. It is approved by the US Food and Drug Administration for use in patients with rheumatologic disorders and cytokine release syndrome induced by chimeric antigen receptor T-cell therapy.

Current National Institutes of Health (NIH) guidelines recommend against the use of tocilizumab as a treatment for COVID-19, despite earlier observational studies that suggested the drug might help patients with moderate to severe disease. Controlled trials were lacking until now.

The most hopeful results in this batch came from the CORIMUNO-19 platform of open-label, randomized controlled trials of immune modulatory treatments for moderate or severe COVID-19 in France.

Published in JAMA Internal Medicine , the trial recruited patients from nine French hospitals. Patients were eligible if they required at least 3 L/min of oxygen without ventilation or admission to the intensive care unit.

The investigators randomly assigned 64 patients to receive tocilizumab 8 mg/kg body weight intravenously plus usual care and 67 patients to usual care alone. Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.

After 4 days, the investigators scored patients on the World Health Organization 10-point Clinical Progression Scale. Twelve of the patients who received tocilizumab scored higher than 5 vs 19 of the patients in the usual care group, with higher scores indicating clinical deterioration.

After 14 days, 24% of the patients taking tocilizumab required either noninvasive ventilation or mechanical ventilation or had died, vs 36% in the usual care group (median posterior hazard ratio [HR], 0.58; 90% credible interval, 0.33 – 1.00).

“We reduced the risk of dying or requiring mechanical ventilation, so for me, the study was positive,” said Olivier Hermine, MD, PhD, a professor of hematology at Paris Descartes University in Paris, France.

However, there was no difference in mortality at 28 days. Hermine hopes to have longer-term outcomes soon, he told Medscape Medical News.

A second randomized controlled trial, also published in JAMA Internal Medicine , provided less hope. In this RCT-TCZ-COVID-19 Study Group trial, conducted at 24 Italian centers, patients were enrolled if their partial pressure of arterial oxygen to fraction of inspired oxygen (PaO₂/FiO₂) ratios were between 200 and 300 mm Hg and if their inflammatory phenotypes were defined by fever and elevated C-reactive protein level.

The investigators randomly assigned 60 patients to receive tocilizumab 8 mg/kg up to a maximum of 800 mg within 8 hours of randomization, followed by a second dose after 12 hours. They assigned 66 patients to a control group that received supportive care until clinical worsening, at which point patients could receive tocilizumab as a rescue therapy.

Of the patients who received tocilizumab, 28.3% showed clinical worsening within 14 days, compared to 27.0% in the control group (rate ratio, 1.05; 95% CI, 0.59 – 1.86). There was no significant difference between the groups in terms of the proportion admitted to intensive care. The researchers stopped the trial prematurely because tocilizumab did not seem to be making a difference.

The BACC Bay Tocilizumab Trial was conducted at seven Boston hospitals. The results, which were published in The New England Journal of Medicine, were also discouraging.

In that trial, enrolled patients met two sets of parameters. First, the patients had at least one of the following signs: C-reactive protein level higher than 50 mg/L, ferritin level higher than 500 ng/mL, D-dimer level higher than 1000 ng/mL, or a lactate dehydrogenase level higher than 250 U/L. Second, the patients had to have at least two of the following signs: body temperature >38° C, pulmonary infiltrates, or the need for supplemental oxygen to maintain an oxygen saturation greater than 92%.

The investigators randomly assigned 161 patients to receive intravenous tocilizumab 8 mg/kg up to 800 mg and 81 to receive a placebo.

They didn’t find a statistically significant difference between the groups. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% CI, 0.38 – 1.81; P = .64). The hazard ratio for disease worsening was 1.11 (95% CI, 0.59 – 2.10; P = .73). At 14 days, the conditions of 18.0% of the patients who received tocilizumab and 14.9% of the patients who received the placebo worsened.

In contrast to these randomized trials, STOP-COVID, a retrospective analysis of 3924 patients, also published in JAMA Internal Medicine, found that the risk for death was lower for patients treated with tocilizumab compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56 – 0.92) over a median follow-up period of 27 days.

Also on the bright side, none of the new studies showed significant adverse reactions to tocilizumab.

More randomized clinical trials are underway. In press releases announcing topline data, Roche reported mostly negative results in its phase 3 COVACTA trial but noted a 44% reduction in the risk for progression to death or ventilation in its phase 3 IMPACTA trial. Roche did not comment on the ethnicity of its COVACTA patients; it said IMPACTA enrolled a majority of Hispanic patients and included large representations of Native American and Black patients.
 

Results don’t support routine use

Commenting on the new studies, editorialists in both JAMA Internal Medicine and The New England Journal of Medicine concluded that the tocilizumab results were not strong enough to support routine use.

“My take-home point from looking at all of these together is that, even if it does help, it’s most likely in a small subset of the population and/or a small effect,” Cennimo told Medscape Medical News.

But the NIH recommendation against tocilizumab goes too far, argued Cristina Mussini, MD, a professor of infectious diseases at the University of Modena and Reggio Emilia in Italy, who is a coauthor of a cohort study of tocilizumab and served on the CORIMUNO-19 Data Safety and Monitoring Board.

“I really think it’s too early to recommend against it because at least two clinical trials showed protection against mechanical ventilation and death,” she said.

She prescribes tocilizumab for patients who have not been helped by dexamethasone. “It’s just a rescue drug,” she told Medscape Medical News. “It’s not something you use for everybody, but it’s the only weapon we have now when the patient is really going to the intensive care unit.”

The BACC Bay Tocilizumab Trial was funded by Genentech/Roche. Genentech/Roche provided the drug for the CORIMUNO and RCT-TCZ-COVID-19 trials. The STOP-COVID study was supported by grants from the NIH and by the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor. Cennimo, Hermine, and Mussini have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Tocilizumab (Actemra/RoActemra) was not found to have any clear role as a treatment for COVID-19 in four new studies.

Three randomized controlled trials showed that the drug either had no benefit or only a modest one, contradicting a large retrospective study that had hinted at a more robust effect.

“This is not a blockbuster,” said David Cennimo, MD, an infectious disease expert at Rutgers New Jersey Medical School, Newark, New Jersey. “This is not something that’s going to revolutionize our treatment of COVID-19.”

But some researchers still regard these studies as showing evidence that the drug benefits certain patients with severe inflammation.

The immune response to SARS-CoV-2 includes elevated levels of the cytokine interleukin-6 (IL-6). In some patients, this response becomes a nonspecific inflammation, a “cytokine storm,” involving edema and inflammatory cell infiltration in the lungs. These cases are among the most severe.

Dexamethasone has proved effective in controlling this inflammation in some patients. Researchers have theorized that a more targeted suppression of IL-6 could be even more effective or work in cases that don’t respond to dexamethasone.

A recombinant monoclonal antibody, tocilizumab blocks IL-6 receptors. It is approved by the US Food and Drug Administration for use in patients with rheumatologic disorders and cytokine release syndrome induced by chimeric antigen receptor T-cell therapy.

Current National Institutes of Health (NIH) guidelines recommend against the use of tocilizumab as a treatment for COVID-19, despite earlier observational studies that suggested the drug might help patients with moderate to severe disease. Controlled trials were lacking until now.

The most hopeful results in this batch came from the CORIMUNO-19 platform of open-label, randomized controlled trials of immune modulatory treatments for moderate or severe COVID-19 in France.

Published in JAMA Internal Medicine , the trial recruited patients from nine French hospitals. Patients were eligible if they required at least 3 L/min of oxygen without ventilation or admission to the intensive care unit.

The investigators randomly assigned 64 patients to receive tocilizumab 8 mg/kg body weight intravenously plus usual care and 67 patients to usual care alone. Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.

After 4 days, the investigators scored patients on the World Health Organization 10-point Clinical Progression Scale. Twelve of the patients who received tocilizumab scored higher than 5 vs 19 of the patients in the usual care group, with higher scores indicating clinical deterioration.

After 14 days, 24% of the patients taking tocilizumab required either noninvasive ventilation or mechanical ventilation or had died, vs 36% in the usual care group (median posterior hazard ratio [HR], 0.58; 90% credible interval, 0.33 – 1.00).

“We reduced the risk of dying or requiring mechanical ventilation, so for me, the study was positive,” said Olivier Hermine, MD, PhD, a professor of hematology at Paris Descartes University in Paris, France.

However, there was no difference in mortality at 28 days. Hermine hopes to have longer-term outcomes soon, he told Medscape Medical News.

A second randomized controlled trial, also published in JAMA Internal Medicine , provided less hope. In this RCT-TCZ-COVID-19 Study Group trial, conducted at 24 Italian centers, patients were enrolled if their partial pressure of arterial oxygen to fraction of inspired oxygen (PaO₂/FiO₂) ratios were between 200 and 300 mm Hg and if their inflammatory phenotypes were defined by fever and elevated C-reactive protein level.

The investigators randomly assigned 60 patients to receive tocilizumab 8 mg/kg up to a maximum of 800 mg within 8 hours of randomization, followed by a second dose after 12 hours. They assigned 66 patients to a control group that received supportive care until clinical worsening, at which point patients could receive tocilizumab as a rescue therapy.

Of the patients who received tocilizumab, 28.3% showed clinical worsening within 14 days, compared to 27.0% in the control group (rate ratio, 1.05; 95% CI, 0.59 – 1.86). There was no significant difference between the groups in terms of the proportion admitted to intensive care. The researchers stopped the trial prematurely because tocilizumab did not seem to be making a difference.

The BACC Bay Tocilizumab Trial was conducted at seven Boston hospitals. The results, which were published in The New England Journal of Medicine, were also discouraging.

In that trial, enrolled patients met two sets of parameters. First, the patients had at least one of the following signs: C-reactive protein level higher than 50 mg/L, ferritin level higher than 500 ng/mL, D-dimer level higher than 1000 ng/mL, or a lactate dehydrogenase level higher than 250 U/L. Second, the patients had to have at least two of the following signs: body temperature >38° C, pulmonary infiltrates, or the need for supplemental oxygen to maintain an oxygen saturation greater than 92%.

The investigators randomly assigned 161 patients to receive intravenous tocilizumab 8 mg/kg up to 800 mg and 81 to receive a placebo.

They didn’t find a statistically significant difference between the groups. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% CI, 0.38 – 1.81; P = .64). The hazard ratio for disease worsening was 1.11 (95% CI, 0.59 – 2.10; P = .73). At 14 days, the conditions of 18.0% of the patients who received tocilizumab and 14.9% of the patients who received the placebo worsened.

In contrast to these randomized trials, STOP-COVID, a retrospective analysis of 3924 patients, also published in JAMA Internal Medicine, found that the risk for death was lower for patients treated with tocilizumab compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56 – 0.92) over a median follow-up period of 27 days.

Also on the bright side, none of the new studies showed significant adverse reactions to tocilizumab.

More randomized clinical trials are underway. In press releases announcing topline data, Roche reported mostly negative results in its phase 3 COVACTA trial but noted a 44% reduction in the risk for progression to death or ventilation in its phase 3 IMPACTA trial. Roche did not comment on the ethnicity of its COVACTA patients; it said IMPACTA enrolled a majority of Hispanic patients and included large representations of Native American and Black patients.
 

Results don’t support routine use

Commenting on the new studies, editorialists in both JAMA Internal Medicine and The New England Journal of Medicine concluded that the tocilizumab results were not strong enough to support routine use.

“My take-home point from looking at all of these together is that, even if it does help, it’s most likely in a small subset of the population and/or a small effect,” Cennimo told Medscape Medical News.

But the NIH recommendation against tocilizumab goes too far, argued Cristina Mussini, MD, a professor of infectious diseases at the University of Modena and Reggio Emilia in Italy, who is a coauthor of a cohort study of tocilizumab and served on the CORIMUNO-19 Data Safety and Monitoring Board.

“I really think it’s too early to recommend against it because at least two clinical trials showed protection against mechanical ventilation and death,” she said.

She prescribes tocilizumab for patients who have not been helped by dexamethasone. “It’s just a rescue drug,” she told Medscape Medical News. “It’s not something you use for everybody, but it’s the only weapon we have now when the patient is really going to the intensive care unit.”

The BACC Bay Tocilizumab Trial was funded by Genentech/Roche. Genentech/Roche provided the drug for the CORIMUNO and RCT-TCZ-COVID-19 trials. The STOP-COVID study was supported by grants from the NIH and by the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor. Cennimo, Hermine, and Mussini have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

New guidelines recommend against retreatment with poly (ADP-ribose) polymerase (PARP) inhibitors in women with epithelial ovarian, tubal, or primary peritoneal cancer (EOC). However, trials investigating retreatment are underway, so this recommendation may change.

The guidelines, from the American Society of Clinical Oncology (ASCO), do not recommend PARP inhibitors for the initial treatment of stage I-II EOC.

However, PARP inhibitor maintenance should be offered to women with newly diagnosed stage III-IV EOC who achieved a complete or partial response with first-line platinum-based chemotherapy, according to the guidelines. Niraparib can be offered to all women meeting those criteria, while olaparib can be considered for patients with mutations in BRCA1/2.

The guidelines, published in the Journal of Clinical Oncology, are based on a systematic review of recent randomized PARP inhibitor trials, including PRIMA and SOLO1, among others.

What’s not available now is overall survival results from key clinical trials, the guideline authors noted. They added that further research is needed to address the issue of conserving platinum sensitivity in patients with disease progression on or after PARP inhibitor maintenance.

“Given the expectation that early treatment may confer the best outcome, maintenance therapy with PARP inhibitors should be offered, with these caveats,” the authors wrote.

Olaparib can also be added to bevacizumab maintenance therapy following response to first-line chemotherapy plus bevacizumab, according to the guidelines, which also address PARP inhibitor use for women with recurrent EOC, as well as management of adverse events.

The guidelines recommend against pairing PARP inhibitors with chemotherapy, targeted therapy, or immunotherapy outside a clinical trial.
 

Which drug, which setting, which dose?

This new ASCO guidelines may help cut through the complexity of treatment decision-making for women with EOC, according to Roisin E. O’Cearbhaill, MD, of Memorial Sloan Kettering Cancer Center in New York.

“Today as clinicians, we have a whole range of opportunities to give our patients PARP inhibitors in the upfront and recurrent setting,” Dr. O’Cearbhaill said in an interview. “It is quite complicated to know which PARP inhibitor should be used in which setting and which patients.”

“We want to make sure that patients who would derive the most benefit from PARP inhibitors are offered these agents but also that we’re careful not to use PARP inhibitors in settings where there is little or no data,” added Dr. O’Cearbhaill, who was not involved in the drafting of the guidelines.

The ASCO guidelines provide a detailed review of 17 clinical trials to address key issues, including the histologic types of EOC and biomarker subsets for which PARP inhibitors are recommended in the newly diagnosed setting, as well as the settings, dose, and duration of treatment that are recommended for patients with recurrent EOC who have not yet received a PARP inhibitor.

While PARP inhibitors are generally well tolerated, some characteristic toxicities – such as anemia, neutropenia, thrombocytopenia, persistent cytopenias, and nausea – may warrant dose reductions, the guidelines state.

Special attention must be paid to low-grade adverse events since PARP inhibitors are administered continuously on a daily basis, according to the guidelines. If a dose is held because of a grade 2 adverse event, the subsequent dose should be reduced to avoid a second dose hold.

“Reescalation or resumption of the initial dose is never recommended,” the guidelines state.
 

Retreatment

Dr. O’Cearbhaill said she is eager to see future guidelines addressing PARP inhibitor retreatment following disease progression, especially since more and more patients will receive these agents in the upfront setting.

Right now, there is little data available to address PARP inhibitor retreatment. However, the ASCO guidelines do mention the ongoing OReO/ENGOT OV-38 phase 3 trial of maintenance retreatment with olaparib in women with EOC.

This study, which includes patients who previously received a PARP inhibitor and who are responding to additional platinum-based chemotherapy, has an estimated completion date in May 2021, according to details on ClinicalTrials.gov.

That’s one of several trials designed to determine how best to incorporate PARP inhibitor retreatment into the treatment paradigm, according to Dr. O’Cearbhaill.

“Even if a high proportion of patients aren’t ultimately cured by this approach, if we can delay progression of disease by the order of months or even years, whilst proactively managing side effects, it would make such a big difference for patients,” she said. “It allows them to have a better quality of life and go about their daily activities without symptomatic ovarian cancer.”

Cochairs of the ASCO expert panel for the guidelines were William P. Tew, MD, of Memorial Sloan Kettering Cancer Center in New York, and Elise C. Kohn, MD, of the National Cancer Institute in Bethesda, Md. Dr. Tew and Dr. Kohn provided no disclosures, while their coauthors reported disclosures related to Roche, AstraZeneca, Tesaro, Clovis Oncology, Merck, Seattle Genetics, and other companies. Dr. O’Cearbhaill disclosed that she is a coauthor on the PRIMA/ENGOT-OV26/GOG-3012 phase 3 clinical trial (NCT02655016) and serves on the steering committee for DUO-O (NCT0373643). She reported personal fees from Clovis, Tesaro, Regeneron, and GlaxoSmithKline.

SOURCE: Tew WP et al. J Clin Oncol. 2020 Aug 13. doi: 10.1200/JCO.20.01924.

New guidelines recommend against retreatment with poly (ADP-ribose) polymerase (PARP) inhibitors in women with epithelial ovarian, tubal, or primary peritoneal cancer (EOC). However, trials investigating retreatment are underway, so this recommendation may change.

The guidelines, from the American Society of Clinical Oncology (ASCO), do not recommend PARP inhibitors for the initial treatment of stage I-II EOC.

However, PARP inhibitor maintenance should be offered to women with newly diagnosed stage III-IV EOC who achieved a complete or partial response with first-line platinum-based chemotherapy, according to the guidelines. Niraparib can be offered to all women meeting those criteria, while olaparib can be considered for patients with mutations in BRCA1/2.

The guidelines, published in the Journal of Clinical Oncology, are based on a systematic review of recent randomized PARP inhibitor trials, including PRIMA and SOLO1, among others.

What’s not available now is overall survival results from key clinical trials, the guideline authors noted. They added that further research is needed to address the issue of conserving platinum sensitivity in patients with disease progression on or after PARP inhibitor maintenance.

“Given the expectation that early treatment may confer the best outcome, maintenance therapy with PARP inhibitors should be offered, with these caveats,” the authors wrote.

Olaparib can also be added to bevacizumab maintenance therapy following response to first-line chemotherapy plus bevacizumab, according to the guidelines, which also address PARP inhibitor use for women with recurrent EOC, as well as management of adverse events.

The guidelines recommend against pairing PARP inhibitors with chemotherapy, targeted therapy, or immunotherapy outside a clinical trial.
 

Which drug, which setting, which dose?

This new ASCO guidelines may help cut through the complexity of treatment decision-making for women with EOC, according to Roisin E. O’Cearbhaill, MD, of Memorial Sloan Kettering Cancer Center in New York.

“Today as clinicians, we have a whole range of opportunities to give our patients PARP inhibitors in the upfront and recurrent setting,” Dr. O’Cearbhaill said in an interview. “It is quite complicated to know which PARP inhibitor should be used in which setting and which patients.”

“We want to make sure that patients who would derive the most benefit from PARP inhibitors are offered these agents but also that we’re careful not to use PARP inhibitors in settings where there is little or no data,” added Dr. O’Cearbhaill, who was not involved in the drafting of the guidelines.

The ASCO guidelines provide a detailed review of 17 clinical trials to address key issues, including the histologic types of EOC and biomarker subsets for which PARP inhibitors are recommended in the newly diagnosed setting, as well as the settings, dose, and duration of treatment that are recommended for patients with recurrent EOC who have not yet received a PARP inhibitor.

While PARP inhibitors are generally well tolerated, some characteristic toxicities – such as anemia, neutropenia, thrombocytopenia, persistent cytopenias, and nausea – may warrant dose reductions, the guidelines state.

Special attention must be paid to low-grade adverse events since PARP inhibitors are administered continuously on a daily basis, according to the guidelines. If a dose is held because of a grade 2 adverse event, the subsequent dose should be reduced to avoid a second dose hold.

“Reescalation or resumption of the initial dose is never recommended,” the guidelines state.
 

Retreatment

Dr. O’Cearbhaill said she is eager to see future guidelines addressing PARP inhibitor retreatment following disease progression, especially since more and more patients will receive these agents in the upfront setting.

Right now, there is little data available to address PARP inhibitor retreatment. However, the ASCO guidelines do mention the ongoing OReO/ENGOT OV-38 phase 3 trial of maintenance retreatment with olaparib in women with EOC.

This study, which includes patients who previously received a PARP inhibitor and who are responding to additional platinum-based chemotherapy, has an estimated completion date in May 2021, according to details on ClinicalTrials.gov.

That’s one of several trials designed to determine how best to incorporate PARP inhibitor retreatment into the treatment paradigm, according to Dr. O’Cearbhaill.

“Even if a high proportion of patients aren’t ultimately cured by this approach, if we can delay progression of disease by the order of months or even years, whilst proactively managing side effects, it would make such a big difference for patients,” she said. “It allows them to have a better quality of life and go about their daily activities without symptomatic ovarian cancer.”

Cochairs of the ASCO expert panel for the guidelines were William P. Tew, MD, of Memorial Sloan Kettering Cancer Center in New York, and Elise C. Kohn, MD, of the National Cancer Institute in Bethesda, Md. Dr. Tew and Dr. Kohn provided no disclosures, while their coauthors reported disclosures related to Roche, AstraZeneca, Tesaro, Clovis Oncology, Merck, Seattle Genetics, and other companies. Dr. O’Cearbhaill disclosed that she is a coauthor on the PRIMA/ENGOT-OV26/GOG-3012 phase 3 clinical trial (NCT02655016) and serves on the steering committee for DUO-O (NCT0373643). She reported personal fees from Clovis, Tesaro, Regeneron, and GlaxoSmithKline.

SOURCE: Tew WP et al. J Clin Oncol. 2020 Aug 13. doi: 10.1200/JCO.20.01924.

New guidelines recommend against retreatment with poly (ADP-ribose) polymerase (PARP) inhibitors in women with epithelial ovarian, tubal, or primary peritoneal cancer (EOC). However, trials investigating retreatment are underway, so this recommendation may change.

The guidelines, from the American Society of Clinical Oncology (ASCO), do not recommend PARP inhibitors for the initial treatment of stage I-II EOC.

However, PARP inhibitor maintenance should be offered to women with newly diagnosed stage III-IV EOC who achieved a complete or partial response with first-line platinum-based chemotherapy, according to the guidelines. Niraparib can be offered to all women meeting those criteria, while olaparib can be considered for patients with mutations in BRCA1/2.

The guidelines, published in the Journal of Clinical Oncology, are based on a systematic review of recent randomized PARP inhibitor trials, including PRIMA and SOLO1, among others.

What’s not available now is overall survival results from key clinical trials, the guideline authors noted. They added that further research is needed to address the issue of conserving platinum sensitivity in patients with disease progression on or after PARP inhibitor maintenance.

“Given the expectation that early treatment may confer the best outcome, maintenance therapy with PARP inhibitors should be offered, with these caveats,” the authors wrote.

Olaparib can also be added to bevacizumab maintenance therapy following response to first-line chemotherapy plus bevacizumab, according to the guidelines, which also address PARP inhibitor use for women with recurrent EOC, as well as management of adverse events.

The guidelines recommend against pairing PARP inhibitors with chemotherapy, targeted therapy, or immunotherapy outside a clinical trial.
 

Which drug, which setting, which dose?

This new ASCO guidelines may help cut through the complexity of treatment decision-making for women with EOC, according to Roisin E. O’Cearbhaill, MD, of Memorial Sloan Kettering Cancer Center in New York.

“Today as clinicians, we have a whole range of opportunities to give our patients PARP inhibitors in the upfront and recurrent setting,” Dr. O’Cearbhaill said in an interview. “It is quite complicated to know which PARP inhibitor should be used in which setting and which patients.”

“We want to make sure that patients who would derive the most benefit from PARP inhibitors are offered these agents but also that we’re careful not to use PARP inhibitors in settings where there is little or no data,” added Dr. O’Cearbhaill, who was not involved in the drafting of the guidelines.

The ASCO guidelines provide a detailed review of 17 clinical trials to address key issues, including the histologic types of EOC and biomarker subsets for which PARP inhibitors are recommended in the newly diagnosed setting, as well as the settings, dose, and duration of treatment that are recommended for patients with recurrent EOC who have not yet received a PARP inhibitor.

While PARP inhibitors are generally well tolerated, some characteristic toxicities – such as anemia, neutropenia, thrombocytopenia, persistent cytopenias, and nausea – may warrant dose reductions, the guidelines state.

Special attention must be paid to low-grade adverse events since PARP inhibitors are administered continuously on a daily basis, according to the guidelines. If a dose is held because of a grade 2 adverse event, the subsequent dose should be reduced to avoid a second dose hold.

“Reescalation or resumption of the initial dose is never recommended,” the guidelines state.
 

Retreatment

Dr. O’Cearbhaill said she is eager to see future guidelines addressing PARP inhibitor retreatment following disease progression, especially since more and more patients will receive these agents in the upfront setting.

Right now, there is little data available to address PARP inhibitor retreatment. However, the ASCO guidelines do mention the ongoing OReO/ENGOT OV-38 phase 3 trial of maintenance retreatment with olaparib in women with EOC.

This study, which includes patients who previously received a PARP inhibitor and who are responding to additional platinum-based chemotherapy, has an estimated completion date in May 2021, according to details on ClinicalTrials.gov.

That’s one of several trials designed to determine how best to incorporate PARP inhibitor retreatment into the treatment paradigm, according to Dr. O’Cearbhaill.

“Even if a high proportion of patients aren’t ultimately cured by this approach, if we can delay progression of disease by the order of months or even years, whilst proactively managing side effects, it would make such a big difference for patients,” she said. “It allows them to have a better quality of life and go about their daily activities without symptomatic ovarian cancer.”

Cochairs of the ASCO expert panel for the guidelines were William P. Tew, MD, of Memorial Sloan Kettering Cancer Center in New York, and Elise C. Kohn, MD, of the National Cancer Institute in Bethesda, Md. Dr. Tew and Dr. Kohn provided no disclosures, while their coauthors reported disclosures related to Roche, AstraZeneca, Tesaro, Clovis Oncology, Merck, Seattle Genetics, and other companies. Dr. O’Cearbhaill disclosed that she is a coauthor on the PRIMA/ENGOT-OV26/GOG-3012 phase 3 clinical trial (NCT02655016) and serves on the steering committee for DUO-O (NCT0373643). She reported personal fees from Clovis, Tesaro, Regeneron, and GlaxoSmithKline.

SOURCE: Tew WP et al. J Clin Oncol. 2020 Aug 13. doi: 10.1200/JCO.20.01924.

Novel therapies are poised to dramatically change frontline therapy for acute myeloid leukemia (AML), and they have the potential to replace chemotherapy, a hematologist/oncologist told colleagues at the virtual Acute Leukemia Forum of Hemedicus.

But more work needs to be done, noted Alexander Perl, MD, MS, associate professor at the University of Pennsylvania, Philadelphia. While advances have transformed AML treatment in the relapsed/refractory setting, “we’re just not seeing that substantive improvement” for newly diagnosed patients, he said. “We need to find the disease-modifying drugs that work in the relapsed/refractory setting and move those frontline. That’s where we’re going to see the transformations.”

Research suggests that low-intensity therapy holds tremendous promise, he said, “with the idea that we could make therapy much more tolerable for the vast majority of patients affected by AML, who, as we know, are older patients.”

Dr. Perl highlighted the 2020 VIALE-A study – venetoclax/azacitidine versus azacitidine/placebo – which reported that “in previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone.”

Venetoclax promotes apoptosis in leukemia cells, Dr. Perl said. “To a certain extent, you can think of it as putting the rubber to the road in terms of what actually chemotherapy is designed to do, which is to make leukemic blasts apoptose. It does so without DNA damage and with much less toxicity to the patient. Therefore it can be added to any number of regimens – granted, with mild suppression, but with relatively little extramedullary toxicity.”

Dr. Perl noted that the venetoclax arm “showed a higher response rate than azacitidine in pretty much every subgroup that was looked at, whether patients had de novo leukemia, secondary leukemia, multiple mutational complements, various different karyotypes. The response rates on this study are as high as what we often will see with intensive chemotherapy.” He added that “the winning arm on this trial seems to hold up against any low-intensity therapy, and I would argue against many high-intensity therapies in older patients.”

As for other targeted agents, isocitrate dehydrogenase (IDH) inhibitors “are very promising drugs in the relapsed/refractory setting, which is primarily where these drugs are given. In regard to frontline treatment, “data are coming from a very small study, but they’re very encouraging. It’s hard to entirely say that we’re ready to change practice based on this. But it’s very encouraging – the idea that earlier use of a drug-targeting IDH mutation might lead to substantially better outcomes.”

Moving forward, he said, “we could put all of our eggs in one basket and use many active drugs [at] front line. Or we can perhaps be smart about sequencing these drugs one after another, or using more intensive approaches followed by maintenance approaches followed by more intensive approaches.”

This approach is similar to strategies in myeloma patients “who less and less are relying on an autologous transplant for durable control of their disease, and more and more are using low-intensity biologically targeted drugs,” he said.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Dr. Perl reported numerous disclosures, including relationships with Daiichi Sankyo, Abbvie, and Astellas.

Novel therapies are poised to dramatically change frontline therapy for acute myeloid leukemia (AML), and they have the potential to replace chemotherapy, a hematologist/oncologist told colleagues at the virtual Acute Leukemia Forum of Hemedicus.

But more work needs to be done, noted Alexander Perl, MD, MS, associate professor at the University of Pennsylvania, Philadelphia. While advances have transformed AML treatment in the relapsed/refractory setting, “we’re just not seeing that substantive improvement” for newly diagnosed patients, he said. “We need to find the disease-modifying drugs that work in the relapsed/refractory setting and move those frontline. That’s where we’re going to see the transformations.”

Research suggests that low-intensity therapy holds tremendous promise, he said, “with the idea that we could make therapy much more tolerable for the vast majority of patients affected by AML, who, as we know, are older patients.”

Dr. Perl highlighted the 2020 VIALE-A study – venetoclax/azacitidine versus azacitidine/placebo – which reported that “in previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone.”

Venetoclax promotes apoptosis in leukemia cells, Dr. Perl said. “To a certain extent, you can think of it as putting the rubber to the road in terms of what actually chemotherapy is designed to do, which is to make leukemic blasts apoptose. It does so without DNA damage and with much less toxicity to the patient. Therefore it can be added to any number of regimens – granted, with mild suppression, but with relatively little extramedullary toxicity.”

Dr. Perl noted that the venetoclax arm “showed a higher response rate than azacitidine in pretty much every subgroup that was looked at, whether patients had de novo leukemia, secondary leukemia, multiple mutational complements, various different karyotypes. The response rates on this study are as high as what we often will see with intensive chemotherapy.” He added that “the winning arm on this trial seems to hold up against any low-intensity therapy, and I would argue against many high-intensity therapies in older patients.”

As for other targeted agents, isocitrate dehydrogenase (IDH) inhibitors “are very promising drugs in the relapsed/refractory setting, which is primarily where these drugs are given. In regard to frontline treatment, “data are coming from a very small study, but they’re very encouraging. It’s hard to entirely say that we’re ready to change practice based on this. But it’s very encouraging – the idea that earlier use of a drug-targeting IDH mutation might lead to substantially better outcomes.”

Moving forward, he said, “we could put all of our eggs in one basket and use many active drugs [at] front line. Or we can perhaps be smart about sequencing these drugs one after another, or using more intensive approaches followed by maintenance approaches followed by more intensive approaches.”

This approach is similar to strategies in myeloma patients “who less and less are relying on an autologous transplant for durable control of their disease, and more and more are using low-intensity biologically targeted drugs,” he said.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Dr. Perl reported numerous disclosures, including relationships with Daiichi Sankyo, Abbvie, and Astellas.

Novel therapies are poised to dramatically change frontline therapy for acute myeloid leukemia (AML), and they have the potential to replace chemotherapy, a hematologist/oncologist told colleagues at the virtual Acute Leukemia Forum of Hemedicus.

But more work needs to be done, noted Alexander Perl, MD, MS, associate professor at the University of Pennsylvania, Philadelphia. While advances have transformed AML treatment in the relapsed/refractory setting, “we’re just not seeing that substantive improvement” for newly diagnosed patients, he said. “We need to find the disease-modifying drugs that work in the relapsed/refractory setting and move those frontline. That’s where we’re going to see the transformations.”

Research suggests that low-intensity therapy holds tremendous promise, he said, “with the idea that we could make therapy much more tolerable for the vast majority of patients affected by AML, who, as we know, are older patients.”

Dr. Perl highlighted the 2020 VIALE-A study – venetoclax/azacitidine versus azacitidine/placebo – which reported that “in previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone.”

Venetoclax promotes apoptosis in leukemia cells, Dr. Perl said. “To a certain extent, you can think of it as putting the rubber to the road in terms of what actually chemotherapy is designed to do, which is to make leukemic blasts apoptose. It does so without DNA damage and with much less toxicity to the patient. Therefore it can be added to any number of regimens – granted, with mild suppression, but with relatively little extramedullary toxicity.”

Dr. Perl noted that the venetoclax arm “showed a higher response rate than azacitidine in pretty much every subgroup that was looked at, whether patients had de novo leukemia, secondary leukemia, multiple mutational complements, various different karyotypes. The response rates on this study are as high as what we often will see with intensive chemotherapy.” He added that “the winning arm on this trial seems to hold up against any low-intensity therapy, and I would argue against many high-intensity therapies in older patients.”

As for other targeted agents, isocitrate dehydrogenase (IDH) inhibitors “are very promising drugs in the relapsed/refractory setting, which is primarily where these drugs are given. In regard to frontline treatment, “data are coming from a very small study, but they’re very encouraging. It’s hard to entirely say that we’re ready to change practice based on this. But it’s very encouraging – the idea that earlier use of a drug-targeting IDH mutation might lead to substantially better outcomes.”

Moving forward, he said, “we could put all of our eggs in one basket and use many active drugs [at] front line. Or we can perhaps be smart about sequencing these drugs one after another, or using more intensive approaches followed by maintenance approaches followed by more intensive approaches.”

This approach is similar to strategies in myeloma patients “who less and less are relying on an autologous transplant for durable control of their disease, and more and more are using low-intensity biologically targeted drugs,” he said.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Dr. Perl reported numerous disclosures, including relationships with Daiichi Sankyo, Abbvie, and Astellas.

Cannabis use is associated with a decrease in the prevalence of steatohepatitis and a slowing of its progression in patients with obesity, results from a retrospective cohort study show.

This suggests “that the anti-inflammatory effects of cannabis may be leading to reduced prevalence of steatohepatitis in cannabis users,” said Ikechukwu Achebe, MD, from the John H. Stroger, Jr. Hospital of Cook County in Chicago.

Liver injuries such as nonalcoholic steatohepatitis are characterized by hepatocellular injury and inflammation, which combine to contribute to an increase in the risk for liver failure, cirrhosis, and hepatocellular carcinoma.

“This is where cannabis comes in,” said Dr. Achebe, who presented the study results at the virtual annual meeting of the American College of Gastroenterology. “It is the most commonly used psychoactive substance worldwide and has been shown to reduce hepatic myofibroblast and stellate cell injury. Studies using mouse models have demonstrated reduced liver fibrosis and cirrhosis as a consequence of cannabis exposure.”

Given this possible connection, Dr. Achebe and colleagues set out to determine whether cannabis use affects the prevalence and progression of nonalcoholic fatty liver disease (NAFLD) in obese patients.

To do so, they analyzed the discharge records of 879,952 obese adults in the 2016 Healthcare Cost and Utilization Project National Inpatient Sample. The primary outcome was the prevalence of the four presentations of NAFLD: steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma.

The researchers compared disease stages in cannabis users and nonusers. In the study cohort of 14,236 patients, 1.6% used cannabis. Steatohepatitis was less common among cannabis users than among nonusers (0.4% vs. 0.7%; P < .001), as was cirrhosis (1.1% vs. 1.5%; P < .001).

After propensity matching, the association between cannabis use and lower rates of steatohepatitis remained significant (0.4% vs. 0.5%; P = .035), but the association between cannabis use and the prevalence of nonalcoholic fatty liver, cirrhosis, and hepatocellular carcinoma did not.

These results might be partly explained by the protective effect of cannabis on hepatocytes regulated by the endocannabinoid system, the researchers concluded.

More studies are needed to explore this relation, said Dr. Achebe.
 

The challenge of self-reported use

The study is “incredibly interesting,” said Nancy S. Reau, MD, from Rush Medical College, Chicago. However, the association between cannabis and nonalcoholic fatty liver needs to be further investigated before clinicians can counsel their patients to use the agent to prevent progression.

It is difficult in a study such as this to tease out other lifestyle factors that might be linked to cannabis use, she explained. For example, “is it possible that the cannabis users exercise more, drink more coffee, or eat differently?”

And “self-reported use is challenging,” Dr. Reau said in an interview. “This cannot differentiate someone who occasionally uses from someone who is a heavy daily user. There must be some minimum level of exposure needed for it to have protective effects, if they exist.”

This study was honored at the meeting as an ACG Newsworthy Abstract and an ACG Outstanding Poster Presenter.

Dr. Achebe disclosed no relevant financial relationships. Dr. Reau reported receiving research support from Genfit and having a consultant relationship with Intercept Pharmaceuticals.

A version of this article originally appeared on Medscape.com.

Cannabis use is associated with a decrease in the prevalence of steatohepatitis and a slowing of its progression in patients with obesity, results from a retrospective cohort study show.

This suggests “that the anti-inflammatory effects of cannabis may be leading to reduced prevalence of steatohepatitis in cannabis users,” said Ikechukwu Achebe, MD, from the John H. Stroger, Jr. Hospital of Cook County in Chicago.

Liver injuries such as nonalcoholic steatohepatitis are characterized by hepatocellular injury and inflammation, which combine to contribute to an increase in the risk for liver failure, cirrhosis, and hepatocellular carcinoma.

“This is where cannabis comes in,” said Dr. Achebe, who presented the study results at the virtual annual meeting of the American College of Gastroenterology. “It is the most commonly used psychoactive substance worldwide and has been shown to reduce hepatic myofibroblast and stellate cell injury. Studies using mouse models have demonstrated reduced liver fibrosis and cirrhosis as a consequence of cannabis exposure.”

Given this possible connection, Dr. Achebe and colleagues set out to determine whether cannabis use affects the prevalence and progression of nonalcoholic fatty liver disease (NAFLD) in obese patients.

To do so, they analyzed the discharge records of 879,952 obese adults in the 2016 Healthcare Cost and Utilization Project National Inpatient Sample. The primary outcome was the prevalence of the four presentations of NAFLD: steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma.

The researchers compared disease stages in cannabis users and nonusers. In the study cohort of 14,236 patients, 1.6% used cannabis. Steatohepatitis was less common among cannabis users than among nonusers (0.4% vs. 0.7%; P < .001), as was cirrhosis (1.1% vs. 1.5%; P < .001).

After propensity matching, the association between cannabis use and lower rates of steatohepatitis remained significant (0.4% vs. 0.5%; P = .035), but the association between cannabis use and the prevalence of nonalcoholic fatty liver, cirrhosis, and hepatocellular carcinoma did not.

These results might be partly explained by the protective effect of cannabis on hepatocytes regulated by the endocannabinoid system, the researchers concluded.

More studies are needed to explore this relation, said Dr. Achebe.
 

The challenge of self-reported use

The study is “incredibly interesting,” said Nancy S. Reau, MD, from Rush Medical College, Chicago. However, the association between cannabis and nonalcoholic fatty liver needs to be further investigated before clinicians can counsel their patients to use the agent to prevent progression.

It is difficult in a study such as this to tease out other lifestyle factors that might be linked to cannabis use, she explained. For example, “is it possible that the cannabis users exercise more, drink more coffee, or eat differently?”

And “self-reported use is challenging,” Dr. Reau said in an interview. “This cannot differentiate someone who occasionally uses from someone who is a heavy daily user. There must be some minimum level of exposure needed for it to have protective effects, if they exist.”

This study was honored at the meeting as an ACG Newsworthy Abstract and an ACG Outstanding Poster Presenter.

Dr. Achebe disclosed no relevant financial relationships. Dr. Reau reported receiving research support from Genfit and having a consultant relationship with Intercept Pharmaceuticals.

A version of this article originally appeared on Medscape.com.

Cannabis use is associated with a decrease in the prevalence of steatohepatitis and a slowing of its progression in patients with obesity, results from a retrospective cohort study show.

This suggests “that the anti-inflammatory effects of cannabis may be leading to reduced prevalence of steatohepatitis in cannabis users,” said Ikechukwu Achebe, MD, from the John H. Stroger, Jr. Hospital of Cook County in Chicago.

Liver injuries such as nonalcoholic steatohepatitis are characterized by hepatocellular injury and inflammation, which combine to contribute to an increase in the risk for liver failure, cirrhosis, and hepatocellular carcinoma.

“This is where cannabis comes in,” said Dr. Achebe, who presented the study results at the virtual annual meeting of the American College of Gastroenterology. “It is the most commonly used psychoactive substance worldwide and has been shown to reduce hepatic myofibroblast and stellate cell injury. Studies using mouse models have demonstrated reduced liver fibrosis and cirrhosis as a consequence of cannabis exposure.”

Given this possible connection, Dr. Achebe and colleagues set out to determine whether cannabis use affects the prevalence and progression of nonalcoholic fatty liver disease (NAFLD) in obese patients.

To do so, they analyzed the discharge records of 879,952 obese adults in the 2016 Healthcare Cost and Utilization Project National Inpatient Sample. The primary outcome was the prevalence of the four presentations of NAFLD: steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma.

The researchers compared disease stages in cannabis users and nonusers. In the study cohort of 14,236 patients, 1.6% used cannabis. Steatohepatitis was less common among cannabis users than among nonusers (0.4% vs. 0.7%; P < .001), as was cirrhosis (1.1% vs. 1.5%; P < .001).

After propensity matching, the association between cannabis use and lower rates of steatohepatitis remained significant (0.4% vs. 0.5%; P = .035), but the association between cannabis use and the prevalence of nonalcoholic fatty liver, cirrhosis, and hepatocellular carcinoma did not.

These results might be partly explained by the protective effect of cannabis on hepatocytes regulated by the endocannabinoid system, the researchers concluded.

More studies are needed to explore this relation, said Dr. Achebe.
 

The challenge of self-reported use

The study is “incredibly interesting,” said Nancy S. Reau, MD, from Rush Medical College, Chicago. However, the association between cannabis and nonalcoholic fatty liver needs to be further investigated before clinicians can counsel their patients to use the agent to prevent progression.

It is difficult in a study such as this to tease out other lifestyle factors that might be linked to cannabis use, she explained. For example, “is it possible that the cannabis users exercise more, drink more coffee, or eat differently?”

And “self-reported use is challenging,” Dr. Reau said in an interview. “This cannot differentiate someone who occasionally uses from someone who is a heavy daily user. There must be some minimum level of exposure needed for it to have protective effects, if they exist.”

This study was honored at the meeting as an ACG Newsworthy Abstract and an ACG Outstanding Poster Presenter.

Dr. Achebe disclosed no relevant financial relationships. Dr. Reau reported receiving research support from Genfit and having a consultant relationship with Intercept Pharmaceuticals.

A version of this article originally appeared on Medscape.com.

Although the efficacy of two pre-exposure prophylaxis (PrEP) regimens containing differing prodrug formulations of tenofovir are virtually identical, the balance between benefit and risk tips in favor of the combination using the older formulation, tenofovir disoproxil fumarate (TDF), a pharmacology researcher said.

An analysis of the pharmacologic profiles of TDF plus emtricitabine (FTC; Truvada and generic) with tenofovir alafenamide (TAF) plus FTC (Descovy) shows that the risk of decreased bone mineral density and renal toxicity with TDF are significantly lower than those of weight gain and related metabolic and cardiovascular problems associated with the newer tenofovir formulation TAF, according to pharmacology research fellow Andrew Hill, MD, PhD, from the University of Liverpool (England).

“I think when we’re comparing these two drugs overall, we have a clear benefit/risk, and we need to take both of these potential toxicities seriously, “ he said in an online presentation during IDWeek 2020, an annual scientific meeting on infectious diseases held virtually this year.

“But in my view, treating women – Black women – with TAF/FTC is a bad thing,” he continued. “I think it’s going lead to more harm, more myocardial infarctions, more cases of diabetes, and potentially more adverse birth outcomes, and I think that is a risk that is not worth taking, given that the apparent benefit in terms of bone mineral density and renal markers is a hypothesis at best, and is not translated into hard clinical endpoints.”
 

Adverse event profiles

Dr. Hill compared the side effect profiles of the two agents when used both in antiretroviral therapy (ART) in combination the integrase inhibitor dolutegravir (DTG; Tivicay), and in PrEP.

World Health Organization guidelines for first-line ART recommend the use of TDF/FTC/DTG, reserving TAF plus lamivudine (3TC) and DTG for use in special circumstances only, Dr. Hill noted.

He pointed to a pooled analysis of data from eight randomized, controlled trials of treatment-naive people living with HIV who started on ART from 2003 to 2015. The authors found that demographic factors associated with weight gain included lower CD4 cell counter, higher levels of HIV type 1 RNA, no injection drug use, female sex, and Black race.

They also found that, among nucleoside/nucleotide reverse transcriptase inhibitors, TAF was associated with more weight gain than TDF, abacavir, or zidovudine.

“This pattern is seen consistently across studies both of pre-exposure prophylaxis or treatment comparing tenofovir with either TAF or other nucleoside analogs,” he said.

The greater weight gain with TAF versus TDF was seen in both treatment trials and in the DISCOVER PrEP trial.

In addition, in a crossover trial conducted in Germany, patients who switched from TDF to TAF had an approximately 2 kg increase in body weight.

TAF has also been associated with higher grade 3 or 4 glucose and LDL cholesterol than TDF in clinical trials for the treatment of hepatitis B infections, and with higher LDL cholesterol and total cholesterol levels as well as diabetes in patients treated with the drugs in combination in the EMERALD HIV trial.

Clinical trials also tend to underestimate the real-world population of persons at highest risk for adverse events from TAF, Dr. Hill said, noting that the percentage of Black women in phase 3 trials for dolutegravir was 9%, compared with 42% among persons infected with HIV worldwide. The respective percentages for Black men are 16% versus 30%. These differences are similar across clinical trial programs for other ART agents.

“Generally, it’s women and Black people who seem to be at greatest risk for safety issues,” he said.

In the ADVANCE trial comparing TAF/FTC/DTG with TDF/FTC/DTG and a control arm of TDF, FTC and efavirenz, the mean change in weight among men after 3 years on the TAF-based regimen was a gain of 7.2 kg (15.9 lbs), compared with 5.5 kg (12 lbs) with TDF, and 2.6 kg (5.7 lbs) with the efavirenz-containing regimen.

In women enrolled in the same trial, the respective mean weight gains were 12.3 kg (27 lbs), 7.4 kg (16.3 lbs), and 5.5 kg (12 lbs).

“All of our analyses so far have shown that the weight continues to go up. We’re actually seeing people doubling in their body weight. We’ve seen some women come into clinic and their doctors don’t even recognize them because they’ve put on so much weight,” he said.

In women, most of the gain in weight occurs as limb or trunk fat, with a predominance of visceral fat.

People taking TAF in the trial were also at significantly greater risk for developing the metabolic syndrome, and at week 96, 27% of women on TAF/FTC/DTG had treatment-emergent obesity, compared with 17% for those on TDF/FTC/DTG and 11% for those on TDF/FTC/EFV. In men, the respective 96-week rates of treatment-emergent obesity were 7%, 3%, and 2%.

Clinical obesity itself is a risk factor for obstetric complications and birth outcomes, Alzheimer’s disease, type 2 diabetes, cardiovascular disease, hypertension and cancer, and an average 4-year reduction in life expectancy, Dr. Hill said. “I think it’s actually very unlikely that the [World Health Organization] guidelines will now change and allow the widespread use of TAF/FTC in combination with integrase inhibitors worldwide given these potential implications.”
 

Modern times

The bad rap that TDF gets for its alleged effects on bone mineral density and kidneys comes from studies where the drug was given in a boosted regimen that can amplify tenofovir toxicities, Dr. Hill said.

He noted that data from Gilead Sciences shows through 7 years of therapy in previously ART-naive patients, the combination of TDF/3TC/EFV showed sustained durable efficacy, no discontinuations to renal adverse effects, and no evidence of clinically relevant bone effects.

“I think we need to be very careful when we look at tenofovir and TAF. We need to look at the more modern way that these drugs are used, which is not with pharmacokinetic boosters anymore, and in that situation the toxicity profile of tenofovir/3TC – the original TDF – is very favorable,” he said.

Robert Goldstein, MD, PhD, an infectious disease specialist and medical director of the transgender health program at Massachusetts General Hospital in Boston, who comoderated the session where Dr. Hill presented his data, said that his clinical experience mirrors the pharmacokinetic findings.

“I certainly have strong feelings about the use of TDF in pre-exposure prophylaxis,” he said in an interview. “TDF is an effective and safe formulation of tenofovir to be used in pre-exposure prophylaxis, and one that we have more experience with. It’s the formulation of tenofovir that I use for all of my patients who are on pre-exposure prophylaxis, and I think it is the most cost-effective.’

No funding source was reported. Andrew Hill consults for Tibotec on clinical trial programs for darunavir, etravirine, and rilpivirine. Dr. Goldstein reported having no relevant disclosures.

Although the efficacy of two pre-exposure prophylaxis (PrEP) regimens containing differing prodrug formulations of tenofovir are virtually identical, the balance between benefit and risk tips in favor of the combination using the older formulation, tenofovir disoproxil fumarate (TDF), a pharmacology researcher said.

An analysis of the pharmacologic profiles of TDF plus emtricitabine (FTC; Truvada and generic) with tenofovir alafenamide (TAF) plus FTC (Descovy) shows that the risk of decreased bone mineral density and renal toxicity with TDF are significantly lower than those of weight gain and related metabolic and cardiovascular problems associated with the newer tenofovir formulation TAF, according to pharmacology research fellow Andrew Hill, MD, PhD, from the University of Liverpool (England).

“I think when we’re comparing these two drugs overall, we have a clear benefit/risk, and we need to take both of these potential toxicities seriously, “ he said in an online presentation during IDWeek 2020, an annual scientific meeting on infectious diseases held virtually this year.

“But in my view, treating women – Black women – with TAF/FTC is a bad thing,” he continued. “I think it’s going lead to more harm, more myocardial infarctions, more cases of diabetes, and potentially more adverse birth outcomes, and I think that is a risk that is not worth taking, given that the apparent benefit in terms of bone mineral density and renal markers is a hypothesis at best, and is not translated into hard clinical endpoints.”
 

Adverse event profiles

Dr. Hill compared the side effect profiles of the two agents when used both in antiretroviral therapy (ART) in combination the integrase inhibitor dolutegravir (DTG; Tivicay), and in PrEP.

World Health Organization guidelines for first-line ART recommend the use of TDF/FTC/DTG, reserving TAF plus lamivudine (3TC) and DTG for use in special circumstances only, Dr. Hill noted.

He pointed to a pooled analysis of data from eight randomized, controlled trials of treatment-naive people living with HIV who started on ART from 2003 to 2015. The authors found that demographic factors associated with weight gain included lower CD4 cell counter, higher levels of HIV type 1 RNA, no injection drug use, female sex, and Black race.

They also found that, among nucleoside/nucleotide reverse transcriptase inhibitors, TAF was associated with more weight gain than TDF, abacavir, or zidovudine.

“This pattern is seen consistently across studies both of pre-exposure prophylaxis or treatment comparing tenofovir with either TAF or other nucleoside analogs,” he said.

The greater weight gain with TAF versus TDF was seen in both treatment trials and in the DISCOVER PrEP trial.

In addition, in a crossover trial conducted in Germany, patients who switched from TDF to TAF had an approximately 2 kg increase in body weight.

TAF has also been associated with higher grade 3 or 4 glucose and LDL cholesterol than TDF in clinical trials for the treatment of hepatitis B infections, and with higher LDL cholesterol and total cholesterol levels as well as diabetes in patients treated with the drugs in combination in the EMERALD HIV trial.

Clinical trials also tend to underestimate the real-world population of persons at highest risk for adverse events from TAF, Dr. Hill said, noting that the percentage of Black women in phase 3 trials for dolutegravir was 9%, compared with 42% among persons infected with HIV worldwide. The respective percentages for Black men are 16% versus 30%. These differences are similar across clinical trial programs for other ART agents.

“Generally, it’s women and Black people who seem to be at greatest risk for safety issues,” he said.

In the ADVANCE trial comparing TAF/FTC/DTG with TDF/FTC/DTG and a control arm of TDF, FTC and efavirenz, the mean change in weight among men after 3 years on the TAF-based regimen was a gain of 7.2 kg (15.9 lbs), compared with 5.5 kg (12 lbs) with TDF, and 2.6 kg (5.7 lbs) with the efavirenz-containing regimen.

In women enrolled in the same trial, the respective mean weight gains were 12.3 kg (27 lbs), 7.4 kg (16.3 lbs), and 5.5 kg (12 lbs).

“All of our analyses so far have shown that the weight continues to go up. We’re actually seeing people doubling in their body weight. We’ve seen some women come into clinic and their doctors don’t even recognize them because they’ve put on so much weight,” he said.

In women, most of the gain in weight occurs as limb or trunk fat, with a predominance of visceral fat.

People taking TAF in the trial were also at significantly greater risk for developing the metabolic syndrome, and at week 96, 27% of women on TAF/FTC/DTG had treatment-emergent obesity, compared with 17% for those on TDF/FTC/DTG and 11% for those on TDF/FTC/EFV. In men, the respective 96-week rates of treatment-emergent obesity were 7%, 3%, and 2%.

Clinical obesity itself is a risk factor for obstetric complications and birth outcomes, Alzheimer’s disease, type 2 diabetes, cardiovascular disease, hypertension and cancer, and an average 4-year reduction in life expectancy, Dr. Hill said. “I think it’s actually very unlikely that the [World Health Organization] guidelines will now change and allow the widespread use of TAF/FTC in combination with integrase inhibitors worldwide given these potential implications.”
 

Modern times

The bad rap that TDF gets for its alleged effects on bone mineral density and kidneys comes from studies where the drug was given in a boosted regimen that can amplify tenofovir toxicities, Dr. Hill said.

He noted that data from Gilead Sciences shows through 7 years of therapy in previously ART-naive patients, the combination of TDF/3TC/EFV showed sustained durable efficacy, no discontinuations to renal adverse effects, and no evidence of clinically relevant bone effects.

“I think we need to be very careful when we look at tenofovir and TAF. We need to look at the more modern way that these drugs are used, which is not with pharmacokinetic boosters anymore, and in that situation the toxicity profile of tenofovir/3TC – the original TDF – is very favorable,” he said.

Robert Goldstein, MD, PhD, an infectious disease specialist and medical director of the transgender health program at Massachusetts General Hospital in Boston, who comoderated the session where Dr. Hill presented his data, said that his clinical experience mirrors the pharmacokinetic findings.

“I certainly have strong feelings about the use of TDF in pre-exposure prophylaxis,” he said in an interview. “TDF is an effective and safe formulation of tenofovir to be used in pre-exposure prophylaxis, and one that we have more experience with. It’s the formulation of tenofovir that I use for all of my patients who are on pre-exposure prophylaxis, and I think it is the most cost-effective.’

No funding source was reported. Andrew Hill consults for Tibotec on clinical trial programs for darunavir, etravirine, and rilpivirine. Dr. Goldstein reported having no relevant disclosures.

Although the efficacy of two pre-exposure prophylaxis (PrEP) regimens containing differing prodrug formulations of tenofovir are virtually identical, the balance between benefit and risk tips in favor of the combination using the older formulation, tenofovir disoproxil fumarate (TDF), a pharmacology researcher said.

An analysis of the pharmacologic profiles of TDF plus emtricitabine (FTC; Truvada and generic) with tenofovir alafenamide (TAF) plus FTC (Descovy) shows that the risk of decreased bone mineral density and renal toxicity with TDF are significantly lower than those of weight gain and related metabolic and cardiovascular problems associated with the newer tenofovir formulation TAF, according to pharmacology research fellow Andrew Hill, MD, PhD, from the University of Liverpool (England).

“I think when we’re comparing these two drugs overall, we have a clear benefit/risk, and we need to take both of these potential toxicities seriously, “ he said in an online presentation during IDWeek 2020, an annual scientific meeting on infectious diseases held virtually this year.

“But in my view, treating women – Black women – with TAF/FTC is a bad thing,” he continued. “I think it’s going lead to more harm, more myocardial infarctions, more cases of diabetes, and potentially more adverse birth outcomes, and I think that is a risk that is not worth taking, given that the apparent benefit in terms of bone mineral density and renal markers is a hypothesis at best, and is not translated into hard clinical endpoints.”
 

Adverse event profiles

Dr. Hill compared the side effect profiles of the two agents when used both in antiretroviral therapy (ART) in combination the integrase inhibitor dolutegravir (DTG; Tivicay), and in PrEP.

World Health Organization guidelines for first-line ART recommend the use of TDF/FTC/DTG, reserving TAF plus lamivudine (3TC) and DTG for use in special circumstances only, Dr. Hill noted.

He pointed to a pooled analysis of data from eight randomized, controlled trials of treatment-naive people living with HIV who started on ART from 2003 to 2015. The authors found that demographic factors associated with weight gain included lower CD4 cell counter, higher levels of HIV type 1 RNA, no injection drug use, female sex, and Black race.

They also found that, among nucleoside/nucleotide reverse transcriptase inhibitors, TAF was associated with more weight gain than TDF, abacavir, or zidovudine.

“This pattern is seen consistently across studies both of pre-exposure prophylaxis or treatment comparing tenofovir with either TAF or other nucleoside analogs,” he said.

The greater weight gain with TAF versus TDF was seen in both treatment trials and in the DISCOVER PrEP trial.

In addition, in a crossover trial conducted in Germany, patients who switched from TDF to TAF had an approximately 2 kg increase in body weight.

TAF has also been associated with higher grade 3 or 4 glucose and LDL cholesterol than TDF in clinical trials for the treatment of hepatitis B infections, and with higher LDL cholesterol and total cholesterol levels as well as diabetes in patients treated with the drugs in combination in the EMERALD HIV trial.

Clinical trials also tend to underestimate the real-world population of persons at highest risk for adverse events from TAF, Dr. Hill said, noting that the percentage of Black women in phase 3 trials for dolutegravir was 9%, compared with 42% among persons infected with HIV worldwide. The respective percentages for Black men are 16% versus 30%. These differences are similar across clinical trial programs for other ART agents.

“Generally, it’s women and Black people who seem to be at greatest risk for safety issues,” he said.

In the ADVANCE trial comparing TAF/FTC/DTG with TDF/FTC/DTG and a control arm of TDF, FTC and efavirenz, the mean change in weight among men after 3 years on the TAF-based regimen was a gain of 7.2 kg (15.9 lbs), compared with 5.5 kg (12 lbs) with TDF, and 2.6 kg (5.7 lbs) with the efavirenz-containing regimen.

In women enrolled in the same trial, the respective mean weight gains were 12.3 kg (27 lbs), 7.4 kg (16.3 lbs), and 5.5 kg (12 lbs).

“All of our analyses so far have shown that the weight continues to go up. We’re actually seeing people doubling in their body weight. We’ve seen some women come into clinic and their doctors don’t even recognize them because they’ve put on so much weight,” he said.

In women, most of the gain in weight occurs as limb or trunk fat, with a predominance of visceral fat.

People taking TAF in the trial were also at significantly greater risk for developing the metabolic syndrome, and at week 96, 27% of women on TAF/FTC/DTG had treatment-emergent obesity, compared with 17% for those on TDF/FTC/DTG and 11% for those on TDF/FTC/EFV. In men, the respective 96-week rates of treatment-emergent obesity were 7%, 3%, and 2%.

Clinical obesity itself is a risk factor for obstetric complications and birth outcomes, Alzheimer’s disease, type 2 diabetes, cardiovascular disease, hypertension and cancer, and an average 4-year reduction in life expectancy, Dr. Hill said. “I think it’s actually very unlikely that the [World Health Organization] guidelines will now change and allow the widespread use of TAF/FTC in combination with integrase inhibitors worldwide given these potential implications.”
 

Modern times

The bad rap that TDF gets for its alleged effects on bone mineral density and kidneys comes from studies where the drug was given in a boosted regimen that can amplify tenofovir toxicities, Dr. Hill said.

He noted that data from Gilead Sciences shows through 7 years of therapy in previously ART-naive patients, the combination of TDF/3TC/EFV showed sustained durable efficacy, no discontinuations to renal adverse effects, and no evidence of clinically relevant bone effects.

“I think we need to be very careful when we look at tenofovir and TAF. We need to look at the more modern way that these drugs are used, which is not with pharmacokinetic boosters anymore, and in that situation the toxicity profile of tenofovir/3TC – the original TDF – is very favorable,” he said.

Robert Goldstein, MD, PhD, an infectious disease specialist and medical director of the transgender health program at Massachusetts General Hospital in Boston, who comoderated the session where Dr. Hill presented his data, said that his clinical experience mirrors the pharmacokinetic findings.

“I certainly have strong feelings about the use of TDF in pre-exposure prophylaxis,” he said in an interview. “TDF is an effective and safe formulation of tenofovir to be used in pre-exposure prophylaxis, and one that we have more experience with. It’s the formulation of tenofovir that I use for all of my patients who are on pre-exposure prophylaxis, and I think it is the most cost-effective.’

No funding source was reported. Andrew Hill consults for Tibotec on clinical trial programs for darunavir, etravirine, and rilpivirine. Dr. Goldstein reported having no relevant disclosures.

A patient-centered approach can help guide persons at risk for HIV exposure to decide on the best choice of pre-exposure prophylaxis (PrEP) regimens for them, stifling the noise generated by direct-to-consumer advertising, an infectious disease specialist recommends.

The decision for patients whether to start or remain on the PrEP combination of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC; Truvada and generic) or on tenofovir alafenamide (TAF) plus FTC (Descovy) is made more fraught by confusion regarding the use of the newer and allegedly safer TAF prodrug of tenofovir in HIV treatment regimens, said Oni Blackstock, MD, founder and executive director of Health Justice and an attending physician in the division of infectious diseases at Harlem Hospital, New York.

“There have been commercials on TV as well as on social media around class-action lawsuits against [Truvada maker] Gilead,” she said in an online presentation during IDWeek 2020, an annual scientific meeting on infectious diseases, held virtually this year.

“These lawsuits focus on TDF for HIV treatment, but they have sown a great deal of confusion about TDF versus TAF for PrEP among potential and actual PrEP users,” she added.

Dr. Blackstock described her approach to shared decision-making regarding TDF/FTC versus TAF/FTC, and to helping patients understand the relative benefits and risks of each formulation.

In January of 2020, Dr. Blackstock, who was then assistant commissioner of the HIV bureau of the New York City Department of Health and Mental Hygiene, issued with other Bureau members a “Dear colleague” letter stating why they believed that TDF/FTC should remain the first-line regimen for PrEP.

That opinion, she said, was bolstered by an editorial published in February 2020 by Douglas E. Krakower, MD, from Beth Israel Deaconess Medical Center in Boston, and colleagues, which questioned the rush to shift from TDF to TAF in HIV treatment, and cautioned against the same approach to PrEP.

“Despite evidence that TAF/FTC would not be cost-effective, compared with generic TDF/FTC , the newer regimen quickly and irrevocably displaced TDF/FTC for HIV treatment in the U.S. A similar shift for PrEP – especially for populations in which TAF/FTC is untested – would be premature, costly, and counterproductive for population impact,” Krakower et al. wrote.
 

Shared decision-making

Clinicians can help patients who may be a candidate for either PrEP regimen by engaging them in shared decision-making.

“The clinician provides information in this case about a prevention strategy, options, benefits and risks, alternatives, and the patient provides their preferences and values, and together the clinician and patient make a decision,” Dr. Blackstock said.

The process differs from the model of informed decision-making, where the clinician gives the patient the information and the patient comes to a decision, or the old, “paternalistic” model in which the clinician gives information and makes recommendations to the patient.

“Shared decision-making has been studied extensively and has been shown to improve patient satisfaction, patient communication, and also potentially reducing health inequities that we see,” she said.

The model for shared decision-making for clinical practice includes three distinct portions: a choice talk, option talk, and decision talk.
 

Choice

To begin the discussion, the physician informs the patients of the availability of choices and justifies them, saying, for example, “there is good information about how these two PrEP options differ that I’d like to discuss with you,” and “the two PrEP options have different side effects … some will matter more to you than other people.”

At this stage the clinician should defer closure by offering a more detailed discussion of the choices.
 

Option

Here the clinician solicits information about what the patient has heard or read about PrEP, describes each option in practical terms, and points out where the two regimens differ, being specific about the pros and cons of each (for example, potential bone mineral density loss or renal complications with TDF, and potential weight gain with subsequent metabolic and cardiovascular consequences with TAF).

The TDF versus TAF-based PrEP discussion could also focus on what’s known about the comparative effectiveness of each regimen.

For example, TDF/FTC has been shown to be about 99% effective at preventing infection in men who have sex with men and in transgender women, also about 99% effective in heterosexual women and men, and 74%-84% effective in persons who inject drugs.

In contrast, TAF/FTC has been shown to be about 99% effective in men who have sex with men and transgender women, but it’s efficacy in the other two categories is unknown, Dr. Blackstock said.

The option discussion should include a comparison of the evidence base for each regimen, including the real-world experience with TDF/FTC since 2012, and much more limited experience with TAF/FTC.

Discussing relative costs, although the wholesale costs of the regimens are similar, there is now a generic version of TDF/FTC made by Teva Pharmaceuticals that sells for about $400 less per month than the brand name, which might make the option more acceptable to health insurers.
 

Decision

The decision talk is about considering the patients preferences and deciding with them what is best.

The clinician could say, for example: “What, from your point of view, matters most to you?”

The clinician should also be willing to allow the patient to defer a decision or to guide them depending on their stated wish, asking something like: “Are you ready to decide, or do you want more time? Do you have more questions? Are there more things we should discuss?

Offering the patient a chance to review the decision can also be a good way to arrive at closure, Dr. Blackstock said.

Robert Goldstein, MD, PhD, an infectious disease specialist and medical director of the transgender health program at Massachusetts General Hospital in Boston, who comoderated the session where Dr. Blackstock presented her talk, said that he also uses a similar approach to the PrEP discussion.

“I use a very patient-centered approach of providing information and talking through the data that are available,” he said.

“I will say that, as patients come to me talking about the transition from TDF to TAF for pre-exposure prophylaxis, I am very clear with them about the limited benefit or no benefit that I see with TAF for pre-exposure prophylaxis, and all of my patients have remained on TDF for pre-exposure prophylaxis,” he added.

No funding source for the presentation was reported. Dr. Blackstock and Dr. Goldstein reported having no conflicts of interest to disclose.

A patient-centered approach can help guide persons at risk for HIV exposure to decide on the best choice of pre-exposure prophylaxis (PrEP) regimens for them, stifling the noise generated by direct-to-consumer advertising, an infectious disease specialist recommends.

The decision for patients whether to start or remain on the PrEP combination of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC; Truvada and generic) or on tenofovir alafenamide (TAF) plus FTC (Descovy) is made more fraught by confusion regarding the use of the newer and allegedly safer TAF prodrug of tenofovir in HIV treatment regimens, said Oni Blackstock, MD, founder and executive director of Health Justice and an attending physician in the division of infectious diseases at Harlem Hospital, New York.

“There have been commercials on TV as well as on social media around class-action lawsuits against [Truvada maker] Gilead,” she said in an online presentation during IDWeek 2020, an annual scientific meeting on infectious diseases, held virtually this year.

“These lawsuits focus on TDF for HIV treatment, but they have sown a great deal of confusion about TDF versus TAF for PrEP among potential and actual PrEP users,” she added.

Dr. Blackstock described her approach to shared decision-making regarding TDF/FTC versus TAF/FTC, and to helping patients understand the relative benefits and risks of each formulation.

In January of 2020, Dr. Blackstock, who was then assistant commissioner of the HIV bureau of the New York City Department of Health and Mental Hygiene, issued with other Bureau members a “Dear colleague” letter stating why they believed that TDF/FTC should remain the first-line regimen for PrEP.

That opinion, she said, was bolstered by an editorial published in February 2020 by Douglas E. Krakower, MD, from Beth Israel Deaconess Medical Center in Boston, and colleagues, which questioned the rush to shift from TDF to TAF in HIV treatment, and cautioned against the same approach to PrEP.

“Despite evidence that TAF/FTC would not be cost-effective, compared with generic TDF/FTC , the newer regimen quickly and irrevocably displaced TDF/FTC for HIV treatment in the U.S. A similar shift for PrEP – especially for populations in which TAF/FTC is untested – would be premature, costly, and counterproductive for population impact,” Krakower et al. wrote.
 

Shared decision-making

Clinicians can help patients who may be a candidate for either PrEP regimen by engaging them in shared decision-making.

“The clinician provides information in this case about a prevention strategy, options, benefits and risks, alternatives, and the patient provides their preferences and values, and together the clinician and patient make a decision,” Dr. Blackstock said.

The process differs from the model of informed decision-making, where the clinician gives the patient the information and the patient comes to a decision, or the old, “paternalistic” model in which the clinician gives information and makes recommendations to the patient.

“Shared decision-making has been studied extensively and has been shown to improve patient satisfaction, patient communication, and also potentially reducing health inequities that we see,” she said.

The model for shared decision-making for clinical practice includes three distinct portions: a choice talk, option talk, and decision talk.
 

Choice

To begin the discussion, the physician informs the patients of the availability of choices and justifies them, saying, for example, “there is good information about how these two PrEP options differ that I’d like to discuss with you,” and “the two PrEP options have different side effects … some will matter more to you than other people.”

At this stage the clinician should defer closure by offering a more detailed discussion of the choices.
 

Option

Here the clinician solicits information about what the patient has heard or read about PrEP, describes each option in practical terms, and points out where the two regimens differ, being specific about the pros and cons of each (for example, potential bone mineral density loss or renal complications with TDF, and potential weight gain with subsequent metabolic and cardiovascular consequences with TAF).

The TDF versus TAF-based PrEP discussion could also focus on what’s known about the comparative effectiveness of each regimen.

For example, TDF/FTC has been shown to be about 99% effective at preventing infection in men who have sex with men and in transgender women, also about 99% effective in heterosexual women and men, and 74%-84% effective in persons who inject drugs.

In contrast, TAF/FTC has been shown to be about 99% effective in men who have sex with men and transgender women, but it’s efficacy in the other two categories is unknown, Dr. Blackstock said.

The option discussion should include a comparison of the evidence base for each regimen, including the real-world experience with TDF/FTC since 2012, and much more limited experience with TAF/FTC.

Discussing relative costs, although the wholesale costs of the regimens are similar, there is now a generic version of TDF/FTC made by Teva Pharmaceuticals that sells for about $400 less per month than the brand name, which might make the option more acceptable to health insurers.
 

Decision

The decision talk is about considering the patients preferences and deciding with them what is best.

The clinician could say, for example: “What, from your point of view, matters most to you?”

The clinician should also be willing to allow the patient to defer a decision or to guide them depending on their stated wish, asking something like: “Are you ready to decide, or do you want more time? Do you have more questions? Are there more things we should discuss?

Offering the patient a chance to review the decision can also be a good way to arrive at closure, Dr. Blackstock said.

Robert Goldstein, MD, PhD, an infectious disease specialist and medical director of the transgender health program at Massachusetts General Hospital in Boston, who comoderated the session where Dr. Blackstock presented her talk, said that he also uses a similar approach to the PrEP discussion.

“I use a very patient-centered approach of providing information and talking through the data that are available,” he said.

“I will say that, as patients come to me talking about the transition from TDF to TAF for pre-exposure prophylaxis, I am very clear with them about the limited benefit or no benefit that I see with TAF for pre-exposure prophylaxis, and all of my patients have remained on TDF for pre-exposure prophylaxis,” he added.

No funding source for the presentation was reported. Dr. Blackstock and Dr. Goldstein reported having no conflicts of interest to disclose.

A patient-centered approach can help guide persons at risk for HIV exposure to decide on the best choice of pre-exposure prophylaxis (PrEP) regimens for them, stifling the noise generated by direct-to-consumer advertising, an infectious disease specialist recommends.

The decision for patients whether to start or remain on the PrEP combination of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC; Truvada and generic) or on tenofovir alafenamide (TAF) plus FTC (Descovy) is made more fraught by confusion regarding the use of the newer and allegedly safer TAF prodrug of tenofovir in HIV treatment regimens, said Oni Blackstock, MD, founder and executive director of Health Justice and an attending physician in the division of infectious diseases at Harlem Hospital, New York.

“There have been commercials on TV as well as on social media around class-action lawsuits against [Truvada maker] Gilead,” she said in an online presentation during IDWeek 2020, an annual scientific meeting on infectious diseases, held virtually this year.

“These lawsuits focus on TDF for HIV treatment, but they have sown a great deal of confusion about TDF versus TAF for PrEP among potential and actual PrEP users,” she added.

Dr. Blackstock described her approach to shared decision-making regarding TDF/FTC versus TAF/FTC, and to helping patients understand the relative benefits and risks of each formulation.

In January of 2020, Dr. Blackstock, who was then assistant commissioner of the HIV bureau of the New York City Department of Health and Mental Hygiene, issued with other Bureau members a “Dear colleague” letter stating why they believed that TDF/FTC should remain the first-line regimen for PrEP.

That opinion, she said, was bolstered by an editorial published in February 2020 by Douglas E. Krakower, MD, from Beth Israel Deaconess Medical Center in Boston, and colleagues, which questioned the rush to shift from TDF to TAF in HIV treatment, and cautioned against the same approach to PrEP.

“Despite evidence that TAF/FTC would not be cost-effective, compared with generic TDF/FTC , the newer regimen quickly and irrevocably displaced TDF/FTC for HIV treatment in the U.S. A similar shift for PrEP – especially for populations in which TAF/FTC is untested – would be premature, costly, and counterproductive for population impact,” Krakower et al. wrote.
 

Shared decision-making

Clinicians can help patients who may be a candidate for either PrEP regimen by engaging them in shared decision-making.

“The clinician provides information in this case about a prevention strategy, options, benefits and risks, alternatives, and the patient provides their preferences and values, and together the clinician and patient make a decision,” Dr. Blackstock said.

The process differs from the model of informed decision-making, where the clinician gives the patient the information and the patient comes to a decision, or the old, “paternalistic” model in which the clinician gives information and makes recommendations to the patient.

“Shared decision-making has been studied extensively and has been shown to improve patient satisfaction, patient communication, and also potentially reducing health inequities that we see,” she said.

The model for shared decision-making for clinical practice includes three distinct portions: a choice talk, option talk, and decision talk.
 

Choice

To begin the discussion, the physician informs the patients of the availability of choices and justifies them, saying, for example, “there is good information about how these two PrEP options differ that I’d like to discuss with you,” and “the two PrEP options have different side effects … some will matter more to you than other people.”

At this stage the clinician should defer closure by offering a more detailed discussion of the choices.
 

Option

Here the clinician solicits information about what the patient has heard or read about PrEP, describes each option in practical terms, and points out where the two regimens differ, being specific about the pros and cons of each (for example, potential bone mineral density loss or renal complications with TDF, and potential weight gain with subsequent metabolic and cardiovascular consequences with TAF).

The TDF versus TAF-based PrEP discussion could also focus on what’s known about the comparative effectiveness of each regimen.

For example, TDF/FTC has been shown to be about 99% effective at preventing infection in men who have sex with men and in transgender women, also about 99% effective in heterosexual women and men, and 74%-84% effective in persons who inject drugs.

In contrast, TAF/FTC has been shown to be about 99% effective in men who have sex with men and transgender women, but it’s efficacy in the other two categories is unknown, Dr. Blackstock said.

The option discussion should include a comparison of the evidence base for each regimen, including the real-world experience with TDF/FTC since 2012, and much more limited experience with TAF/FTC.

Discussing relative costs, although the wholesale costs of the regimens are similar, there is now a generic version of TDF/FTC made by Teva Pharmaceuticals that sells for about $400 less per month than the brand name, which might make the option more acceptable to health insurers.
 

Decision

The decision talk is about considering the patients preferences and deciding with them what is best.

The clinician could say, for example: “What, from your point of view, matters most to you?”

The clinician should also be willing to allow the patient to defer a decision or to guide them depending on their stated wish, asking something like: “Are you ready to decide, or do you want more time? Do you have more questions? Are there more things we should discuss?

Offering the patient a chance to review the decision can also be a good way to arrive at closure, Dr. Blackstock said.

Robert Goldstein, MD, PhD, an infectious disease specialist and medical director of the transgender health program at Massachusetts General Hospital in Boston, who comoderated the session where Dr. Blackstock presented her talk, said that he also uses a similar approach to the PrEP discussion.

“I use a very patient-centered approach of providing information and talking through the data that are available,” he said.

“I will say that, as patients come to me talking about the transition from TDF to TAF for pre-exposure prophylaxis, I am very clear with them about the limited benefit or no benefit that I see with TAF for pre-exposure prophylaxis, and all of my patients have remained on TDF for pre-exposure prophylaxis,” he added.

No funding source for the presentation was reported. Dr. Blackstock and Dr. Goldstein reported having no conflicts of interest to disclose.