Nancy A. Melville

A diet rich in vegetables and low in carbs – a so-called low glycemic index (GI) diet – is associated with clinically significant benefits beyond those provided by existing medications for people with type 1 and type 2 diabetes, compared with a higher glycemic diet, findings from a new meta-analysis show.

marilyna/iStock/Getty Images Plus

“Although the effects were small, which is not surprising in clinical trials in nutrition, they were clinically meaningful improvements for which our certainty in the effects were moderate to high,” first author Laura Chiavaroli, PhD, of the department of nutritional sciences, Temerty Faculty of Medicine, University of Toronto, said in an interview.

The GI rates foods on the basis of how quickly they affect blood glucose levels.

Fruits, vegetables, and whole grains have a low GI. They also help to regulate blood sugar levels. Such foods are linked to a reduced risk for heart disease among people with diabetes.

But guidelines on this – such as those from the European Association for the Study of Diabetes – reflect research published more than 15 years ago, before several key trials were published.

Dr. Chiavaroli and colleagues identified 27 randomized controlled trials – the most recent of which was published in May 2021 – that involved a total of 1,617 adults with type 1 or 2 diabetes. For the patients in these trials, diabetes was moderately controlled with glucose-lowering drugs or insulin. All of the included trials examined the effects of a low GI diet or a low glycemic load (GL) diet for people with diabetes over a period 3 or more weeks. The majority of patients in the studies were overweight or had obesity, and they were largely middle-aged.

The meta-analysis, which included new data, was published Aug. 5 in The BMJ. The study “expands the number of relevant intermediate cardiometabolic outcomes, and assesses the certainty of the evidence using GRADE [grading of recommendations assessment, development, and evaluation],” Dr. Chiavaroli and colleagues noted.

“The available evidence provides a good indication of the likely benefit in this population and supports existing recommendations for the use of low GI dietary patterns in the management of diabetes,” they emphasized.
 

Improvements in A1c, fasting glucose, cholesterol, and triglycerides

Overall, compared with people who consumed diets with higher GI/GL ratings, for those who consumed lower glycemic diets, glycemic control was significantly improved, as reflected in A1c level, which was the primary outcome of the study (mean difference, –0.31%; P < .001).

This “would meet the threshold of ≥ 0.3% reduction in HbA1c proposed by the European Medicines Agency as clinically relevant for risk reduction of diabetic complications,” the authors noted.

Those who consumed low glycemic diets also showed improvements in secondary outcomes, including fasting glucose level, which was reduced by 0.36 mmol/L (–6.5 mg/dL), a 6% reduction in low-density cholesterol (LDL-C) (–0.17 mmol/L), and a fall in triglyceride levels (–0.09 mmol/L).

They also lost marginally more body weight, at –0.66 kg (–1.5 pounds). Body mass index was lower by –0.38, and inflammation was reduced (C-reactive protein, –.41 mg/L; all P < .05).

No significant differences were observed between the groups in blood insulin level, high-density lipoprotein cholesterol level, waist circumference, or blood pressure.

Three of the studies showed that participants developed a preference for the low GI diet. “In recent years, there has been a growing interest in whole-food plant-based diets, and there are more options, for example, for pulse-based products,” Dr. Chiavaroli said.

This meta-analysis should support the recommendation of the low-glycemic diet, particularly among people with diabetes, she reiterated.
 

Will larger randomized trial show effect on outcomes?

The authors noted, however, that to determine whether these small improvements in intermediate cardiometabolic risk factors observed with low GI diets translate to reductions in cardiovascular disease, nephropathy, and retinopathy among people with diabetes, larger randomized trials are needed.

One such trial, the Low Glycemic Index Diet for Type 2 Diabetics, includes 169 high-risk patients with type 2 diabetes and subclinical atherosclerosis. The investigators are evaluating the effect of a low GI diet on the progression of atherosclerosis, as assessed by vascular MRI over 3 years.

“We await the results,” they said.

The study received funding from the Diabetes and Nutrition Study Group of the European Association for the Study of Diabetes (EASD) as part of the development of the EASD Clinical Practice Guidelines for Nutrition Therapy. The study was also supported by the Canadian Institutes of Health Research through the Canada-wide Human Nutrition Trialists’ Network. The Diet, Digestive Tract, and Disease (3D) Center, which is funded through the Canada Foundation for Innovation and the Ministry of Research and Innovation’s Ontario Research Fund, provided the infrastructure for the study.

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

A diet rich in vegetables and low in carbs – a so-called low glycemic index (GI) diet – is associated with clinically significant benefits beyond those provided by existing medications for people with type 1 and type 2 diabetes, compared with a higher glycemic diet, findings from a new meta-analysis show.

marilyna/iStock/Getty Images Plus

“Although the effects were small, which is not surprising in clinical trials in nutrition, they were clinically meaningful improvements for which our certainty in the effects were moderate to high,” first author Laura Chiavaroli, PhD, of the department of nutritional sciences, Temerty Faculty of Medicine, University of Toronto, said in an interview.

The GI rates foods on the basis of how quickly they affect blood glucose levels.

Fruits, vegetables, and whole grains have a low GI. They also help to regulate blood sugar levels. Such foods are linked to a reduced risk for heart disease among people with diabetes.

But guidelines on this – such as those from the European Association for the Study of Diabetes – reflect research published more than 15 years ago, before several key trials were published.

Dr. Chiavaroli and colleagues identified 27 randomized controlled trials – the most recent of which was published in May 2021 – that involved a total of 1,617 adults with type 1 or 2 diabetes. For the patients in these trials, diabetes was moderately controlled with glucose-lowering drugs or insulin. All of the included trials examined the effects of a low GI diet or a low glycemic load (GL) diet for people with diabetes over a period 3 or more weeks. The majority of patients in the studies were overweight or had obesity, and they were largely middle-aged.

The meta-analysis, which included new data, was published Aug. 5 in The BMJ. The study “expands the number of relevant intermediate cardiometabolic outcomes, and assesses the certainty of the evidence using GRADE [grading of recommendations assessment, development, and evaluation],” Dr. Chiavaroli and colleagues noted.

“The available evidence provides a good indication of the likely benefit in this population and supports existing recommendations for the use of low GI dietary patterns in the management of diabetes,” they emphasized.
 

Improvements in A1c, fasting glucose, cholesterol, and triglycerides

Overall, compared with people who consumed diets with higher GI/GL ratings, for those who consumed lower glycemic diets, glycemic control was significantly improved, as reflected in A1c level, which was the primary outcome of the study (mean difference, –0.31%; P < .001).

This “would meet the threshold of ≥ 0.3% reduction in HbA1c proposed by the European Medicines Agency as clinically relevant for risk reduction of diabetic complications,” the authors noted.

Those who consumed low glycemic diets also showed improvements in secondary outcomes, including fasting glucose level, which was reduced by 0.36 mmol/L (–6.5 mg/dL), a 6% reduction in low-density cholesterol (LDL-C) (–0.17 mmol/L), and a fall in triglyceride levels (–0.09 mmol/L).

They also lost marginally more body weight, at –0.66 kg (–1.5 pounds). Body mass index was lower by –0.38, and inflammation was reduced (C-reactive protein, –.41 mg/L; all P < .05).

No significant differences were observed between the groups in blood insulin level, high-density lipoprotein cholesterol level, waist circumference, or blood pressure.

Three of the studies showed that participants developed a preference for the low GI diet. “In recent years, there has been a growing interest in whole-food plant-based diets, and there are more options, for example, for pulse-based products,” Dr. Chiavaroli said.

This meta-analysis should support the recommendation of the low-glycemic diet, particularly among people with diabetes, she reiterated.
 

Will larger randomized trial show effect on outcomes?

The authors noted, however, that to determine whether these small improvements in intermediate cardiometabolic risk factors observed with low GI diets translate to reductions in cardiovascular disease, nephropathy, and retinopathy among people with diabetes, larger randomized trials are needed.

One such trial, the Low Glycemic Index Diet for Type 2 Diabetics, includes 169 high-risk patients with type 2 diabetes and subclinical atherosclerosis. The investigators are evaluating the effect of a low GI diet on the progression of atherosclerosis, as assessed by vascular MRI over 3 years.

“We await the results,” they said.

The study received funding from the Diabetes and Nutrition Study Group of the European Association for the Study of Diabetes (EASD) as part of the development of the EASD Clinical Practice Guidelines for Nutrition Therapy. The study was also supported by the Canadian Institutes of Health Research through the Canada-wide Human Nutrition Trialists’ Network. The Diet, Digestive Tract, and Disease (3D) Center, which is funded through the Canada Foundation for Innovation and the Ministry of Research and Innovation’s Ontario Research Fund, provided the infrastructure for the study.

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

A diet rich in vegetables and low in carbs – a so-called low glycemic index (GI) diet – is associated with clinically significant benefits beyond those provided by existing medications for people with type 1 and type 2 diabetes, compared with a higher glycemic diet, findings from a new meta-analysis show.

marilyna/iStock/Getty Images Plus

“Although the effects were small, which is not surprising in clinical trials in nutrition, they were clinically meaningful improvements for which our certainty in the effects were moderate to high,” first author Laura Chiavaroli, PhD, of the department of nutritional sciences, Temerty Faculty of Medicine, University of Toronto, said in an interview.

The GI rates foods on the basis of how quickly they affect blood glucose levels.

Fruits, vegetables, and whole grains have a low GI. They also help to regulate blood sugar levels. Such foods are linked to a reduced risk for heart disease among people with diabetes.

But guidelines on this – such as those from the European Association for the Study of Diabetes – reflect research published more than 15 years ago, before several key trials were published.

Dr. Chiavaroli and colleagues identified 27 randomized controlled trials – the most recent of which was published in May 2021 – that involved a total of 1,617 adults with type 1 or 2 diabetes. For the patients in these trials, diabetes was moderately controlled with glucose-lowering drugs or insulin. All of the included trials examined the effects of a low GI diet or a low glycemic load (GL) diet for people with diabetes over a period 3 or more weeks. The majority of patients in the studies were overweight or had obesity, and they were largely middle-aged.

The meta-analysis, which included new data, was published Aug. 5 in The BMJ. The study “expands the number of relevant intermediate cardiometabolic outcomes, and assesses the certainty of the evidence using GRADE [grading of recommendations assessment, development, and evaluation],” Dr. Chiavaroli and colleagues noted.

“The available evidence provides a good indication of the likely benefit in this population and supports existing recommendations for the use of low GI dietary patterns in the management of diabetes,” they emphasized.
 

Improvements in A1c, fasting glucose, cholesterol, and triglycerides

Overall, compared with people who consumed diets with higher GI/GL ratings, for those who consumed lower glycemic diets, glycemic control was significantly improved, as reflected in A1c level, which was the primary outcome of the study (mean difference, –0.31%; P < .001).

This “would meet the threshold of ≥ 0.3% reduction in HbA1c proposed by the European Medicines Agency as clinically relevant for risk reduction of diabetic complications,” the authors noted.

Those who consumed low glycemic diets also showed improvements in secondary outcomes, including fasting glucose level, which was reduced by 0.36 mmol/L (–6.5 mg/dL), a 6% reduction in low-density cholesterol (LDL-C) (–0.17 mmol/L), and a fall in triglyceride levels (–0.09 mmol/L).

They also lost marginally more body weight, at –0.66 kg (–1.5 pounds). Body mass index was lower by –0.38, and inflammation was reduced (C-reactive protein, –.41 mg/L; all P < .05).

No significant differences were observed between the groups in blood insulin level, high-density lipoprotein cholesterol level, waist circumference, or blood pressure.

Three of the studies showed that participants developed a preference for the low GI diet. “In recent years, there has been a growing interest in whole-food plant-based diets, and there are more options, for example, for pulse-based products,” Dr. Chiavaroli said.

This meta-analysis should support the recommendation of the low-glycemic diet, particularly among people with diabetes, she reiterated.
 

Will larger randomized trial show effect on outcomes?

The authors noted, however, that to determine whether these small improvements in intermediate cardiometabolic risk factors observed with low GI diets translate to reductions in cardiovascular disease, nephropathy, and retinopathy among people with diabetes, larger randomized trials are needed.

One such trial, the Low Glycemic Index Diet for Type 2 Diabetics, includes 169 high-risk patients with type 2 diabetes and subclinical atherosclerosis. The investigators are evaluating the effect of a low GI diet on the progression of atherosclerosis, as assessed by vascular MRI over 3 years.

“We await the results,” they said.

The study received funding from the Diabetes and Nutrition Study Group of the European Association for the Study of Diabetes (EASD) as part of the development of the EASD Clinical Practice Guidelines for Nutrition Therapy. The study was also supported by the Canadian Institutes of Health Research through the Canada-wide Human Nutrition Trialists’ Network. The Diet, Digestive Tract, and Disease (3D) Center, which is funded through the Canada Foundation for Innovation and the Ministry of Research and Innovation’s Ontario Research Fund, provided the infrastructure for the study.

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

In the largest comparison of angiotensin receptor blockers (ARBs) and ACE inhibitors to date, a study of nearly 2.3 million patients starting the drugs as monotherapy shows no significant differences between the two in the long-term prevention of hypertension-related cardiovascular events.

However, side effects were notably lower with ARBs.

“This is a very large, well-executed observational study that confirms that ARBs appear to have fewer side effects than ACE inhibitors, and no unexpected ARB side effects were detected,” senior author George Hripcsak, MD, professor and chair of biomedical informatics at Columbia University, New York, told this news organization.

“Despite being equally guideline-recommended first-line therapies for hypertension, these results support preferentially starting ARBs rather than ACE inhibitors when initiating treatment for hypertension for physicians and patients considering renin-angiotensin system (RAS) inhibition,” the authors added in the study, published online July 26, 2021, in the journal Hypertension.

They noted that both drug classes have been on the market a long time, with proven efficacy in hypertension and “a wide availability of inexpensive generic forms.”

They also stressed that their findings only apply to patients with hypertension for whom a RAS inhibitor would be the best choice of therapy.

Commenting on the research, George Bakris, MD, of the American Heart Association’s Comprehensive Hypertension Center at the University of Chicago, said the findings were consistent with his experience in prescribing as well as researching the two drug classes.

“I have been in practice for over 30 years and studied both classes, including head-to-head prospective trials to assess blood pressure, and found in many cases better blood pressure lowering by some ARBs and always better tolerability,” he told this news organization. “I think this study confirms and extends my thoughts between the two classes of blood pressure–lowering agents.”
 

Head-to-head comparisons of ACE inhibitors and ARBs limited to date

ACE inhibitors and ARBs each have extensive evidence supporting their roles as first-line medications in the treatment of hypertension, and each have the strongest recommendations in international guidelines.

However, ACE inhibitors are prescribed more commonly than ARBs as the first-line drug for lowering blood pressure, and head-to-head comparisons of the two are limited, with conflicting results.

For the study, Dr. Hripcsak and colleagues evaluated data on almost 3 million patients starting monotherapy with an ACE inhibitor or ARB for the first time between 1996 and 2018 in the United States, Germany, and South Korea, who had no history of heart disease or stroke.

They identified a total of 2,297,881 patients initiating ACE inhibitors and 673,938 starting ARBs. Among new users of ACE inhibitors, most received lisinopril (80%), followed by ramipril and enalapril, while most patients prescribed ARBs received losartan (45%), followed by valsartan and olmesartan.

With follow-up times ranging from about 4 months to more than 18 months, the data show no statistically significant differences between ACE inhibitors versus ARBs in the primary outcomes of acute myocardial infarction (hazard ratio, 1.11), heart failure (HR, 1.03), stroke (HR, 1.07), or composite cardiovascular events (HR, 1.06).

For secondary and safety outcomes, including an analysis of 51 possible side effects, ACE inhibitors, compared with ARBs, were associated with a significantly higher risk of angioedema (HR, 3.31; P < .01), cough (HR, 1.32; P < .01), acute pancreatitis (HR, 1.32; P = .02), gastrointestinal bleeding (HR, 1.18; P = .04), and abnormal weight loss (HR, 1.18; P = .04).

While the link between ACE inhibitors and pancreatitis has been previously reported, the association with GI bleeding may be a novel finding, with no prior studies comparing those effects in the two drug classes, the authors noted.

Despite most patients taking just a couple of drugs in either class, Dr. Hripcsak said, “we don’t expect that other drugs from those classes will have fewer differences. It is possible, of course, but that is not our expectation.”
 

Results only applicable to those starting therapy with RAS inhibitors

First author RuiJun Chen, MD, added that, importantly, the results may not apply to patients switching therapies or adding on therapy, “such as for the patient whose hypertension is not effectively controlled with one drug and requires the addition of a second medication,” he said in an interview.

“Also, the suggestion of preferentially prescribing ARBs only applies to those patients and providers intending to control blood pressure through RAS inhibition,” said Dr. Chen, an assistant professor in translational data science and informatics at Geisinger Medical Center in Danville, Pa., who was a National Library of Medicine postdoctoral fellow at Columbia University at the time of the study.

Hence, he stressed the results do not extend to other classes of recommended first-line blood pressure medications.

“Essentially, since this is an ACE inhibitor versus ARB study, we would not claim that ARBs are preferred over all other types of hypertension medications which were not studied here,” the researchers emphasize.

In addition to ARBs and ACE inhibitors, other medications recommended by the AHA/American College of Cardiology in the 2017 “Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults” for the primary treatment of hypertension include thiazide diuretics and calcium channel blockers.

The study received support from the National Library of Medicine and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the National Science Foundation; and the Ministries of Health & Welfare and of Trade, Industry & Energy of the Republic of Korea. Dr. Hripcsak reported receiving grants from the National Library of Medicine during the study and grants from Janssen Research outside the submitted work. Dr. Bakris reported being a consultant for Merck, KBP Biosciences, and Ionis.

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

In the largest comparison of angiotensin receptor blockers (ARBs) and ACE inhibitors to date, a study of nearly 2.3 million patients starting the drugs as monotherapy shows no significant differences between the two in the long-term prevention of hypertension-related cardiovascular events.

However, side effects were notably lower with ARBs.

“This is a very large, well-executed observational study that confirms that ARBs appear to have fewer side effects than ACE inhibitors, and no unexpected ARB side effects were detected,” senior author George Hripcsak, MD, professor and chair of biomedical informatics at Columbia University, New York, told this news organization.

“Despite being equally guideline-recommended first-line therapies for hypertension, these results support preferentially starting ARBs rather than ACE inhibitors when initiating treatment for hypertension for physicians and patients considering renin-angiotensin system (RAS) inhibition,” the authors added in the study, published online July 26, 2021, in the journal Hypertension.

They noted that both drug classes have been on the market a long time, with proven efficacy in hypertension and “a wide availability of inexpensive generic forms.”

They also stressed that their findings only apply to patients with hypertension for whom a RAS inhibitor would be the best choice of therapy.

Commenting on the research, George Bakris, MD, of the American Heart Association’s Comprehensive Hypertension Center at the University of Chicago, said the findings were consistent with his experience in prescribing as well as researching the two drug classes.

“I have been in practice for over 30 years and studied both classes, including head-to-head prospective trials to assess blood pressure, and found in many cases better blood pressure lowering by some ARBs and always better tolerability,” he told this news organization. “I think this study confirms and extends my thoughts between the two classes of blood pressure–lowering agents.”
 

Head-to-head comparisons of ACE inhibitors and ARBs limited to date

ACE inhibitors and ARBs each have extensive evidence supporting their roles as first-line medications in the treatment of hypertension, and each have the strongest recommendations in international guidelines.

However, ACE inhibitors are prescribed more commonly than ARBs as the first-line drug for lowering blood pressure, and head-to-head comparisons of the two are limited, with conflicting results.

For the study, Dr. Hripcsak and colleagues evaluated data on almost 3 million patients starting monotherapy with an ACE inhibitor or ARB for the first time between 1996 and 2018 in the United States, Germany, and South Korea, who had no history of heart disease or stroke.

They identified a total of 2,297,881 patients initiating ACE inhibitors and 673,938 starting ARBs. Among new users of ACE inhibitors, most received lisinopril (80%), followed by ramipril and enalapril, while most patients prescribed ARBs received losartan (45%), followed by valsartan and olmesartan.

With follow-up times ranging from about 4 months to more than 18 months, the data show no statistically significant differences between ACE inhibitors versus ARBs in the primary outcomes of acute myocardial infarction (hazard ratio, 1.11), heart failure (HR, 1.03), stroke (HR, 1.07), or composite cardiovascular events (HR, 1.06).

For secondary and safety outcomes, including an analysis of 51 possible side effects, ACE inhibitors, compared with ARBs, were associated with a significantly higher risk of angioedema (HR, 3.31; P < .01), cough (HR, 1.32; P < .01), acute pancreatitis (HR, 1.32; P = .02), gastrointestinal bleeding (HR, 1.18; P = .04), and abnormal weight loss (HR, 1.18; P = .04).

While the link between ACE inhibitors and pancreatitis has been previously reported, the association with GI bleeding may be a novel finding, with no prior studies comparing those effects in the two drug classes, the authors noted.

Despite most patients taking just a couple of drugs in either class, Dr. Hripcsak said, “we don’t expect that other drugs from those classes will have fewer differences. It is possible, of course, but that is not our expectation.”
 

Results only applicable to those starting therapy with RAS inhibitors

First author RuiJun Chen, MD, added that, importantly, the results may not apply to patients switching therapies or adding on therapy, “such as for the patient whose hypertension is not effectively controlled with one drug and requires the addition of a second medication,” he said in an interview.

“Also, the suggestion of preferentially prescribing ARBs only applies to those patients and providers intending to control blood pressure through RAS inhibition,” said Dr. Chen, an assistant professor in translational data science and informatics at Geisinger Medical Center in Danville, Pa., who was a National Library of Medicine postdoctoral fellow at Columbia University at the time of the study.

Hence, he stressed the results do not extend to other classes of recommended first-line blood pressure medications.

“Essentially, since this is an ACE inhibitor versus ARB study, we would not claim that ARBs are preferred over all other types of hypertension medications which were not studied here,” the researchers emphasize.

In addition to ARBs and ACE inhibitors, other medications recommended by the AHA/American College of Cardiology in the 2017 “Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults” for the primary treatment of hypertension include thiazide diuretics and calcium channel blockers.

The study received support from the National Library of Medicine and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the National Science Foundation; and the Ministries of Health & Welfare and of Trade, Industry & Energy of the Republic of Korea. Dr. Hripcsak reported receiving grants from the National Library of Medicine during the study and grants from Janssen Research outside the submitted work. Dr. Bakris reported being a consultant for Merck, KBP Biosciences, and Ionis.

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

In the largest comparison of angiotensin receptor blockers (ARBs) and ACE inhibitors to date, a study of nearly 2.3 million patients starting the drugs as monotherapy shows no significant differences between the two in the long-term prevention of hypertension-related cardiovascular events.

However, side effects were notably lower with ARBs.

“This is a very large, well-executed observational study that confirms that ARBs appear to have fewer side effects than ACE inhibitors, and no unexpected ARB side effects were detected,” senior author George Hripcsak, MD, professor and chair of biomedical informatics at Columbia University, New York, told this news organization.

“Despite being equally guideline-recommended first-line therapies for hypertension, these results support preferentially starting ARBs rather than ACE inhibitors when initiating treatment for hypertension for physicians and patients considering renin-angiotensin system (RAS) inhibition,” the authors added in the study, published online July 26, 2021, in the journal Hypertension.

They noted that both drug classes have been on the market a long time, with proven efficacy in hypertension and “a wide availability of inexpensive generic forms.”

They also stressed that their findings only apply to patients with hypertension for whom a RAS inhibitor would be the best choice of therapy.

Commenting on the research, George Bakris, MD, of the American Heart Association’s Comprehensive Hypertension Center at the University of Chicago, said the findings were consistent with his experience in prescribing as well as researching the two drug classes.

“I have been in practice for over 30 years and studied both classes, including head-to-head prospective trials to assess blood pressure, and found in many cases better blood pressure lowering by some ARBs and always better tolerability,” he told this news organization. “I think this study confirms and extends my thoughts between the two classes of blood pressure–lowering agents.”
 

Head-to-head comparisons of ACE inhibitors and ARBs limited to date

ACE inhibitors and ARBs each have extensive evidence supporting their roles as first-line medications in the treatment of hypertension, and each have the strongest recommendations in international guidelines.

However, ACE inhibitors are prescribed more commonly than ARBs as the first-line drug for lowering blood pressure, and head-to-head comparisons of the two are limited, with conflicting results.

For the study, Dr. Hripcsak and colleagues evaluated data on almost 3 million patients starting monotherapy with an ACE inhibitor or ARB for the first time between 1996 and 2018 in the United States, Germany, and South Korea, who had no history of heart disease or stroke.

They identified a total of 2,297,881 patients initiating ACE inhibitors and 673,938 starting ARBs. Among new users of ACE inhibitors, most received lisinopril (80%), followed by ramipril and enalapril, while most patients prescribed ARBs received losartan (45%), followed by valsartan and olmesartan.

With follow-up times ranging from about 4 months to more than 18 months, the data show no statistically significant differences between ACE inhibitors versus ARBs in the primary outcomes of acute myocardial infarction (hazard ratio, 1.11), heart failure (HR, 1.03), stroke (HR, 1.07), or composite cardiovascular events (HR, 1.06).

For secondary and safety outcomes, including an analysis of 51 possible side effects, ACE inhibitors, compared with ARBs, were associated with a significantly higher risk of angioedema (HR, 3.31; P < .01), cough (HR, 1.32; P < .01), acute pancreatitis (HR, 1.32; P = .02), gastrointestinal bleeding (HR, 1.18; P = .04), and abnormal weight loss (HR, 1.18; P = .04).

While the link between ACE inhibitors and pancreatitis has been previously reported, the association with GI bleeding may be a novel finding, with no prior studies comparing those effects in the two drug classes, the authors noted.

Despite most patients taking just a couple of drugs in either class, Dr. Hripcsak said, “we don’t expect that other drugs from those classes will have fewer differences. It is possible, of course, but that is not our expectation.”
 

Results only applicable to those starting therapy with RAS inhibitors

First author RuiJun Chen, MD, added that, importantly, the results may not apply to patients switching therapies or adding on therapy, “such as for the patient whose hypertension is not effectively controlled with one drug and requires the addition of a second medication,” he said in an interview.

“Also, the suggestion of preferentially prescribing ARBs only applies to those patients and providers intending to control blood pressure through RAS inhibition,” said Dr. Chen, an assistant professor in translational data science and informatics at Geisinger Medical Center in Danville, Pa., who was a National Library of Medicine postdoctoral fellow at Columbia University at the time of the study.

Hence, he stressed the results do not extend to other classes of recommended first-line blood pressure medications.

“Essentially, since this is an ACE inhibitor versus ARB study, we would not claim that ARBs are preferred over all other types of hypertension medications which were not studied here,” the researchers emphasize.

In addition to ARBs and ACE inhibitors, other medications recommended by the AHA/American College of Cardiology in the 2017 “Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults” for the primary treatment of hypertension include thiazide diuretics and calcium channel blockers.

The study received support from the National Library of Medicine and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the National Science Foundation; and the Ministries of Health & Welfare and of Trade, Industry & Energy of the Republic of Korea. Dr. Hripcsak reported receiving grants from the National Library of Medicine during the study and grants from Janssen Research outside the submitted work. Dr. Bakris reported being a consultant for Merck, KBP Biosciences, and Ionis.

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

A two-drug fixed-dose tablet therapy of dolutegravir/lamivudine (Dovato, ViiV Healthcare; DTG/3TC) shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral (ART) regimens. But, DTG/3TC also shows feasibility as a first-line regimen in a test-and-treat setting, according to two studies presented at the virtual meeting of the International AIDS Society.

The results on the switch to DTG/3TC are from the phase 3 SALSA trial, which compared patients with HIV-1 who either remained on any current three- or four-drug ART regimen or who switched to the two-drug dolutegravir option.

For the primary endpoint, rates of virologic failure at 48 weeks were noninferior in the DTG/3TC group versus the three- or four-drug regimen (.4% vs. 1.2; adjusted difference: –.8% [95% confidence interval, –2.4%, .8%]).

In addition, rates of virologic suppression at week 48 were noninferior, with 94.3% of patients achieving HIV-1 RNA < 50 c/mL in the DTG/3TC group versus 92.7% in the three- or four-drug regimen (adjusted difference: 1.6% [95% CI, –2.8%, 5.9%).

“These data build upon the previous TANGO study and support DTG/3TC as a robust switch option with high levels of efficacy, good safety and tolerability, and a high barrier of resistance,” first author Josep M. Llibre, MD, PhD, consultant, infectious diseases department, Germans Trias i Pujol University Hospital, Barcelona, said in presenting the findings.

The two-drug dolutegravir-based regimen had previously been shown in the phase 3 GEMINI-1 and GEMINI-2 trials to have virologic noninferiority and safety compared with three- or four-drug DTG plus tenofovir/emtricitabine (TDF/FTC) ART regimens in treatment-naive individuals, and, in the subsequent TANGO trial, the regimen was also noninferior versus tenofovir alafenamide–based regimens among treatment-experienced patients, at 144 weeks in both studies.


 

Trial details

The new SALSA trial, designed to broaden the comparison to treatment with any current three- or four-drug ART regimen, involved 493 patients at 120 study sites in 17 countries.

All patients were initially on a three- or four-drug regimen, with HIV-1 RNA of less than 50 c/mL for more than 6 months, and without prior virologic failure or nucleoside reverse transcriptase inhibitors or dolutegravir resistance-associated mutations.

The participants were randomized 1:1 to remain on their current regimen (n = 247) or to switch to the once-daily, fixed-dose tablet two-drug combination of dolutegravir 50 mg/lamivudine 300 mg (n = 246) for 52 weeks.

In addition to the noninferior virologic outcomes, there were no serious drug-related adverse events, no confirmed virologic withdrawals, and no resistance mutations in either group.

Of note, weight increase was higher in the DTG/3TC group (8%; n = 20) versus the current ART arm (2%; n = 5), as has been observed in previous studies. The adjusted mean change in weight from baseline to week 48 in the DTG arm was 2.1 kg versus 0.6 kg in the current ART arm.

Dr. Llibre pointed out that many of the participants who switched were discontinuing regimens such as TDF and efavirenz that are associated with weight loss, “so discontinuation could be more related to weight gain than the introduction of dolutegravir, but this deserves further study,” he noted.

There were no significant differences in changes in eGFR and fasting lipids, or in changes in inflammatory biomarkers between the groups.

Bone and renal biomarkers were more favorable in the dolutegravir two-drug arm, suggesting that bone and renal function was either maintained or even improved with the drug switch, Dr. Llibre noted.

STAT trial: Feasibility of two-drug DTG/3TC as first-line treatment

In further findings presented at the meeting on the STAT trial, researchers evaluated the feasibility not of switching to, but of initiating patients on, the two-drug DTG treatment as a first-line therapy, within 14 days of HIV-1 diagnosis.

The “test-and-treat” approach counters common belief that the regimen should be started only after the traditional three-drug regimens, because of the potential of transmitted resistance and baseline hepatitis B virus coinfection.

In the study of 131 patients, at week 48, 82% (107/131) of all participants and 97% (107/110) of those with available data achieved HIV-1 RNA levels of < 50 c/mL.

While two participants had confirmed virologic failure in the study, there were no treatment-emergent resistance-associated mutations, and neither patient discontinued the two-drug DTG treatment. There were low rates of drug-related adverse events (8%) and they were not serious.

A two-drug fixed-dose tablet therapy of dolutegravir/lamivudine (Dovato, ViiV Healthcare; DTG/3TC) shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral (ART) regimens. But, DTG/3TC also shows feasibility as a first-line regimen in a test-and-treat setting, according to two studies presented at the virtual meeting of the International AIDS Society.

The results on the switch to DTG/3TC are from the phase 3 SALSA trial, which compared patients with HIV-1 who either remained on any current three- or four-drug ART regimen or who switched to the two-drug dolutegravir option.

For the primary endpoint, rates of virologic failure at 48 weeks were noninferior in the DTG/3TC group versus the three- or four-drug regimen (.4% vs. 1.2; adjusted difference: –.8% [95% confidence interval, –2.4%, .8%]).

In addition, rates of virologic suppression at week 48 were noninferior, with 94.3% of patients achieving HIV-1 RNA < 50 c/mL in the DTG/3TC group versus 92.7% in the three- or four-drug regimen (adjusted difference: 1.6% [95% CI, –2.8%, 5.9%).

“These data build upon the previous TANGO study and support DTG/3TC as a robust switch option with high levels of efficacy, good safety and tolerability, and a high barrier of resistance,” first author Josep M. Llibre, MD, PhD, consultant, infectious diseases department, Germans Trias i Pujol University Hospital, Barcelona, said in presenting the findings.

The two-drug dolutegravir-based regimen had previously been shown in the phase 3 GEMINI-1 and GEMINI-2 trials to have virologic noninferiority and safety compared with three- or four-drug DTG plus tenofovir/emtricitabine (TDF/FTC) ART regimens in treatment-naive individuals, and, in the subsequent TANGO trial, the regimen was also noninferior versus tenofovir alafenamide–based regimens among treatment-experienced patients, at 144 weeks in both studies.


 

Trial details

The new SALSA trial, designed to broaden the comparison to treatment with any current three- or four-drug ART regimen, involved 493 patients at 120 study sites in 17 countries.

All patients were initially on a three- or four-drug regimen, with HIV-1 RNA of less than 50 c/mL for more than 6 months, and without prior virologic failure or nucleoside reverse transcriptase inhibitors or dolutegravir resistance-associated mutations.

The participants were randomized 1:1 to remain on their current regimen (n = 247) or to switch to the once-daily, fixed-dose tablet two-drug combination of dolutegravir 50 mg/lamivudine 300 mg (n = 246) for 52 weeks.

In addition to the noninferior virologic outcomes, there were no serious drug-related adverse events, no confirmed virologic withdrawals, and no resistance mutations in either group.

Of note, weight increase was higher in the DTG/3TC group (8%; n = 20) versus the current ART arm (2%; n = 5), as has been observed in previous studies. The adjusted mean change in weight from baseline to week 48 in the DTG arm was 2.1 kg versus 0.6 kg in the current ART arm.

Dr. Llibre pointed out that many of the participants who switched were discontinuing regimens such as TDF and efavirenz that are associated with weight loss, “so discontinuation could be more related to weight gain than the introduction of dolutegravir, but this deserves further study,” he noted.

There were no significant differences in changes in eGFR and fasting lipids, or in changes in inflammatory biomarkers between the groups.

Bone and renal biomarkers were more favorable in the dolutegravir two-drug arm, suggesting that bone and renal function was either maintained or even improved with the drug switch, Dr. Llibre noted.

STAT trial: Feasibility of two-drug DTG/3TC as first-line treatment

In further findings presented at the meeting on the STAT trial, researchers evaluated the feasibility not of switching to, but of initiating patients on, the two-drug DTG treatment as a first-line therapy, within 14 days of HIV-1 diagnosis.

The “test-and-treat” approach counters common belief that the regimen should be started only after the traditional three-drug regimens, because of the potential of transmitted resistance and baseline hepatitis B virus coinfection.

In the study of 131 patients, at week 48, 82% (107/131) of all participants and 97% (107/110) of those with available data achieved HIV-1 RNA levels of < 50 c/mL.

While two participants had confirmed virologic failure in the study, there were no treatment-emergent resistance-associated mutations, and neither patient discontinued the two-drug DTG treatment. There were low rates of drug-related adverse events (8%) and they were not serious.

A two-drug fixed-dose tablet therapy of dolutegravir/lamivudine (Dovato, ViiV Healthcare; DTG/3TC) shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral (ART) regimens. But, DTG/3TC also shows feasibility as a first-line regimen in a test-and-treat setting, according to two studies presented at the virtual meeting of the International AIDS Society.

The results on the switch to DTG/3TC are from the phase 3 SALSA trial, which compared patients with HIV-1 who either remained on any current three- or four-drug ART regimen or who switched to the two-drug dolutegravir option.

For the primary endpoint, rates of virologic failure at 48 weeks were noninferior in the DTG/3TC group versus the three- or four-drug regimen (.4% vs. 1.2; adjusted difference: –.8% [95% confidence interval, –2.4%, .8%]).

In addition, rates of virologic suppression at week 48 were noninferior, with 94.3% of patients achieving HIV-1 RNA < 50 c/mL in the DTG/3TC group versus 92.7% in the three- or four-drug regimen (adjusted difference: 1.6% [95% CI, –2.8%, 5.9%).

“These data build upon the previous TANGO study and support DTG/3TC as a robust switch option with high levels of efficacy, good safety and tolerability, and a high barrier of resistance,” first author Josep M. Llibre, MD, PhD, consultant, infectious diseases department, Germans Trias i Pujol University Hospital, Barcelona, said in presenting the findings.

The two-drug dolutegravir-based regimen had previously been shown in the phase 3 GEMINI-1 and GEMINI-2 trials to have virologic noninferiority and safety compared with three- or four-drug DTG plus tenofovir/emtricitabine (TDF/FTC) ART regimens in treatment-naive individuals, and, in the subsequent TANGO trial, the regimen was also noninferior versus tenofovir alafenamide–based regimens among treatment-experienced patients, at 144 weeks in both studies.


 

Trial details

The new SALSA trial, designed to broaden the comparison to treatment with any current three- or four-drug ART regimen, involved 493 patients at 120 study sites in 17 countries.

All patients were initially on a three- or four-drug regimen, with HIV-1 RNA of less than 50 c/mL for more than 6 months, and without prior virologic failure or nucleoside reverse transcriptase inhibitors or dolutegravir resistance-associated mutations.

The participants were randomized 1:1 to remain on their current regimen (n = 247) or to switch to the once-daily, fixed-dose tablet two-drug combination of dolutegravir 50 mg/lamivudine 300 mg (n = 246) for 52 weeks.

In addition to the noninferior virologic outcomes, there were no serious drug-related adverse events, no confirmed virologic withdrawals, and no resistance mutations in either group.

Of note, weight increase was higher in the DTG/3TC group (8%; n = 20) versus the current ART arm (2%; n = 5), as has been observed in previous studies. The adjusted mean change in weight from baseline to week 48 in the DTG arm was 2.1 kg versus 0.6 kg in the current ART arm.

Dr. Llibre pointed out that many of the participants who switched were discontinuing regimens such as TDF and efavirenz that are associated with weight loss, “so discontinuation could be more related to weight gain than the introduction of dolutegravir, but this deserves further study,” he noted.

There were no significant differences in changes in eGFR and fasting lipids, or in changes in inflammatory biomarkers between the groups.

Bone and renal biomarkers were more favorable in the dolutegravir two-drug arm, suggesting that bone and renal function was either maintained or even improved with the drug switch, Dr. Llibre noted.

STAT trial: Feasibility of two-drug DTG/3TC as first-line treatment

In further findings presented at the meeting on the STAT trial, researchers evaluated the feasibility not of switching to, but of initiating patients on, the two-drug DTG treatment as a first-line therapy, within 14 days of HIV-1 diagnosis.

The “test-and-treat” approach counters common belief that the regimen should be started only after the traditional three-drug regimens, because of the potential of transmitted resistance and baseline hepatitis B virus coinfection.

In the study of 131 patients, at week 48, 82% (107/131) of all participants and 97% (107/110) of those with available data achieved HIV-1 RNA levels of < 50 c/mL.

While two participants had confirmed virologic failure in the study, there were no treatment-emergent resistance-associated mutations, and neither patient discontinued the two-drug DTG treatment. There were low rates of drug-related adverse events (8%) and they were not serious.

A single high dose of the antifungal agent liposomal amphotericin B (L-AmB; AmBisome, Gilead Sciences), with a background regimen of flucytosine and fluconazole, is non-inferior and significantly safer in preventing mortality in HIV-associated cryptococcal meningitis than a conventional seven-day regimen that is the current standard of care, according to a new study.

The much-anticipated results suggest an important alternative amid controversy over the drug’s cost and availability.

“The results of this phase 3 [AMBITION-cm] trial make it clear that this approach is just as good as the current World Health Organization-recommended first-line treatment in preventing death,” first author David S. Lawrence, MD, AMBITION study lead clinician, of the London School of Hygiene and Tropical Medicine, United Kingdom, said in an interview.

“The fact that this was the largest ever trial [on HIV-associated cryptococcal meningitis] conducted to date… gives us a high level of confidence in these results,” he said of the study, which was presented at the virtual annual meeting of the International AIDS Society.

“We believe that this should become the WHO-recommended first-line regimen,” he emphasized.

In commenting on the study, Meg Doherty, MD, PhD, director of global HIV, hepatitis, and STI programs at WHO, agreed that a shorter regimen could be vital, particularly in settings with limited resources.

“The results from the AMBITION trial are important for low- and middle-income countries, where the cost and complexity of implementing the current standard seven-day course of L-ambisome or cryptococcal meningitis treatment can put this out of reach for many,” she told this news organization.

“Simplification that maintains the highest quality of care is an important component of the public health approach for HIV treatment and care,” she added.

Dr. Doherty could not comment on any possible changes to WHO recommendations, which are formulated by an independent guideline development group, but a spokesperson said that “WHO is preparing an updated review of the evidence for treating cryptococcal disease as a first step towards updating guidance.”

Conventional treatment toxicities

Cryptococcal meningitis is a leading cause of death in HIV, and the conventional treatment of amphotericin B deoxycholate, though less expensive than L-AmB, is more toxic, causing anemia, renal impairment, and electrolyte abnormalities, Dr. Lawrence explained

Having previously shown a single 10 mg/kg dose of L-AmB to be as effective as the longer regimen of 14 daily doses in terms of clearing cryptococcus from the cerebrospinal fluid, Dr. Lawrence and his colleagues conducted the phase 3 AMBITION-Cm trial to evaluate the effect on mortality, enrolling 844 patients in Botswana, Malawi, South Africa, Uganda, and Zimbabwe who were HIV-positive and had a first episode of cryptococcal meningitis.

Participants in the study were randomized to treatment either with single, high-dose L-AmB (10 mg/kg), combined with 14 days of flucytosine 100 mg/kg/day and fluconazole 1,200 mg/day or to a control group receiving 7 daily doses of AmB deoxycholate (1 mg/kg) plus 7 days of flucytosine 100 mg/kg/day, followed by 7 days of fluconazole 1,200 mg/day.

All patients were also provided with consolidation therapy of fluconazole 800 mg/day for eight weeks. Of the patients, 60.2% were male, their median age was 37, and their median CD4 count was 27 cells/mm³.

For the primary endpoint in the intention-to-treat analysis of 814 patients, the 10-week mortality rate in the single-dose L-AmB group was 24.82% (101 of 407) and 28.75% (117 of 407) in the control arm, for a difference (-3.93%) that was well within the pre-specified non-inferiority margin of 10%.

As expected, the safety measures were significantly improved with the single-dose of L-AmB: Rates of grade 3 or 4 adverse events within the initial 21 days of treatment in the single-dose L-AmB group were 50% versus 62.3% in the control group, and severe anemia occurred in just 13% of single-dose L-AmB participants, compared with 41% in the AmB deoxycholate control arm (both P < .001), Dr. Lawrence reported.

Furthermore, the average decline in hemoglobin over the first week was 0.3 g/dL in the single-dose L-AmB arm and 1.9 g/dL in the control arm, resulting in the need for more blood transfusions in the control arm (P < .001).

The impact on kidney function was also worse in the higher dose arm, with an average increase in creatinine over the first week of 20.2% in the L-AmB group versus 49.7% in the control group, while hypokalemia and thrombophlebitis were also more common with the higher dose group, Dr. Lawrence noted.

In the adjusted analysis, the single-dose L-AmB measures were in fact superior after adjusting for factors including research site, age, sex, baseline Glasgow Coma Scale, CD4 count, CSF cryptococcal colony-forming units/mL, antiretroviral therapy status, hemoglobin, and CSF opening pressure.

Mortality rate still high – but significantly reduced

The mortality rate of about 25% in the study after the treatment is still significantly higher than typically seen in high-income countries such as the United States, where HIV-associated cryptococcal meningitis is less common and associated with a mortality of roughly 10-15%, Dr. Lawrence noted.

The rate is nevertheless among the lowest mortality rates ever reported within a clinical trial conducted in resource-limited settings, he explained.

“These results are a step in the right direction and a significant improvement on the rates of 40% to 45% reported with two-week L-AmB-based regimens in African settings,” Dr. Lawrence underscored.

Higher cost — but potentially more cost-effective

With a higher cost than AmB deoxycholate, L-AmB’s utilization in resource-limited settings has been a challenge: A single vial of L-AmB ranges from $80 to $200, according to some reports, and while 14-day dosing requires as many as 42 vials of L-AmB, even a 7-day regimen still requires 21 vials.

In comparison, the single-dose L-AmB regimen only requires an average of 10 to 11 vials per patient, but the regimen’s higher safety could translate to far greater cost savings, Dr. Lawrence explained.

“While the AmBisome regimen is technically more expensive in terms of drugs, we expect it to be cost-effective or possibly cost-saving when taking into account that there is less toxicity, fewer blood tests, less transfusions, etc., and possibly shorter duration of hospital admission,” he said.

Cost, supply controversy: ‘Black fungus’-related demand

The drug’s cost — as well as supply issues — have meanwhile become even more of a problem as L-AmB has unexpectedly also become urgently needed in the treatment of mucormycosis in India and Nepal, where the otherwise rare fungal disease, commonly known as “black fungus,” has been increasingly affecting COVID-19 patients and survivors.

Gilead had previously announced in 2018 its intention to make L-AmB more widely available at a price of $16.25 per vial, but “implementation of this has been slow,” Dr. Lawrence said.

As a result, Gilead is facing heightened pressure to implement the lower prices – and also improve substantial supply issues, with Médecins Sans Frontières (Doctors Without Borders) and dozens of other global organizations issuing an open letter to Gilead and partner Viatris in June calling for immediate action to implement the lower price and improve supply of L-AmB.

In a company statement, Gilead responded, detailing its “commit[ment] to the non-profit pricing for the treatment of cryptococcal meningitis” and to efforts to improve the public health crisis in India.

For their part, Dr. Lawrence and his colleagues are working on producing more research on the issue.

“We hope that the conclusive results of the AMBITION trial will give a much needed push to implement this program,” he said.

“We are also currently completing the cost-effectiveness analysis of the study, which we hope will provide additional evidence to support widespread implementation of this regimen and highlight further the urgent need to broaden access to AmBisome and flucytosine,” he said.

The trial was supported by a grant through the European Developing Countries Clinical Trials Partnership (EDCTP), the Swedish International Development Cooperation Agency (SIDA) (TRIA2015-1092), and the Wellcome Trust / Medical Research Council (UK)/UKAID Joint Global Health Trials (MR/P006922/1. The AmBisome was donated by Gilead Sciences. Dr. Lawrence had no disclosures to report.

A single high dose of the antifungal agent liposomal amphotericin B (L-AmB; AmBisome, Gilead Sciences), with a background regimen of flucytosine and fluconazole, is non-inferior and significantly safer in preventing mortality in HIV-associated cryptococcal meningitis than a conventional seven-day regimen that is the current standard of care, according to a new study.

The much-anticipated results suggest an important alternative amid controversy over the drug’s cost and availability.

“The results of this phase 3 [AMBITION-cm] trial make it clear that this approach is just as good as the current World Health Organization-recommended first-line treatment in preventing death,” first author David S. Lawrence, MD, AMBITION study lead clinician, of the London School of Hygiene and Tropical Medicine, United Kingdom, said in an interview.

“The fact that this was the largest ever trial [on HIV-associated cryptococcal meningitis] conducted to date… gives us a high level of confidence in these results,” he said of the study, which was presented at the virtual annual meeting of the International AIDS Society.

“We believe that this should become the WHO-recommended first-line regimen,” he emphasized.

In commenting on the study, Meg Doherty, MD, PhD, director of global HIV, hepatitis, and STI programs at WHO, agreed that a shorter regimen could be vital, particularly in settings with limited resources.

“The results from the AMBITION trial are important for low- and middle-income countries, where the cost and complexity of implementing the current standard seven-day course of L-ambisome or cryptococcal meningitis treatment can put this out of reach for many,” she told this news organization.

“Simplification that maintains the highest quality of care is an important component of the public health approach for HIV treatment and care,” she added.

Dr. Doherty could not comment on any possible changes to WHO recommendations, which are formulated by an independent guideline development group, but a spokesperson said that “WHO is preparing an updated review of the evidence for treating cryptococcal disease as a first step towards updating guidance.”

Conventional treatment toxicities

Cryptococcal meningitis is a leading cause of death in HIV, and the conventional treatment of amphotericin B deoxycholate, though less expensive than L-AmB, is more toxic, causing anemia, renal impairment, and electrolyte abnormalities, Dr. Lawrence explained

Having previously shown a single 10 mg/kg dose of L-AmB to be as effective as the longer regimen of 14 daily doses in terms of clearing cryptococcus from the cerebrospinal fluid, Dr. Lawrence and his colleagues conducted the phase 3 AMBITION-Cm trial to evaluate the effect on mortality, enrolling 844 patients in Botswana, Malawi, South Africa, Uganda, and Zimbabwe who were HIV-positive and had a first episode of cryptococcal meningitis.

Participants in the study were randomized to treatment either with single, high-dose L-AmB (10 mg/kg), combined with 14 days of flucytosine 100 mg/kg/day and fluconazole 1,200 mg/day or to a control group receiving 7 daily doses of AmB deoxycholate (1 mg/kg) plus 7 days of flucytosine 100 mg/kg/day, followed by 7 days of fluconazole 1,200 mg/day.

All patients were also provided with consolidation therapy of fluconazole 800 mg/day for eight weeks. Of the patients, 60.2% were male, their median age was 37, and their median CD4 count was 27 cells/mm³.

For the primary endpoint in the intention-to-treat analysis of 814 patients, the 10-week mortality rate in the single-dose L-AmB group was 24.82% (101 of 407) and 28.75% (117 of 407) in the control arm, for a difference (-3.93%) that was well within the pre-specified non-inferiority margin of 10%.

As expected, the safety measures were significantly improved with the single-dose of L-AmB: Rates of grade 3 or 4 adverse events within the initial 21 days of treatment in the single-dose L-AmB group were 50% versus 62.3% in the control group, and severe anemia occurred in just 13% of single-dose L-AmB participants, compared with 41% in the AmB deoxycholate control arm (both P < .001), Dr. Lawrence reported.

Furthermore, the average decline in hemoglobin over the first week was 0.3 g/dL in the single-dose L-AmB arm and 1.9 g/dL in the control arm, resulting in the need for more blood transfusions in the control arm (P < .001).

The impact on kidney function was also worse in the higher dose arm, with an average increase in creatinine over the first week of 20.2% in the L-AmB group versus 49.7% in the control group, while hypokalemia and thrombophlebitis were also more common with the higher dose group, Dr. Lawrence noted.

In the adjusted analysis, the single-dose L-AmB measures were in fact superior after adjusting for factors including research site, age, sex, baseline Glasgow Coma Scale, CD4 count, CSF cryptococcal colony-forming units/mL, antiretroviral therapy status, hemoglobin, and CSF opening pressure.

Mortality rate still high – but significantly reduced

The mortality rate of about 25% in the study after the treatment is still significantly higher than typically seen in high-income countries such as the United States, where HIV-associated cryptococcal meningitis is less common and associated with a mortality of roughly 10-15%, Dr. Lawrence noted.

The rate is nevertheless among the lowest mortality rates ever reported within a clinical trial conducted in resource-limited settings, he explained.

“These results are a step in the right direction and a significant improvement on the rates of 40% to 45% reported with two-week L-AmB-based regimens in African settings,” Dr. Lawrence underscored.

Higher cost — but potentially more cost-effective

With a higher cost than AmB deoxycholate, L-AmB’s utilization in resource-limited settings has been a challenge: A single vial of L-AmB ranges from $80 to $200, according to some reports, and while 14-day dosing requires as many as 42 vials of L-AmB, even a 7-day regimen still requires 21 vials.

In comparison, the single-dose L-AmB regimen only requires an average of 10 to 11 vials per patient, but the regimen’s higher safety could translate to far greater cost savings, Dr. Lawrence explained.

“While the AmBisome regimen is technically more expensive in terms of drugs, we expect it to be cost-effective or possibly cost-saving when taking into account that there is less toxicity, fewer blood tests, less transfusions, etc., and possibly shorter duration of hospital admission,” he said.

Cost, supply controversy: ‘Black fungus’-related demand

The drug’s cost — as well as supply issues — have meanwhile become even more of a problem as L-AmB has unexpectedly also become urgently needed in the treatment of mucormycosis in India and Nepal, where the otherwise rare fungal disease, commonly known as “black fungus,” has been increasingly affecting COVID-19 patients and survivors.

Gilead had previously announced in 2018 its intention to make L-AmB more widely available at a price of $16.25 per vial, but “implementation of this has been slow,” Dr. Lawrence said.

As a result, Gilead is facing heightened pressure to implement the lower prices – and also improve substantial supply issues, with Médecins Sans Frontières (Doctors Without Borders) and dozens of other global organizations issuing an open letter to Gilead and partner Viatris in June calling for immediate action to implement the lower price and improve supply of L-AmB.

In a company statement, Gilead responded, detailing its “commit[ment] to the non-profit pricing for the treatment of cryptococcal meningitis” and to efforts to improve the public health crisis in India.

For their part, Dr. Lawrence and his colleagues are working on producing more research on the issue.

“We hope that the conclusive results of the AMBITION trial will give a much needed push to implement this program,” he said.

“We are also currently completing the cost-effectiveness analysis of the study, which we hope will provide additional evidence to support widespread implementation of this regimen and highlight further the urgent need to broaden access to AmBisome and flucytosine,” he said.

The trial was supported by a grant through the European Developing Countries Clinical Trials Partnership (EDCTP), the Swedish International Development Cooperation Agency (SIDA) (TRIA2015-1092), and the Wellcome Trust / Medical Research Council (UK)/UKAID Joint Global Health Trials (MR/P006922/1. The AmBisome was donated by Gilead Sciences. Dr. Lawrence had no disclosures to report.

A single high dose of the antifungal agent liposomal amphotericin B (L-AmB; AmBisome, Gilead Sciences), with a background regimen of flucytosine and fluconazole, is non-inferior and significantly safer in preventing mortality in HIV-associated cryptococcal meningitis than a conventional seven-day regimen that is the current standard of care, according to a new study.

The much-anticipated results suggest an important alternative amid controversy over the drug’s cost and availability.

“The results of this phase 3 [AMBITION-cm] trial make it clear that this approach is just as good as the current World Health Organization-recommended first-line treatment in preventing death,” first author David S. Lawrence, MD, AMBITION study lead clinician, of the London School of Hygiene and Tropical Medicine, United Kingdom, said in an interview.

“The fact that this was the largest ever trial [on HIV-associated cryptococcal meningitis] conducted to date… gives us a high level of confidence in these results,” he said of the study, which was presented at the virtual annual meeting of the International AIDS Society.

“We believe that this should become the WHO-recommended first-line regimen,” he emphasized.

In commenting on the study, Meg Doherty, MD, PhD, director of global HIV, hepatitis, and STI programs at WHO, agreed that a shorter regimen could be vital, particularly in settings with limited resources.

“The results from the AMBITION trial are important for low- and middle-income countries, where the cost and complexity of implementing the current standard seven-day course of L-ambisome or cryptococcal meningitis treatment can put this out of reach for many,” she told this news organization.

“Simplification that maintains the highest quality of care is an important component of the public health approach for HIV treatment and care,” she added.

Dr. Doherty could not comment on any possible changes to WHO recommendations, which are formulated by an independent guideline development group, but a spokesperson said that “WHO is preparing an updated review of the evidence for treating cryptococcal disease as a first step towards updating guidance.”

Conventional treatment toxicities

Cryptococcal meningitis is a leading cause of death in HIV, and the conventional treatment of amphotericin B deoxycholate, though less expensive than L-AmB, is more toxic, causing anemia, renal impairment, and electrolyte abnormalities, Dr. Lawrence explained

Having previously shown a single 10 mg/kg dose of L-AmB to be as effective as the longer regimen of 14 daily doses in terms of clearing cryptococcus from the cerebrospinal fluid, Dr. Lawrence and his colleagues conducted the phase 3 AMBITION-Cm trial to evaluate the effect on mortality, enrolling 844 patients in Botswana, Malawi, South Africa, Uganda, and Zimbabwe who were HIV-positive and had a first episode of cryptococcal meningitis.

Participants in the study were randomized to treatment either with single, high-dose L-AmB (10 mg/kg), combined with 14 days of flucytosine 100 mg/kg/day and fluconazole 1,200 mg/day or to a control group receiving 7 daily doses of AmB deoxycholate (1 mg/kg) plus 7 days of flucytosine 100 mg/kg/day, followed by 7 days of fluconazole 1,200 mg/day.

All patients were also provided with consolidation therapy of fluconazole 800 mg/day for eight weeks. Of the patients, 60.2% were male, their median age was 37, and their median CD4 count was 27 cells/mm³.

For the primary endpoint in the intention-to-treat analysis of 814 patients, the 10-week mortality rate in the single-dose L-AmB group was 24.82% (101 of 407) and 28.75% (117 of 407) in the control arm, for a difference (-3.93%) that was well within the pre-specified non-inferiority margin of 10%.

As expected, the safety measures were significantly improved with the single-dose of L-AmB: Rates of grade 3 or 4 adverse events within the initial 21 days of treatment in the single-dose L-AmB group were 50% versus 62.3% in the control group, and severe anemia occurred in just 13% of single-dose L-AmB participants, compared with 41% in the AmB deoxycholate control arm (both P < .001), Dr. Lawrence reported.

Furthermore, the average decline in hemoglobin over the first week was 0.3 g/dL in the single-dose L-AmB arm and 1.9 g/dL in the control arm, resulting in the need for more blood transfusions in the control arm (P < .001).

The impact on kidney function was also worse in the higher dose arm, with an average increase in creatinine over the first week of 20.2% in the L-AmB group versus 49.7% in the control group, while hypokalemia and thrombophlebitis were also more common with the higher dose group, Dr. Lawrence noted.

In the adjusted analysis, the single-dose L-AmB measures were in fact superior after adjusting for factors including research site, age, sex, baseline Glasgow Coma Scale, CD4 count, CSF cryptococcal colony-forming units/mL, antiretroviral therapy status, hemoglobin, and CSF opening pressure.

Mortality rate still high – but significantly reduced

The mortality rate of about 25% in the study after the treatment is still significantly higher than typically seen in high-income countries such as the United States, where HIV-associated cryptococcal meningitis is less common and associated with a mortality of roughly 10-15%, Dr. Lawrence noted.

The rate is nevertheless among the lowest mortality rates ever reported within a clinical trial conducted in resource-limited settings, he explained.

“These results are a step in the right direction and a significant improvement on the rates of 40% to 45% reported with two-week L-AmB-based regimens in African settings,” Dr. Lawrence underscored.

Higher cost — but potentially more cost-effective

With a higher cost than AmB deoxycholate, L-AmB’s utilization in resource-limited settings has been a challenge: A single vial of L-AmB ranges from $80 to $200, according to some reports, and while 14-day dosing requires as many as 42 vials of L-AmB, even a 7-day regimen still requires 21 vials.

In comparison, the single-dose L-AmB regimen only requires an average of 10 to 11 vials per patient, but the regimen’s higher safety could translate to far greater cost savings, Dr. Lawrence explained.

“While the AmBisome regimen is technically more expensive in terms of drugs, we expect it to be cost-effective or possibly cost-saving when taking into account that there is less toxicity, fewer blood tests, less transfusions, etc., and possibly shorter duration of hospital admission,” he said.

Cost, supply controversy: ‘Black fungus’-related demand

The drug’s cost — as well as supply issues — have meanwhile become even more of a problem as L-AmB has unexpectedly also become urgently needed in the treatment of mucormycosis in India and Nepal, where the otherwise rare fungal disease, commonly known as “black fungus,” has been increasingly affecting COVID-19 patients and survivors.

Gilead had previously announced in 2018 its intention to make L-AmB more widely available at a price of $16.25 per vial, but “implementation of this has been slow,” Dr. Lawrence said.

As a result, Gilead is facing heightened pressure to implement the lower prices – and also improve substantial supply issues, with Médecins Sans Frontières (Doctors Without Borders) and dozens of other global organizations issuing an open letter to Gilead and partner Viatris in June calling for immediate action to implement the lower price and improve supply of L-AmB.

In a company statement, Gilead responded, detailing its “commit[ment] to the non-profit pricing for the treatment of cryptococcal meningitis” and to efforts to improve the public health crisis in India.

For their part, Dr. Lawrence and his colleagues are working on producing more research on the issue.

“We hope that the conclusive results of the AMBITION trial will give a much needed push to implement this program,” he said.

“We are also currently completing the cost-effectiveness analysis of the study, which we hope will provide additional evidence to support widespread implementation of this regimen and highlight further the urgent need to broaden access to AmBisome and flucytosine,” he said.

The trial was supported by a grant through the European Developing Countries Clinical Trials Partnership (EDCTP), the Swedish International Development Cooperation Agency (SIDA) (TRIA2015-1092), and the Wellcome Trust / Medical Research Council (UK)/UKAID Joint Global Health Trials (MR/P006922/1. The AmBisome was donated by Gilead Sciences. Dr. Lawrence had no disclosures to report.

The long-acting drug lenacapavir, a first-in-class capsid inhibitor, shows sustained viral suppression in a small cohort of heavily treatment-experienced patients with multidrug-resistant HIV at 26 weeks when combined with an optimized antiretroviral therapy. With regulatory approval, lenacapavir could become the only HIV-1 treatment option given every 6 months.
 

“These data support the use of lenacapavir in patients with multidrug-resistant viruses, and according to its long half-life of two subcutaneous injections per year, [it] could help reduce pill burden,” first author Jean-Michel Molina, MD, PhD, professor of infectious diseases and head of the infectious diseases department at the Saint-Louis and Lariboisière Hospitals, Paris, said in an interview.

Presenting the updated findings from the phase 2/3 CAPELLA trial at the virtual annual meeting of the International AIDS Society conference, Dr. Molina underscored the need for longer-term treatments.

“These patients with multidrug resistances are usually those who have not been fully adherent to their regimen,” he said. “Being able to provide the drug, given every 6 months subcutaneously, provides an ideal treatment for overcoming resistance and lack of adherence.”

The study showed that, after 26 weeks, 81% of heavily treatment-experienced people with HIV in a randomized cohort who were treated with a subcutaneous injection of lenacapavir (927 mg) combined with an optimized background antiretroviral regimen achieved sustained virologic suppression, with an undetectable viral load (<50 copies/mL).

In addition, the lenacapavir-treated patients had a clinically meaningful mean increase in CD4 counts of 81 cells/mcL over the 26 weeks.

The drug was well tolerated, with no drug-related serious adverse events or adverse events leading to discontinuation. The most common adverse events were injection-site reactions, which occurred in 56% of participants, with most being mild or moderate.

Importantly, four participants developed emergent resistances to lenacapavir. One was suppressed with a change in the background regimen and two others were suppressed without a change in regimen.

“We know that these mutations affect viral fitness,” Dr. Molina said in an interview. “We need more studies to assess the real impact of these mutations.”

Dr. Molina noted that a phase 2 study is already underway to evaluate how a pairing of lenacapavir with fellow investigational long-acting drug islatravir (Merck) could offset the risk of developing resistances.

Asked by an audience member whether a two-drug regimen with something like islatravir is likely to successfully prevent resistances, Dr. Molina responded that “it’s too early to know what’s going to happen with [combinations], but these first results are really encouraging when you see the very high rate of being fully suppressed after 26 weeks. The efficacy that we’ve seen after [a previous 2-week analysis] is long lasting.”
 

Lenacapavir targets multiple viral stages

Unlike other antiviral drugs that target just a single stage of viral replication, lenacapavir takes aim at multiple steps in the viral life cycle, including capsid-mediated uptake of HIV-1 proviral DNA, virus assembly and release, and capsid core formation, Dr. Molina explained.

The CAPELLA trial included participants at research centers in North America, Europe, and Asia, with a median age of 52 years; 25% were female, 38% were Black, and their mean HIV-1 RNA (viral load) was 4.17 log copies/mL.

Overall, 72 patients were divided into two cohorts of 36 patients each, including a randomized and nonrandomized cohort. Dr. Molina primarily reported results from the randomized group.

In that group, patients received either a lead-in of oral lenacapavir (600 mg on day 1 and 2 and 300 mg on day 8) or placebo, in combination with patients’ current failing drug regimens in both groups.

At day 15, all participants were switched to the investigator-selected, optimized background treatment regimen, tailored according to patients’ drug-resistance profiles, and those in the lenacapavir group received the subcutaneous injection of lenacapavir; those in the placebo group were switched to the oral lead-in, followed by subcutaneous lenacapavir every 6 months.

Combined data that included six patients from the nonrandomized cohort showed that 79% of patients had a viral load of less than 50 copies/mL at week 26. The 81% viral suppression rate represented the randomized group (29 of 36).

International AIDS Society cochair Hendrik Streeck, MD, director of the Institute of Virology and Institute for HIV Research at the University Bonn (Germany), said a twice-a-year drug could possibly have profound benefits with a reduction in daily pill burden.

“What makes this an interesting drug is that it is long acting, so one can imagine it has the potential to treat individuals such as those who are not very adherent to the antiretroviral therapy, or who can’t easily access treatment, for example in resource-limited settings,” he said in an interview. “The option to treat patients for the next months in advance could be a very important next step.”
 

Further data from CALIBRATE

Additional data on lenacapavir from the phase 2 CALIBRATE study, presented in a separate session, further showed the drug, given orally or subcutaneously in combination with oral daily emtricitabine/tenofovir alafenamide, resulted in high rates of viral suppression among 94% of 157 treatment-naive patients after 28 weeks.

Commenting on the research, session moderator Alexandra Calmy, MD, PhD, of the HIV/AIDS unit and LIPO & Metabolism group, infectious diseases division, Geneva University Hospitals, noted the study offered “interesting data indeed” – with some caveats: “Why position a new drug class in naive patients [when] we already have good options, available for a large range of various populations?”

Dr. Calmy noted that, in general, lenacapavir “would certainly be an added value with an adapted 6-monthly companion drug.”

But she raised another key issue: “When will we have data on pregnancy that would allow lenacapavir to really be a game changer worldwide?”

The study was funded by Gilead Sciences. Dr. Molina reported receiving research funding from Gilead and being on advisory boards for Gilead, Merck, ViiV, and Janssen. Dr. Calmy and Dr. Streeck reported no relevant financial relationships.

The long-acting drug lenacapavir, a first-in-class capsid inhibitor, shows sustained viral suppression in a small cohort of heavily treatment-experienced patients with multidrug-resistant HIV at 26 weeks when combined with an optimized antiretroviral therapy. With regulatory approval, lenacapavir could become the only HIV-1 treatment option given every 6 months.
 

“These data support the use of lenacapavir in patients with multidrug-resistant viruses, and according to its long half-life of two subcutaneous injections per year, [it] could help reduce pill burden,” first author Jean-Michel Molina, MD, PhD, professor of infectious diseases and head of the infectious diseases department at the Saint-Louis and Lariboisière Hospitals, Paris, said in an interview.

Presenting the updated findings from the phase 2/3 CAPELLA trial at the virtual annual meeting of the International AIDS Society conference, Dr. Molina underscored the need for longer-term treatments.

“These patients with multidrug resistances are usually those who have not been fully adherent to their regimen,” he said. “Being able to provide the drug, given every 6 months subcutaneously, provides an ideal treatment for overcoming resistance and lack of adherence.”

The study showed that, after 26 weeks, 81% of heavily treatment-experienced people with HIV in a randomized cohort who were treated with a subcutaneous injection of lenacapavir (927 mg) combined with an optimized background antiretroviral regimen achieved sustained virologic suppression, with an undetectable viral load (<50 copies/mL).

In addition, the lenacapavir-treated patients had a clinically meaningful mean increase in CD4 counts of 81 cells/mcL over the 26 weeks.

The drug was well tolerated, with no drug-related serious adverse events or adverse events leading to discontinuation. The most common adverse events were injection-site reactions, which occurred in 56% of participants, with most being mild or moderate.

Importantly, four participants developed emergent resistances to lenacapavir. One was suppressed with a change in the background regimen and two others were suppressed without a change in regimen.

“We know that these mutations affect viral fitness,” Dr. Molina said in an interview. “We need more studies to assess the real impact of these mutations.”

Dr. Molina noted that a phase 2 study is already underway to evaluate how a pairing of lenacapavir with fellow investigational long-acting drug islatravir (Merck) could offset the risk of developing resistances.

Asked by an audience member whether a two-drug regimen with something like islatravir is likely to successfully prevent resistances, Dr. Molina responded that “it’s too early to know what’s going to happen with [combinations], but these first results are really encouraging when you see the very high rate of being fully suppressed after 26 weeks. The efficacy that we’ve seen after [a previous 2-week analysis] is long lasting.”
 

Lenacapavir targets multiple viral stages

Unlike other antiviral drugs that target just a single stage of viral replication, lenacapavir takes aim at multiple steps in the viral life cycle, including capsid-mediated uptake of HIV-1 proviral DNA, virus assembly and release, and capsid core formation, Dr. Molina explained.

The CAPELLA trial included participants at research centers in North America, Europe, and Asia, with a median age of 52 years; 25% were female, 38% were Black, and their mean HIV-1 RNA (viral load) was 4.17 log copies/mL.

Overall, 72 patients were divided into two cohorts of 36 patients each, including a randomized and nonrandomized cohort. Dr. Molina primarily reported results from the randomized group.

In that group, patients received either a lead-in of oral lenacapavir (600 mg on day 1 and 2 and 300 mg on day 8) or placebo, in combination with patients’ current failing drug regimens in both groups.

At day 15, all participants were switched to the investigator-selected, optimized background treatment regimen, tailored according to patients’ drug-resistance profiles, and those in the lenacapavir group received the subcutaneous injection of lenacapavir; those in the placebo group were switched to the oral lead-in, followed by subcutaneous lenacapavir every 6 months.

Combined data that included six patients from the nonrandomized cohort showed that 79% of patients had a viral load of less than 50 copies/mL at week 26. The 81% viral suppression rate represented the randomized group (29 of 36).

International AIDS Society cochair Hendrik Streeck, MD, director of the Institute of Virology and Institute for HIV Research at the University Bonn (Germany), said a twice-a-year drug could possibly have profound benefits with a reduction in daily pill burden.

“What makes this an interesting drug is that it is long acting, so one can imagine it has the potential to treat individuals such as those who are not very adherent to the antiretroviral therapy, or who can’t easily access treatment, for example in resource-limited settings,” he said in an interview. “The option to treat patients for the next months in advance could be a very important next step.”
 

Further data from CALIBRATE

Additional data on lenacapavir from the phase 2 CALIBRATE study, presented in a separate session, further showed the drug, given orally or subcutaneously in combination with oral daily emtricitabine/tenofovir alafenamide, resulted in high rates of viral suppression among 94% of 157 treatment-naive patients after 28 weeks.

Commenting on the research, session moderator Alexandra Calmy, MD, PhD, of the HIV/AIDS unit and LIPO & Metabolism group, infectious diseases division, Geneva University Hospitals, noted the study offered “interesting data indeed” – with some caveats: “Why position a new drug class in naive patients [when] we already have good options, available for a large range of various populations?”

Dr. Calmy noted that, in general, lenacapavir “would certainly be an added value with an adapted 6-monthly companion drug.”

But she raised another key issue: “When will we have data on pregnancy that would allow lenacapavir to really be a game changer worldwide?”

The study was funded by Gilead Sciences. Dr. Molina reported receiving research funding from Gilead and being on advisory boards for Gilead, Merck, ViiV, and Janssen. Dr. Calmy and Dr. Streeck reported no relevant financial relationships.

The long-acting drug lenacapavir, a first-in-class capsid inhibitor, shows sustained viral suppression in a small cohort of heavily treatment-experienced patients with multidrug-resistant HIV at 26 weeks when combined with an optimized antiretroviral therapy. With regulatory approval, lenacapavir could become the only HIV-1 treatment option given every 6 months.
 

“These data support the use of lenacapavir in patients with multidrug-resistant viruses, and according to its long half-life of two subcutaneous injections per year, [it] could help reduce pill burden,” first author Jean-Michel Molina, MD, PhD, professor of infectious diseases and head of the infectious diseases department at the Saint-Louis and Lariboisière Hospitals, Paris, said in an interview.

Presenting the updated findings from the phase 2/3 CAPELLA trial at the virtual annual meeting of the International AIDS Society conference, Dr. Molina underscored the need for longer-term treatments.

“These patients with multidrug resistances are usually those who have not been fully adherent to their regimen,” he said. “Being able to provide the drug, given every 6 months subcutaneously, provides an ideal treatment for overcoming resistance and lack of adherence.”

The study showed that, after 26 weeks, 81% of heavily treatment-experienced people with HIV in a randomized cohort who were treated with a subcutaneous injection of lenacapavir (927 mg) combined with an optimized background antiretroviral regimen achieved sustained virologic suppression, with an undetectable viral load (<50 copies/mL).

In addition, the lenacapavir-treated patients had a clinically meaningful mean increase in CD4 counts of 81 cells/mcL over the 26 weeks.

The drug was well tolerated, with no drug-related serious adverse events or adverse events leading to discontinuation. The most common adverse events were injection-site reactions, which occurred in 56% of participants, with most being mild or moderate.

Importantly, four participants developed emergent resistances to lenacapavir. One was suppressed with a change in the background regimen and two others were suppressed without a change in regimen.

“We know that these mutations affect viral fitness,” Dr. Molina said in an interview. “We need more studies to assess the real impact of these mutations.”

Dr. Molina noted that a phase 2 study is already underway to evaluate how a pairing of lenacapavir with fellow investigational long-acting drug islatravir (Merck) could offset the risk of developing resistances.

Asked by an audience member whether a two-drug regimen with something like islatravir is likely to successfully prevent resistances, Dr. Molina responded that “it’s too early to know what’s going to happen with [combinations], but these first results are really encouraging when you see the very high rate of being fully suppressed after 26 weeks. The efficacy that we’ve seen after [a previous 2-week analysis] is long lasting.”
 

Lenacapavir targets multiple viral stages

Unlike other antiviral drugs that target just a single stage of viral replication, lenacapavir takes aim at multiple steps in the viral life cycle, including capsid-mediated uptake of HIV-1 proviral DNA, virus assembly and release, and capsid core formation, Dr. Molina explained.

The CAPELLA trial included participants at research centers in North America, Europe, and Asia, with a median age of 52 years; 25% were female, 38% were Black, and their mean HIV-1 RNA (viral load) was 4.17 log copies/mL.

Overall, 72 patients were divided into two cohorts of 36 patients each, including a randomized and nonrandomized cohort. Dr. Molina primarily reported results from the randomized group.

In that group, patients received either a lead-in of oral lenacapavir (600 mg on day 1 and 2 and 300 mg on day 8) or placebo, in combination with patients’ current failing drug regimens in both groups.

At day 15, all participants were switched to the investigator-selected, optimized background treatment regimen, tailored according to patients’ drug-resistance profiles, and those in the lenacapavir group received the subcutaneous injection of lenacapavir; those in the placebo group were switched to the oral lead-in, followed by subcutaneous lenacapavir every 6 months.

Combined data that included six patients from the nonrandomized cohort showed that 79% of patients had a viral load of less than 50 copies/mL at week 26. The 81% viral suppression rate represented the randomized group (29 of 36).

International AIDS Society cochair Hendrik Streeck, MD, director of the Institute of Virology and Institute for HIV Research at the University Bonn (Germany), said a twice-a-year drug could possibly have profound benefits with a reduction in daily pill burden.

“What makes this an interesting drug is that it is long acting, so one can imagine it has the potential to treat individuals such as those who are not very adherent to the antiretroviral therapy, or who can’t easily access treatment, for example in resource-limited settings,” he said in an interview. “The option to treat patients for the next months in advance could be a very important next step.”
 

Further data from CALIBRATE

Additional data on lenacapavir from the phase 2 CALIBRATE study, presented in a separate session, further showed the drug, given orally or subcutaneously in combination with oral daily emtricitabine/tenofovir alafenamide, resulted in high rates of viral suppression among 94% of 157 treatment-naive patients after 28 weeks.

Commenting on the research, session moderator Alexandra Calmy, MD, PhD, of the HIV/AIDS unit and LIPO & Metabolism group, infectious diseases division, Geneva University Hospitals, noted the study offered “interesting data indeed” – with some caveats: “Why position a new drug class in naive patients [when] we already have good options, available for a large range of various populations?”

Dr. Calmy noted that, in general, lenacapavir “would certainly be an added value with an adapted 6-monthly companion drug.”

But she raised another key issue: “When will we have data on pregnancy that would allow lenacapavir to really be a game changer worldwide?”

The study was funded by Gilead Sciences. Dr. Molina reported receiving research funding from Gilead and being on advisory boards for Gilead, Merck, ViiV, and Janssen. Dr. Calmy and Dr. Streeck reported no relevant financial relationships.

Lower doses of linezolid in the BPaL drug regimen (bedaquiline, pretomanid, and linezolid) significantly reduce the adverse events associated with the treatment for patients with highly drug-resistant tuberculosis (TB) without compromising its high efficacy, new research shows.

“The ZeNix trial shows that reduced doses and/or shorter durations of linezolid appear to have high efficacy and improved safety,” said first author Francesca Conradie, MB, BCh, of the clinical HIV research unit, faculty of health sciences, University of Witwatersrand, Johannesburg, South Africa, in presenting the findings at the virtual meeting of the International AIDS Society conference.

As recently reported in the pivotal Nix-TB trial, the BPaL regimen yielded a 90% treatment success rate among people with highly drug-resistant forms of TB.

However, a 6-month regimen that included linezolid 1,200 mg resulted in toxic effects: 81% of patients in the study experienced peripheral neuropathy, and myelosuppression occurred in 48%. These effects often led to dose reductions or treatment interruption.

Adjustments in the dose of linezolid in the new ZeNix trial substantially reduced peripheral neuropathy to 13% and myelosuppression to 7%, with no significant reduction in the treatment response.

Importantly, the results were similar among patients with and those without HIV. This is of note because TB is the leading cause of death among patients with HIV.

“In the ZeNix trial, only 20% of patients were HIV infected, but in the [previous] Nix-TB trial, 30% were infected, so we have experience now in about 70 patients who were infected, and the outcomes were no different,” Dr. Conradie said in an interview.

Experts say the findings represent an important turn in the steep challenge of tackling highly resistant TB.

“In our opinion, these are exciting results that could change treatment guidelines for highly drug-resistant tuberculosis, with real benefits for the patients,” said Hendrik Streeck, MD, International AIDS Society cochair and director of the Institute of Virology and the Institute for HIV Research at the University Bonn (Germany), in a press conference.

Payam Nahid, MD, MPH, director of the Center for Tuberculosis at theUniversity of California, San Francisco, agreed.

“The results of this trial will impact global practices in treating drug-resistant TB as well as the design and conduct of future TB clinical trials,” Dr. Nahid said in an interview.
 

ZeNix trial

The phase 3 ZeNix trial included 181 patients with highly resistant TB in South Africa, Russia, Georgia, and Moldova. The mean age of the patients was 37 years; 67.4% were men, 63.5% were White, and 19.9% were HIV positive.

All patients were treated for 6 months with bedaquiline 200 mg daily for 8 weeks followed by 100 mg daily for 18 weeks, as well as pretomanid 200 mg daily.

The patients were randomly assigned to receive one of four daily doses of linezolid: 1,200 mg for 6 months (the original dose from the Nix-TB trial; n = 45) or 2 months (n = 46), or 600 mg for 6 or 2 months (45 patients each).

Percentages of patients with HIV were equal among the four groups, at about 20% each.

The primary outcomes – resolution of clinical disease and a negative culture status after 6 months – were observed across all linezolid dose groups. The success rate was 93% for those receiving 1,200 mg for 6 months, 89% for those receiving 1,200 mg for 2 months, 91% for those receiving 600 mg for 6 months, and 84% for those receiving 600 mg for 2 months.

With regard to the key adverse events of peripheral neuropathy and myelosuppression, manifested as anemia, the highest rates were among those who received linezolid 1,200 mg for 6 month, at 38% and 22%, respectively, compared with 24% and 17.4% among those who received 1,200 mg for 2 months, 24% and 2% among those who received 600 mg for 6 months, and 13% and 6.7% among those who received 600 mg for 2 months.

Four cases of optic neuropathy occurred among those who received 1,200 mg for 6 months; all cases resolved.

Patients who received 1,200 mg for 6 months required the highest number of linezolid dose modifications; 51% required changes that included reduction, interruption, or discontinuation, compared with 28% among those who received 1,200 mg for 2 months and 13% each in the other two groups.

On the basis of these results, “my personal opinion is that 600 mg at 6 months [of linezolid] is most likely the best strategy for the treatment of this highly resistant treatment population group,” Dr. Conradie told this news organization.
 

Findings represent ‘great news’ in addressing concerns

Dr. Nahid further commented that the results are highly encouraging in light of the ongoing concerns about the effects of linezolid in the BPaL regimen.

“This is great news,” he said. “The ZeNix trial addresses a key concern that providers and patients have had regarding the safety and tolerability of taking 6 months of linezolid at 1200 mg/d as part of the BPaL regimen.

“The findings that doses lower and durations shorter than the current 1,200 mg linezolid daily for 6 months will significantly expand the usability of the BPaL regimen worldwide.”

The inclusion of patients with HIV was essential in the trial, he noted.

“There are drug-drug interactions to be considered, among other factors that impact drug exposure,” Dr. Nahid said.

“Inclusion of patients living with HIV in this study means that any modifications to the BPaL regimen considered by the WHO [World Health Organization] and other policy decision makers will include data from this key population,” he said. “Of course, more data are needed on safety, tolerability, and efficacy on BPaL in general, and there are international cohorts and demonstration projects underway that will enhance our understanding of the regimen in HIV and in other special populations.”

The authors, Dr. Streeck, and Dr. Nahid have disclosed no relevant financial relationships.

This article was updated 7/21/21.

Lower doses of linezolid in the BPaL drug regimen (bedaquiline, pretomanid, and linezolid) significantly reduce the adverse events associated with the treatment for patients with highly drug-resistant tuberculosis (TB) without compromising its high efficacy, new research shows.

“The ZeNix trial shows that reduced doses and/or shorter durations of linezolid appear to have high efficacy and improved safety,” said first author Francesca Conradie, MB, BCh, of the clinical HIV research unit, faculty of health sciences, University of Witwatersrand, Johannesburg, South Africa, in presenting the findings at the virtual meeting of the International AIDS Society conference.

As recently reported in the pivotal Nix-TB trial, the BPaL regimen yielded a 90% treatment success rate among people with highly drug-resistant forms of TB.

However, a 6-month regimen that included linezolid 1,200 mg resulted in toxic effects: 81% of patients in the study experienced peripheral neuropathy, and myelosuppression occurred in 48%. These effects often led to dose reductions or treatment interruption.

Adjustments in the dose of linezolid in the new ZeNix trial substantially reduced peripheral neuropathy to 13% and myelosuppression to 7%, with no significant reduction in the treatment response.

Importantly, the results were similar among patients with and those without HIV. This is of note because TB is the leading cause of death among patients with HIV.

“In the ZeNix trial, only 20% of patients were HIV infected, but in the [previous] Nix-TB trial, 30% were infected, so we have experience now in about 70 patients who were infected, and the outcomes were no different,” Dr. Conradie said in an interview.

Experts say the findings represent an important turn in the steep challenge of tackling highly resistant TB.

“In our opinion, these are exciting results that could change treatment guidelines for highly drug-resistant tuberculosis, with real benefits for the patients,” said Hendrik Streeck, MD, International AIDS Society cochair and director of the Institute of Virology and the Institute for HIV Research at the University Bonn (Germany), in a press conference.

Payam Nahid, MD, MPH, director of the Center for Tuberculosis at theUniversity of California, San Francisco, agreed.

“The results of this trial will impact global practices in treating drug-resistant TB as well as the design and conduct of future TB clinical trials,” Dr. Nahid said in an interview.
 

ZeNix trial

The phase 3 ZeNix trial included 181 patients with highly resistant TB in South Africa, Russia, Georgia, and Moldova. The mean age of the patients was 37 years; 67.4% were men, 63.5% were White, and 19.9% were HIV positive.

All patients were treated for 6 months with bedaquiline 200 mg daily for 8 weeks followed by 100 mg daily for 18 weeks, as well as pretomanid 200 mg daily.

The patients were randomly assigned to receive one of four daily doses of linezolid: 1,200 mg for 6 months (the original dose from the Nix-TB trial; n = 45) or 2 months (n = 46), or 600 mg for 6 or 2 months (45 patients each).

Percentages of patients with HIV were equal among the four groups, at about 20% each.

The primary outcomes – resolution of clinical disease and a negative culture status after 6 months – were observed across all linezolid dose groups. The success rate was 93% for those receiving 1,200 mg for 6 months, 89% for those receiving 1,200 mg for 2 months, 91% for those receiving 600 mg for 6 months, and 84% for those receiving 600 mg for 2 months.

With regard to the key adverse events of peripheral neuropathy and myelosuppression, manifested as anemia, the highest rates were among those who received linezolid 1,200 mg for 6 month, at 38% and 22%, respectively, compared with 24% and 17.4% among those who received 1,200 mg for 2 months, 24% and 2% among those who received 600 mg for 6 months, and 13% and 6.7% among those who received 600 mg for 2 months.

Four cases of optic neuropathy occurred among those who received 1,200 mg for 6 months; all cases resolved.

Patients who received 1,200 mg for 6 months required the highest number of linezolid dose modifications; 51% required changes that included reduction, interruption, or discontinuation, compared with 28% among those who received 1,200 mg for 2 months and 13% each in the other two groups.

On the basis of these results, “my personal opinion is that 600 mg at 6 months [of linezolid] is most likely the best strategy for the treatment of this highly resistant treatment population group,” Dr. Conradie told this news organization.
 

Findings represent ‘great news’ in addressing concerns

Dr. Nahid further commented that the results are highly encouraging in light of the ongoing concerns about the effects of linezolid in the BPaL regimen.

“This is great news,” he said. “The ZeNix trial addresses a key concern that providers and patients have had regarding the safety and tolerability of taking 6 months of linezolid at 1200 mg/d as part of the BPaL regimen.

“The findings that doses lower and durations shorter than the current 1,200 mg linezolid daily for 6 months will significantly expand the usability of the BPaL regimen worldwide.”

The inclusion of patients with HIV was essential in the trial, he noted.

“There are drug-drug interactions to be considered, among other factors that impact drug exposure,” Dr. Nahid said.

“Inclusion of patients living with HIV in this study means that any modifications to the BPaL regimen considered by the WHO [World Health Organization] and other policy decision makers will include data from this key population,” he said. “Of course, more data are needed on safety, tolerability, and efficacy on BPaL in general, and there are international cohorts and demonstration projects underway that will enhance our understanding of the regimen in HIV and in other special populations.”

The authors, Dr. Streeck, and Dr. Nahid have disclosed no relevant financial relationships.

This article was updated 7/21/21.

Lower doses of linezolid in the BPaL drug regimen (bedaquiline, pretomanid, and linezolid) significantly reduce the adverse events associated with the treatment for patients with highly drug-resistant tuberculosis (TB) without compromising its high efficacy, new research shows.

“The ZeNix trial shows that reduced doses and/or shorter durations of linezolid appear to have high efficacy and improved safety,” said first author Francesca Conradie, MB, BCh, of the clinical HIV research unit, faculty of health sciences, University of Witwatersrand, Johannesburg, South Africa, in presenting the findings at the virtual meeting of the International AIDS Society conference.

As recently reported in the pivotal Nix-TB trial, the BPaL regimen yielded a 90% treatment success rate among people with highly drug-resistant forms of TB.

However, a 6-month regimen that included linezolid 1,200 mg resulted in toxic effects: 81% of patients in the study experienced peripheral neuropathy, and myelosuppression occurred in 48%. These effects often led to dose reductions or treatment interruption.

Adjustments in the dose of linezolid in the new ZeNix trial substantially reduced peripheral neuropathy to 13% and myelosuppression to 7%, with no significant reduction in the treatment response.

Importantly, the results were similar among patients with and those without HIV. This is of note because TB is the leading cause of death among patients with HIV.

“In the ZeNix trial, only 20% of patients were HIV infected, but in the [previous] Nix-TB trial, 30% were infected, so we have experience now in about 70 patients who were infected, and the outcomes were no different,” Dr. Conradie said in an interview.

Experts say the findings represent an important turn in the steep challenge of tackling highly resistant TB.

“In our opinion, these are exciting results that could change treatment guidelines for highly drug-resistant tuberculosis, with real benefits for the patients,” said Hendrik Streeck, MD, International AIDS Society cochair and director of the Institute of Virology and the Institute for HIV Research at the University Bonn (Germany), in a press conference.

Payam Nahid, MD, MPH, director of the Center for Tuberculosis at theUniversity of California, San Francisco, agreed.

“The results of this trial will impact global practices in treating drug-resistant TB as well as the design and conduct of future TB clinical trials,” Dr. Nahid said in an interview.
 

ZeNix trial

The phase 3 ZeNix trial included 181 patients with highly resistant TB in South Africa, Russia, Georgia, and Moldova. The mean age of the patients was 37 years; 67.4% were men, 63.5% were White, and 19.9% were HIV positive.

All patients were treated for 6 months with bedaquiline 200 mg daily for 8 weeks followed by 100 mg daily for 18 weeks, as well as pretomanid 200 mg daily.

The patients were randomly assigned to receive one of four daily doses of linezolid: 1,200 mg for 6 months (the original dose from the Nix-TB trial; n = 45) or 2 months (n = 46), or 600 mg for 6 or 2 months (45 patients each).

Percentages of patients with HIV were equal among the four groups, at about 20% each.

The primary outcomes – resolution of clinical disease and a negative culture status after 6 months – were observed across all linezolid dose groups. The success rate was 93% for those receiving 1,200 mg for 6 months, 89% for those receiving 1,200 mg for 2 months, 91% for those receiving 600 mg for 6 months, and 84% for those receiving 600 mg for 2 months.

With regard to the key adverse events of peripheral neuropathy and myelosuppression, manifested as anemia, the highest rates were among those who received linezolid 1,200 mg for 6 month, at 38% and 22%, respectively, compared with 24% and 17.4% among those who received 1,200 mg for 2 months, 24% and 2% among those who received 600 mg for 6 months, and 13% and 6.7% among those who received 600 mg for 2 months.

Four cases of optic neuropathy occurred among those who received 1,200 mg for 6 months; all cases resolved.

Patients who received 1,200 mg for 6 months required the highest number of linezolid dose modifications; 51% required changes that included reduction, interruption, or discontinuation, compared with 28% among those who received 1,200 mg for 2 months and 13% each in the other two groups.

On the basis of these results, “my personal opinion is that 600 mg at 6 months [of linezolid] is most likely the best strategy for the treatment of this highly resistant treatment population group,” Dr. Conradie told this news organization.
 

Findings represent ‘great news’ in addressing concerns

Dr. Nahid further commented that the results are highly encouraging in light of the ongoing concerns about the effects of linezolid in the BPaL regimen.

“This is great news,” he said. “The ZeNix trial addresses a key concern that providers and patients have had regarding the safety and tolerability of taking 6 months of linezolid at 1200 mg/d as part of the BPaL regimen.

“The findings that doses lower and durations shorter than the current 1,200 mg linezolid daily for 6 months will significantly expand the usability of the BPaL regimen worldwide.”

The inclusion of patients with HIV was essential in the trial, he noted.

“There are drug-drug interactions to be considered, among other factors that impact drug exposure,” Dr. Nahid said.

“Inclusion of patients living with HIV in this study means that any modifications to the BPaL regimen considered by the WHO [World Health Organization] and other policy decision makers will include data from this key population,” he said. “Of course, more data are needed on safety, tolerability, and efficacy on BPaL in general, and there are international cohorts and demonstration projects underway that will enhance our understanding of the regimen in HIV and in other special populations.”

The authors, Dr. Streeck, and Dr. Nahid have disclosed no relevant financial relationships.

This article was updated 7/21/21.

Most U.S. prescriptions for the thyroid hormone replacement drug levothyroxine are not appropriate for patients with mild subclinical hypothyroidism, a trend that has remained steady for a decade despite evidence showing no significant benefits for those patients, new research shows.

“These results suggest substantial overuse of levothyroxine during the entire duration of the study, suggesting opportunities to improve care,” wrote the authors of the study published in JAMA Internal Medicine.

“There have been previous reports of increased levothyroxine overuse in the U.S., but this is the first paper to describe the nature of the drivers of the overuse,” first author Juan P. Brito, MD, of the division of endocrinology, diabetes, metabolism and nutrition, department of internal medicine, Mayo Clinic, Rochester, Minn., said in an interview.

The findings underscore the need to improve awareness of the ongoing overuse, said the authors of an accompanying editorial.

“We hope [this study] resonates as a call to action for clinicians to stop treating patients with mild subclinical hypothyroidism,” they wrote.
 

Only 8% of those receiving levothyroxine had overt hypothyroidism

For the study, Dr. Brito and colleagues analyzed data of adults enrolled in Medicare Advantage who filled levothyroxine prescriptions between January 2008 and December 2018 and had thyrotropin levels measured within 3 months prior to the prescription. Patients with a history of thyroid surgery, thyroid cancer, central hypothyroidism, or who were pregnant, were excluded from the study.

In the 110,842 patients who started levothyroxine during the study period, there were no significant changes in median thyrotropin levels at the time of treatment initiation, with a median level in 2008 of 5.8 mIU/L and a level in 2018 of 5.3 mIU/L (P = .79).

In a subanalysis of 58,706 patients for whom thyrotropin as well as free thyroxine (FT4 or T4) levels were available – which allowed for the determination of the level of hypothyroidism – levothyroxine was initiated for overt hypothyroidism in only 8.4% of cases.

In as many as 61.0% of cases, patients had subclinical hypothyroidism, and in 30.5% of cases, patients had normal thyroid levels.

While the proportion of adults with overt hypothyroidism initiated on levothyroxine significantly increased over the 10 years (7.6% to 8.4%; P = .02), rates of those with subclinical hypothyroidism remained unchanged (59.3% to 65.7%; P = .36), as did the proportion with normal thyroid function (32.9% to 26.2%; P = .84).

A closer look at patients specifically with subclinical hypothyroidism showed there were also no changes in the proportion with mild subclinical hypothyroidism (thyrotropin level of 4.5 mIU/L to <10 mIU/L with normal FT4 or T4) between the beginning and end of the study period (48.2% vs. 57.9%; P = .73). Rates of moderate subclinical hypothyroidism (thyrotropin level 10-19.9 mIU/L) were also similar (8.5% to 6.4%; P = .16).
 

No significant benefit, but ample undesirable effects

The authors underscore that levothyroxine has been shown time and again to offer no significant benefit to patients with subclinical hypothyroidism of any type, emphasized in a 2018 meta-analysis of 21 randomized, controlled trials.

“Frequent initiation of levothyroxine in these patients is at odds with evidence demonstrating no significant association of levothyroxine replacement with measures of health-related quality of life, thyroid-related symptoms, depressive symptoms, fatigue, or cognitive function,” they explained.

In addition to showing no benefit for subclinical hypothyroidism, levothyroxine is associated with a host of unwanted side effects, noted editorialists William K. Silverstein, MD, of Sunnybrook Health Sciences Centre, department of medicine, University of Toronto, and Deborah Grady, MD, of the department of medicine, University of California, San Francisco.

Some studies have shown a link between long-term levothyroxine therapy and an increased risk of cardiovascular disease, cardiac dysrhythmias, osteoporosis, and fractures, they explained.

In addition, unnecessary treatment “increases pill burden and costs, necessitates routine physician visits and blood work, and requires modification of daily routines so that patients can take medications on an empty stomach,” the editorialists wrote.

Importantly, evidence shows that once levothyroxine treatment for subclinical hypothyroidism is started, most patients will continue the therapy for life, they added.

The fact that levothyroxine is among the most commonly prescribed drugs in the United States, with about 7% of the population estimated to have an active prescription when overt hypothyroidism affects only about 0.2%-2% of the population, underscores the extent of levothyroxine overuse, Dr. Silverstein said in an interview. 

“The really notable surprise was how pervasive inappropriate use of levothyroxine was,” he said. “The fact that only 8% of patients had a biochemical indication for treatment is striking.”
 

Potential solutions: ‘Shift the conversation’

In terms of potential solutions to the problem, Dr. Silverstein suggested laboratories change reference ranges so that only thyrotropin values greater than 10 mIU/L are reported as abnormal.

“Studies have shown that changing the thyrotropin reference range is associated with clinicians’ prescribing patterns,” he noted.

Dr. Brito agreed, noting that “there are many guidelines with different hypothyroidism thresholds, so we need to be more consistent about the message to clinicians.

“In addition, we have to come up with different approaches to symptoms that have nothing to do with levothyroxine,” Dr. Brito said.

“I try to explain to patients that it’s very unlikely that subclinical hypothyroidism would be driving significant symptoms like fatigue, weight gain, and hair loss,” Dr. Brito said. “So, one approach is to shift the conversation from how your thyroid is causing this to ‘how are we going to treat the symptoms?’ ”

The study was supported by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. Dr. Silverstein has reported no relevant financial relationships.

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

Most U.S. prescriptions for the thyroid hormone replacement drug levothyroxine are not appropriate for patients with mild subclinical hypothyroidism, a trend that has remained steady for a decade despite evidence showing no significant benefits for those patients, new research shows.

“These results suggest substantial overuse of levothyroxine during the entire duration of the study, suggesting opportunities to improve care,” wrote the authors of the study published in JAMA Internal Medicine.

“There have been previous reports of increased levothyroxine overuse in the U.S., but this is the first paper to describe the nature of the drivers of the overuse,” first author Juan P. Brito, MD, of the division of endocrinology, diabetes, metabolism and nutrition, department of internal medicine, Mayo Clinic, Rochester, Minn., said in an interview.

The findings underscore the need to improve awareness of the ongoing overuse, said the authors of an accompanying editorial.

“We hope [this study] resonates as a call to action for clinicians to stop treating patients with mild subclinical hypothyroidism,” they wrote.
 

Only 8% of those receiving levothyroxine had overt hypothyroidism

For the study, Dr. Brito and colleagues analyzed data of adults enrolled in Medicare Advantage who filled levothyroxine prescriptions between January 2008 and December 2018 and had thyrotropin levels measured within 3 months prior to the prescription. Patients with a history of thyroid surgery, thyroid cancer, central hypothyroidism, or who were pregnant, were excluded from the study.

In the 110,842 patients who started levothyroxine during the study period, there were no significant changes in median thyrotropin levels at the time of treatment initiation, with a median level in 2008 of 5.8 mIU/L and a level in 2018 of 5.3 mIU/L (P = .79).

In a subanalysis of 58,706 patients for whom thyrotropin as well as free thyroxine (FT4 or T4) levels were available – which allowed for the determination of the level of hypothyroidism – levothyroxine was initiated for overt hypothyroidism in only 8.4% of cases.

In as many as 61.0% of cases, patients had subclinical hypothyroidism, and in 30.5% of cases, patients had normal thyroid levels.

While the proportion of adults with overt hypothyroidism initiated on levothyroxine significantly increased over the 10 years (7.6% to 8.4%; P = .02), rates of those with subclinical hypothyroidism remained unchanged (59.3% to 65.7%; P = .36), as did the proportion with normal thyroid function (32.9% to 26.2%; P = .84).

A closer look at patients specifically with subclinical hypothyroidism showed there were also no changes in the proportion with mild subclinical hypothyroidism (thyrotropin level of 4.5 mIU/L to <10 mIU/L with normal FT4 or T4) between the beginning and end of the study period (48.2% vs. 57.9%; P = .73). Rates of moderate subclinical hypothyroidism (thyrotropin level 10-19.9 mIU/L) were also similar (8.5% to 6.4%; P = .16).
 

No significant benefit, but ample undesirable effects

The authors underscore that levothyroxine has been shown time and again to offer no significant benefit to patients with subclinical hypothyroidism of any type, emphasized in a 2018 meta-analysis of 21 randomized, controlled trials.

“Frequent initiation of levothyroxine in these patients is at odds with evidence demonstrating no significant association of levothyroxine replacement with measures of health-related quality of life, thyroid-related symptoms, depressive symptoms, fatigue, or cognitive function,” they explained.

In addition to showing no benefit for subclinical hypothyroidism, levothyroxine is associated with a host of unwanted side effects, noted editorialists William K. Silverstein, MD, of Sunnybrook Health Sciences Centre, department of medicine, University of Toronto, and Deborah Grady, MD, of the department of medicine, University of California, San Francisco.

Some studies have shown a link between long-term levothyroxine therapy and an increased risk of cardiovascular disease, cardiac dysrhythmias, osteoporosis, and fractures, they explained.

In addition, unnecessary treatment “increases pill burden and costs, necessitates routine physician visits and blood work, and requires modification of daily routines so that patients can take medications on an empty stomach,” the editorialists wrote.

Importantly, evidence shows that once levothyroxine treatment for subclinical hypothyroidism is started, most patients will continue the therapy for life, they added.

The fact that levothyroxine is among the most commonly prescribed drugs in the United States, with about 7% of the population estimated to have an active prescription when overt hypothyroidism affects only about 0.2%-2% of the population, underscores the extent of levothyroxine overuse, Dr. Silverstein said in an interview. 

“The really notable surprise was how pervasive inappropriate use of levothyroxine was,” he said. “The fact that only 8% of patients had a biochemical indication for treatment is striking.”
 

Potential solutions: ‘Shift the conversation’

In terms of potential solutions to the problem, Dr. Silverstein suggested laboratories change reference ranges so that only thyrotropin values greater than 10 mIU/L are reported as abnormal.

“Studies have shown that changing the thyrotropin reference range is associated with clinicians’ prescribing patterns,” he noted.

Dr. Brito agreed, noting that “there are many guidelines with different hypothyroidism thresholds, so we need to be more consistent about the message to clinicians.

“In addition, we have to come up with different approaches to symptoms that have nothing to do with levothyroxine,” Dr. Brito said.

“I try to explain to patients that it’s very unlikely that subclinical hypothyroidism would be driving significant symptoms like fatigue, weight gain, and hair loss,” Dr. Brito said. “So, one approach is to shift the conversation from how your thyroid is causing this to ‘how are we going to treat the symptoms?’ ”

The study was supported by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. Dr. Silverstein has reported no relevant financial relationships.

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

Most U.S. prescriptions for the thyroid hormone replacement drug levothyroxine are not appropriate for patients with mild subclinical hypothyroidism, a trend that has remained steady for a decade despite evidence showing no significant benefits for those patients, new research shows.

“These results suggest substantial overuse of levothyroxine during the entire duration of the study, suggesting opportunities to improve care,” wrote the authors of the study published in JAMA Internal Medicine.

“There have been previous reports of increased levothyroxine overuse in the U.S., but this is the first paper to describe the nature of the drivers of the overuse,” first author Juan P. Brito, MD, of the division of endocrinology, diabetes, metabolism and nutrition, department of internal medicine, Mayo Clinic, Rochester, Minn., said in an interview.

The findings underscore the need to improve awareness of the ongoing overuse, said the authors of an accompanying editorial.

“We hope [this study] resonates as a call to action for clinicians to stop treating patients with mild subclinical hypothyroidism,” they wrote.
 

Only 8% of those receiving levothyroxine had overt hypothyroidism

For the study, Dr. Brito and colleagues analyzed data of adults enrolled in Medicare Advantage who filled levothyroxine prescriptions between January 2008 and December 2018 and had thyrotropin levels measured within 3 months prior to the prescription. Patients with a history of thyroid surgery, thyroid cancer, central hypothyroidism, or who were pregnant, were excluded from the study.

In the 110,842 patients who started levothyroxine during the study period, there were no significant changes in median thyrotropin levels at the time of treatment initiation, with a median level in 2008 of 5.8 mIU/L and a level in 2018 of 5.3 mIU/L (P = .79).

In a subanalysis of 58,706 patients for whom thyrotropin as well as free thyroxine (FT4 or T4) levels were available – which allowed for the determination of the level of hypothyroidism – levothyroxine was initiated for overt hypothyroidism in only 8.4% of cases.

In as many as 61.0% of cases, patients had subclinical hypothyroidism, and in 30.5% of cases, patients had normal thyroid levels.

While the proportion of adults with overt hypothyroidism initiated on levothyroxine significantly increased over the 10 years (7.6% to 8.4%; P = .02), rates of those with subclinical hypothyroidism remained unchanged (59.3% to 65.7%; P = .36), as did the proportion with normal thyroid function (32.9% to 26.2%; P = .84).

A closer look at patients specifically with subclinical hypothyroidism showed there were also no changes in the proportion with mild subclinical hypothyroidism (thyrotropin level of 4.5 mIU/L to <10 mIU/L with normal FT4 or T4) between the beginning and end of the study period (48.2% vs. 57.9%; P = .73). Rates of moderate subclinical hypothyroidism (thyrotropin level 10-19.9 mIU/L) were also similar (8.5% to 6.4%; P = .16).
 

No significant benefit, but ample undesirable effects

The authors underscore that levothyroxine has been shown time and again to offer no significant benefit to patients with subclinical hypothyroidism of any type, emphasized in a 2018 meta-analysis of 21 randomized, controlled trials.

“Frequent initiation of levothyroxine in these patients is at odds with evidence demonstrating no significant association of levothyroxine replacement with measures of health-related quality of life, thyroid-related symptoms, depressive symptoms, fatigue, or cognitive function,” they explained.

In addition to showing no benefit for subclinical hypothyroidism, levothyroxine is associated with a host of unwanted side effects, noted editorialists William K. Silverstein, MD, of Sunnybrook Health Sciences Centre, department of medicine, University of Toronto, and Deborah Grady, MD, of the department of medicine, University of California, San Francisco.

Some studies have shown a link between long-term levothyroxine therapy and an increased risk of cardiovascular disease, cardiac dysrhythmias, osteoporosis, and fractures, they explained.

In addition, unnecessary treatment “increases pill burden and costs, necessitates routine physician visits and blood work, and requires modification of daily routines so that patients can take medications on an empty stomach,” the editorialists wrote.

Importantly, evidence shows that once levothyroxine treatment for subclinical hypothyroidism is started, most patients will continue the therapy for life, they added.

The fact that levothyroxine is among the most commonly prescribed drugs in the United States, with about 7% of the population estimated to have an active prescription when overt hypothyroidism affects only about 0.2%-2% of the population, underscores the extent of levothyroxine overuse, Dr. Silverstein said in an interview. 

“The really notable surprise was how pervasive inappropriate use of levothyroxine was,” he said. “The fact that only 8% of patients had a biochemical indication for treatment is striking.”
 

Potential solutions: ‘Shift the conversation’

In terms of potential solutions to the problem, Dr. Silverstein suggested laboratories change reference ranges so that only thyrotropin values greater than 10 mIU/L are reported as abnormal.

“Studies have shown that changing the thyrotropin reference range is associated with clinicians’ prescribing patterns,” he noted.

Dr. Brito agreed, noting that “there are many guidelines with different hypothyroidism thresholds, so we need to be more consistent about the message to clinicians.

“In addition, we have to come up with different approaches to symptoms that have nothing to do with levothyroxine,” Dr. Brito said.

“I try to explain to patients that it’s very unlikely that subclinical hypothyroidism would be driving significant symptoms like fatigue, weight gain, and hair loss,” Dr. Brito said. “So, one approach is to shift the conversation from how your thyroid is causing this to ‘how are we going to treat the symptoms?’ ”

The study was supported by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. Dr. Silverstein has reported no relevant financial relationships.

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

Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.

“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.

Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.

Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”

“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.

Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.

HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.

However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.

To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.

Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.

In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.

In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.

In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.

The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.

In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).

In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).

Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).

Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).

In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.

An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).

Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).

The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.

They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).

However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.

“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.

“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.

“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.

In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.

“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.

“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.

Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.

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

Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.

“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.

Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.

Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”

“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.

Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.

HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.

However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.

To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.

Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.

In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.

In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.

In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.

The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.

In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).

In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).

Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).

Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).

In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.

An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).

Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).

The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.

They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).

However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.

“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.

“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.

“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.

In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.

“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.

“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.

Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.

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

Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.

“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.

Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.

Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”

“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.

Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.

HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.

However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.

To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.

Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.

In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.

In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.

In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.

The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.

In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).

In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).

Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).

Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).

In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.

An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).

Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).

The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.

They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).

However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.

“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.

“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.

“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.

In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.

“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.

“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.

Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.

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

Being overweight or having obesity significantly increases the risk for liver disease and the likelihood of dying from it compared with being of normal weight, regardless of level of alcohol consumption, new research shows. 
"People in the overweight or obese range who drank were found to be at greater risk of liver diseases compared with participants within a healthy weight range who consumed alcohol at the same level," senior author Emmanuel Stamatakis, PhD, of the Charles Perkins Centre and the Faculty of Medicine and Health, Sydney, said in a press statement. 
"Even for people who drank within alcohol guidelines, participants classified as obese were at over 50% greater risk of liver disease," he said. 
"Obesity is an independent risk factor for steatosis, acute alcoholic hepatitis, and cirrhosis in alcoholic liver disease (ALD), which may increase the risk of mortality in ALD patients," the study's first author, Elif Inan-Eroglu, PhD, a postdoctoral research fellow at the Charles Perkins Centre, said in an interview. 
Further prospective studies are needed to better understand the underlying mechanisms behind the association between alcohol consumption and liver disease across different adiposity levels, the authors say. 
Meanwhile, the take-home message from the findings should be that "clinicians should consider the presence of overweight and obesity when they discuss defining safe alcohol levels for their patients, keeping in mind that there is no 'safe' level of alcohol," Dr. Inan-Eroglu said. 
"Alcohol drinking guidelines need to acknowledge that two-thirds of the adult population are overweight or obese and consider specific recommendations for this majority population group," he said.  

First and largest study of its kind 

Obesity, well-known to be an independent risk factor for nonalcoholic fatty liver disease (NAFLD), is also known to worsen outcomes in ALD. And likewise, alcohol consumption, the cause of ALD, can promote obesity and therefore increase the risk of NAFLD. 
Dr. Stamatakis and colleagues sought to evaluate the roles of the combined factors in terms of incidence and mortality in both ALD and NAFLD. 
For the study, published online May 31 in the European Journal of Clinical Nutrition, they evaluated data from 465,437 participants in the U.K. Biobank. The study is said to be the first and largest of its kind. 
In the cohort, a total of 1,090 liver disease deaths were recorded, including 230 deaths from ALD and 192 from NAFLD over an average follow-up of 10.5 years. 
After a multivariate adjustment, the overall risk of ALD, NAFLD, and liver disease incidence and mortality were significantly higher in participants who were overweight or had obesity, compared with those of normal weight, at all levels of alcohol consumption. 
For instance, among those with alcohol use exceeding guidelines, the risk of ALD was significantly increased in normal weight individuals versus never-drinkers (hazard ratio [HR], 5.38), and the risk was even higher among those who were also overweight or had obesity (HR, 8.58). 
In terms of the risk of death related to ALD, among those reporting alcohol consumption above guidelines, the risk was nearly double among those who were overweight or had obesity (HR, 10.29) versus those with normal weight (HR, 5.84), when each group was compared to those drinking within guidelines. 
Regarding NAFLD, consistent with evidence that low to moderate alcohol consumption is, in fact, linked to a reduced risk, those in the study who reported alcohol consumption within guidelines and normal weight did show a reduced risk of NAFLD compared with an index group of never-drinkers (HR, 0.85). 
However, being overweight or having obesity increased the risk of NAFLD in those participants (HR, 1.51). 
Furthermore, even those reporting alcohol consumption above guidelines who were of normal weight had a reduced risk of NAFLD compared with never drinkers of normal weight (HR, 0.89).   
Regarding the risk of liver disease among those reporting alcohol consumption above guidelines compared with never-drinkers, the risk was again lower among those of normal weight versus those who were overweight or had obesity (HR, 0.95 vs. 1.52), as were the risks of mortality (HR, 1.24 vs. 2.20). 
Overall, "we found evidence that being overweight/[having obesity] amplified the harmful effect of alcohol on the liver disease incidence and mortality," the authors conclude. 
The authors have reported no relevant financial relationships. 
A version of this article first appeared on Medscape.com

Being overweight or having obesity significantly increases the risk for liver disease and the likelihood of dying from it compared with being of normal weight, regardless of level of alcohol consumption, new research shows. 
"People in the overweight or obese range who drank were found to be at greater risk of liver diseases compared with participants within a healthy weight range who consumed alcohol at the same level," senior author Emmanuel Stamatakis, PhD, of the Charles Perkins Centre and the Faculty of Medicine and Health, Sydney, said in a press statement. 
"Even for people who drank within alcohol guidelines, participants classified as obese were at over 50% greater risk of liver disease," he said. 
"Obesity is an independent risk factor for steatosis, acute alcoholic hepatitis, and cirrhosis in alcoholic liver disease (ALD), which may increase the risk of mortality in ALD patients," the study's first author, Elif Inan-Eroglu, PhD, a postdoctoral research fellow at the Charles Perkins Centre, said in an interview. 
Further prospective studies are needed to better understand the underlying mechanisms behind the association between alcohol consumption and liver disease across different adiposity levels, the authors say. 
Meanwhile, the take-home message from the findings should be that "clinicians should consider the presence of overweight and obesity when they discuss defining safe alcohol levels for their patients, keeping in mind that there is no 'safe' level of alcohol," Dr. Inan-Eroglu said. 
"Alcohol drinking guidelines need to acknowledge that two-thirds of the adult population are overweight or obese and consider specific recommendations for this majority population group," he said.  

First and largest study of its kind 

Obesity, well-known to be an independent risk factor for nonalcoholic fatty liver disease (NAFLD), is also known to worsen outcomes in ALD. And likewise, alcohol consumption, the cause of ALD, can promote obesity and therefore increase the risk of NAFLD. 
Dr. Stamatakis and colleagues sought to evaluate the roles of the combined factors in terms of incidence and mortality in both ALD and NAFLD. 
For the study, published online May 31 in the European Journal of Clinical Nutrition, they evaluated data from 465,437 participants in the U.K. Biobank. The study is said to be the first and largest of its kind. 
In the cohort, a total of 1,090 liver disease deaths were recorded, including 230 deaths from ALD and 192 from NAFLD over an average follow-up of 10.5 years. 
After a multivariate adjustment, the overall risk of ALD, NAFLD, and liver disease incidence and mortality were significantly higher in participants who were overweight or had obesity, compared with those of normal weight, at all levels of alcohol consumption. 
For instance, among those with alcohol use exceeding guidelines, the risk of ALD was significantly increased in normal weight individuals versus never-drinkers (hazard ratio [HR], 5.38), and the risk was even higher among those who were also overweight or had obesity (HR, 8.58). 
In terms of the risk of death related to ALD, among those reporting alcohol consumption above guidelines, the risk was nearly double among those who were overweight or had obesity (HR, 10.29) versus those with normal weight (HR, 5.84), when each group was compared to those drinking within guidelines. 
Regarding NAFLD, consistent with evidence that low to moderate alcohol consumption is, in fact, linked to a reduced risk, those in the study who reported alcohol consumption within guidelines and normal weight did show a reduced risk of NAFLD compared with an index group of never-drinkers (HR, 0.85). 
However, being overweight or having obesity increased the risk of NAFLD in those participants (HR, 1.51). 
Furthermore, even those reporting alcohol consumption above guidelines who were of normal weight had a reduced risk of NAFLD compared with never drinkers of normal weight (HR, 0.89).   
Regarding the risk of liver disease among those reporting alcohol consumption above guidelines compared with never-drinkers, the risk was again lower among those of normal weight versus those who were overweight or had obesity (HR, 0.95 vs. 1.52), as were the risks of mortality (HR, 1.24 vs. 2.20). 
Overall, "we found evidence that being overweight/[having obesity] amplified the harmful effect of alcohol on the liver disease incidence and mortality," the authors conclude. 
The authors have reported no relevant financial relationships. 
A version of this article first appeared on Medscape.com

Being overweight or having obesity significantly increases the risk for liver disease and the likelihood of dying from it compared with being of normal weight, regardless of level of alcohol consumption, new research shows. 
"People in the overweight or obese range who drank were found to be at greater risk of liver diseases compared with participants within a healthy weight range who consumed alcohol at the same level," senior author Emmanuel Stamatakis, PhD, of the Charles Perkins Centre and the Faculty of Medicine and Health, Sydney, said in a press statement. 
"Even for people who drank within alcohol guidelines, participants classified as obese were at over 50% greater risk of liver disease," he said. 
"Obesity is an independent risk factor for steatosis, acute alcoholic hepatitis, and cirrhosis in alcoholic liver disease (ALD), which may increase the risk of mortality in ALD patients," the study's first author, Elif Inan-Eroglu, PhD, a postdoctoral research fellow at the Charles Perkins Centre, said in an interview. 
Further prospective studies are needed to better understand the underlying mechanisms behind the association between alcohol consumption and liver disease across different adiposity levels, the authors say. 
Meanwhile, the take-home message from the findings should be that "clinicians should consider the presence of overweight and obesity when they discuss defining safe alcohol levels for their patients, keeping in mind that there is no 'safe' level of alcohol," Dr. Inan-Eroglu said. 
"Alcohol drinking guidelines need to acknowledge that two-thirds of the adult population are overweight or obese and consider specific recommendations for this majority population group," he said.  

First and largest study of its kind 

Obesity, well-known to be an independent risk factor for nonalcoholic fatty liver disease (NAFLD), is also known to worsen outcomes in ALD. And likewise, alcohol consumption, the cause of ALD, can promote obesity and therefore increase the risk of NAFLD. 
Dr. Stamatakis and colleagues sought to evaluate the roles of the combined factors in terms of incidence and mortality in both ALD and NAFLD. 
For the study, published online May 31 in the European Journal of Clinical Nutrition, they evaluated data from 465,437 participants in the U.K. Biobank. The study is said to be the first and largest of its kind. 
In the cohort, a total of 1,090 liver disease deaths were recorded, including 230 deaths from ALD and 192 from NAFLD over an average follow-up of 10.5 years. 
After a multivariate adjustment, the overall risk of ALD, NAFLD, and liver disease incidence and mortality were significantly higher in participants who were overweight or had obesity, compared with those of normal weight, at all levels of alcohol consumption. 
For instance, among those with alcohol use exceeding guidelines, the risk of ALD was significantly increased in normal weight individuals versus never-drinkers (hazard ratio [HR], 5.38), and the risk was even higher among those who were also overweight or had obesity (HR, 8.58). 
In terms of the risk of death related to ALD, among those reporting alcohol consumption above guidelines, the risk was nearly double among those who were overweight or had obesity (HR, 10.29) versus those with normal weight (HR, 5.84), when each group was compared to those drinking within guidelines. 
Regarding NAFLD, consistent with evidence that low to moderate alcohol consumption is, in fact, linked to a reduced risk, those in the study who reported alcohol consumption within guidelines and normal weight did show a reduced risk of NAFLD compared with an index group of never-drinkers (HR, 0.85). 
However, being overweight or having obesity increased the risk of NAFLD in those participants (HR, 1.51). 
Furthermore, even those reporting alcohol consumption above guidelines who were of normal weight had a reduced risk of NAFLD compared with never drinkers of normal weight (HR, 0.89).   
Regarding the risk of liver disease among those reporting alcohol consumption above guidelines compared with never-drinkers, the risk was again lower among those of normal weight versus those who were overweight or had obesity (HR, 0.95 vs. 1.52), as were the risks of mortality (HR, 1.24 vs. 2.20). 
Overall, "we found evidence that being overweight/[having obesity] amplified the harmful effect of alcohol on the liver disease incidence and mortality," the authors conclude. 
The authors have reported no relevant financial relationships. 
A version of this article first appeared on Medscape.com

Women with osteoporosis, low bone density, or a previous vertebral fracture show significant increases in the risk of hearing loss compared to those without osteoporosis, according to a new study with more than 3 decades of follow-up.

The use of bisphosphonate therapy did not alter the risk, the researchers found.

“To the best of our knowledge, this is the first large longitudinal study to evaluate the relations of bone density, bisphosphonate use, fractures, and risk of hearing loss,” reported Sharon Curhan, MD, and colleagues in research published online in the Journal of the American Geriatric Society.

“In this large nationwide longitudinal study of nearly 144,000 women with up to 34 years of follow-up, we found that osteoporosis or low bone density was independently associated with higher risk of incident moderate or worse hearing loss,” the authors wrote.

“The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates,” they added.
 

Participants were from the nurses’ health study and NHS II

With recent research suggesting a potential link between bisphosphonate use and prevention of noise-induced hearing loss in mice, Dr. Curhan, of the Channing Division of Network Medicine at Brigham and Women’s Hospital, Boston, and colleagues turned to the large longitudinal cohorts of the Nurses’ Health Study (NHS), conducted from 1982 to 2016, and the Nurses’ Health Study II (NHS II), from 1995 to 2017.

In total, the primary analysis included 60,821 women in the NHS and 83,078 in the NHS II.

Women in the NHS were aged 36-61 years at baseline and 70-95 years at the end of follow-up, while in the NHS II, women were aged 31-48 years at baseline and 53-70 years at the end of follow-up.

After multivariate adjustment for key factors including age, race/ethnicity, oral hormone use, and a variety of other factors, women in the NHS with osteoporosis had an increased risk of moderate or worse hearing loss, as self-reported every 2 years, compared to those without osteoporosis (relative risk, 1.14; 95% confidence interval, 1.09-1.19).

And in the NHS II, which also included data on low bone density, the risk of self-reported hearing loss was higher among those with osteoporosis or low bone density (RR, 1.30; 95% CI, 1.21-1.40).

No significant differences were observed in hearing loss risk based on whether women were treated with bisphosphonates, with the mean duration of use of the medication being 5.8 years in the NHS and 3.4 years in the NHS II.

Those who sustained a vertebral fracture also had a higher risk of hearing loss in both studies (NHS: RR, 1.31; NHS II: RR, 1.39).

However, the increased risk of hearing loss was not observed with hip fracture.

“Our findings of up to a 40% higher risk among women with vertebral fracture, but not hip fracture, were intriguing and merit further study,” the authors noted.

“The discordant findings between these skeletal sites may reflect differences in composition and metabolism of bones in the spine and hip and could provide insight into the pathophysiological changes in the ear that may lead to hearing loss,” they added.
 

Audiometric subanalysis

In an analysis of a subcohort of 3,749 women looking at audiometric thresholds for a more precise measure of hearing loss, women with osteoporosis or low bone density continued to show significantly worse hearing loss when treated with bisphosphonates compared to those without osteoporosis or low bone density.

However, there were no significant hearing loss differences among those with osteoporosis who did not take bisphosphonates versus those without osteoporosis.

The authors speculate that the use of bisphosphonates could have been indicative of more severe osteoporosis, hence the poorer audiometric thresholds.

In an interview, Dr. Curhan said the details of bisphosphonate use, such as type and duration, and their role in hearing loss should be further evaluated.

“Possibly, a potential influence of bisphosphonates on the relation of osteoporosis and hearing loss in humans may depend on the type, dose, and timing of bisphosphonate administration,” she observed. “This is an important question for further study.”
 

Mechanisms: Bone loss may extend to ear structures

In terms of the mechanisms linking osteoporosis itself to hearing loss, the authors noted that bone loss, in addition to compromising more prominent skeletal sites, could logically extend to bone-related structures in the ear.

“Bone mass at peripheral sites is correlated with bone mass at central sites, such as hip and spine, with correlation coefficients between 0.6 and 0.7,” they explained. “Plausibly, systemic bone demineralization could involve the temporal bone, the otic capsule, and the middle ear ossicles.”

They noted that hearing loss has been linked to other pathologic bone disorders, including otosclerosis and Paget disease.

Furthermore, imbalances in bone formation and resorption in osteoporosis may lead to alterations in ionic metabolism, which can lead to hearing loss.

Looking ahead, Dr. Curhan and colleagues plan to further examine whether calcium and vitamin D, which are associated with the prevention of osteoporosis, have a role in preventing hearing loss.

In the meantime, the findings underscore that clinicians treating patients with osteoporosis should routinely check patients’ hearing, Dr. Curhan said.

“Undetected and untreated hearing loss can adversely impact social interactions, physical and mental well-being, and daily life,” she said.

“Early detection of hearing loss offers greater opportunity for successful management and to learn strategies for rehabilitation and prevention of further progression.”

The study received support from the National Institutes of Health.
 

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

Women with osteoporosis, low bone density, or a previous vertebral fracture show significant increases in the risk of hearing loss compared to those without osteoporosis, according to a new study with more than 3 decades of follow-up.

The use of bisphosphonate therapy did not alter the risk, the researchers found.

“To the best of our knowledge, this is the first large longitudinal study to evaluate the relations of bone density, bisphosphonate use, fractures, and risk of hearing loss,” reported Sharon Curhan, MD, and colleagues in research published online in the Journal of the American Geriatric Society.

“In this large nationwide longitudinal study of nearly 144,000 women with up to 34 years of follow-up, we found that osteoporosis or low bone density was independently associated with higher risk of incident moderate or worse hearing loss,” the authors wrote.

“The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates,” they added.
 

Participants were from the nurses’ health study and NHS II

With recent research suggesting a potential link between bisphosphonate use and prevention of noise-induced hearing loss in mice, Dr. Curhan, of the Channing Division of Network Medicine at Brigham and Women’s Hospital, Boston, and colleagues turned to the large longitudinal cohorts of the Nurses’ Health Study (NHS), conducted from 1982 to 2016, and the Nurses’ Health Study II (NHS II), from 1995 to 2017.

In total, the primary analysis included 60,821 women in the NHS and 83,078 in the NHS II.

Women in the NHS were aged 36-61 years at baseline and 70-95 years at the end of follow-up, while in the NHS II, women were aged 31-48 years at baseline and 53-70 years at the end of follow-up.

After multivariate adjustment for key factors including age, race/ethnicity, oral hormone use, and a variety of other factors, women in the NHS with osteoporosis had an increased risk of moderate or worse hearing loss, as self-reported every 2 years, compared to those without osteoporosis (relative risk, 1.14; 95% confidence interval, 1.09-1.19).

And in the NHS II, which also included data on low bone density, the risk of self-reported hearing loss was higher among those with osteoporosis or low bone density (RR, 1.30; 95% CI, 1.21-1.40).

No significant differences were observed in hearing loss risk based on whether women were treated with bisphosphonates, with the mean duration of use of the medication being 5.8 years in the NHS and 3.4 years in the NHS II.

Those who sustained a vertebral fracture also had a higher risk of hearing loss in both studies (NHS: RR, 1.31; NHS II: RR, 1.39).

However, the increased risk of hearing loss was not observed with hip fracture.

“Our findings of up to a 40% higher risk among women with vertebral fracture, but not hip fracture, were intriguing and merit further study,” the authors noted.

“The discordant findings between these skeletal sites may reflect differences in composition and metabolism of bones in the spine and hip and could provide insight into the pathophysiological changes in the ear that may lead to hearing loss,” they added.
 

Audiometric subanalysis

In an analysis of a subcohort of 3,749 women looking at audiometric thresholds for a more precise measure of hearing loss, women with osteoporosis or low bone density continued to show significantly worse hearing loss when treated with bisphosphonates compared to those without osteoporosis or low bone density.

However, there were no significant hearing loss differences among those with osteoporosis who did not take bisphosphonates versus those without osteoporosis.

The authors speculate that the use of bisphosphonates could have been indicative of more severe osteoporosis, hence the poorer audiometric thresholds.

In an interview, Dr. Curhan said the details of bisphosphonate use, such as type and duration, and their role in hearing loss should be further evaluated.

“Possibly, a potential influence of bisphosphonates on the relation of osteoporosis and hearing loss in humans may depend on the type, dose, and timing of bisphosphonate administration,” she observed. “This is an important question for further study.”
 

Mechanisms: Bone loss may extend to ear structures

In terms of the mechanisms linking osteoporosis itself to hearing loss, the authors noted that bone loss, in addition to compromising more prominent skeletal sites, could logically extend to bone-related structures in the ear.

“Bone mass at peripheral sites is correlated with bone mass at central sites, such as hip and spine, with correlation coefficients between 0.6 and 0.7,” they explained. “Plausibly, systemic bone demineralization could involve the temporal bone, the otic capsule, and the middle ear ossicles.”

They noted that hearing loss has been linked to other pathologic bone disorders, including otosclerosis and Paget disease.

Furthermore, imbalances in bone formation and resorption in osteoporosis may lead to alterations in ionic metabolism, which can lead to hearing loss.

Looking ahead, Dr. Curhan and colleagues plan to further examine whether calcium and vitamin D, which are associated with the prevention of osteoporosis, have a role in preventing hearing loss.

In the meantime, the findings underscore that clinicians treating patients with osteoporosis should routinely check patients’ hearing, Dr. Curhan said.

“Undetected and untreated hearing loss can adversely impact social interactions, physical and mental well-being, and daily life,” she said.

“Early detection of hearing loss offers greater opportunity for successful management and to learn strategies for rehabilitation and prevention of further progression.”

The study received support from the National Institutes of Health.
 

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

Women with osteoporosis, low bone density, or a previous vertebral fracture show significant increases in the risk of hearing loss compared to those without osteoporosis, according to a new study with more than 3 decades of follow-up.

The use of bisphosphonate therapy did not alter the risk, the researchers found.

“To the best of our knowledge, this is the first large longitudinal study to evaluate the relations of bone density, bisphosphonate use, fractures, and risk of hearing loss,” reported Sharon Curhan, MD, and colleagues in research published online in the Journal of the American Geriatric Society.

“In this large nationwide longitudinal study of nearly 144,000 women with up to 34 years of follow-up, we found that osteoporosis or low bone density was independently associated with higher risk of incident moderate or worse hearing loss,” the authors wrote.

“The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates,” they added.
 

Participants were from the nurses’ health study and NHS II

With recent research suggesting a potential link between bisphosphonate use and prevention of noise-induced hearing loss in mice, Dr. Curhan, of the Channing Division of Network Medicine at Brigham and Women’s Hospital, Boston, and colleagues turned to the large longitudinal cohorts of the Nurses’ Health Study (NHS), conducted from 1982 to 2016, and the Nurses’ Health Study II (NHS II), from 1995 to 2017.

In total, the primary analysis included 60,821 women in the NHS and 83,078 in the NHS II.

Women in the NHS were aged 36-61 years at baseline and 70-95 years at the end of follow-up, while in the NHS II, women were aged 31-48 years at baseline and 53-70 years at the end of follow-up.

After multivariate adjustment for key factors including age, race/ethnicity, oral hormone use, and a variety of other factors, women in the NHS with osteoporosis had an increased risk of moderate or worse hearing loss, as self-reported every 2 years, compared to those without osteoporosis (relative risk, 1.14; 95% confidence interval, 1.09-1.19).

And in the NHS II, which also included data on low bone density, the risk of self-reported hearing loss was higher among those with osteoporosis or low bone density (RR, 1.30; 95% CI, 1.21-1.40).

No significant differences were observed in hearing loss risk based on whether women were treated with bisphosphonates, with the mean duration of use of the medication being 5.8 years in the NHS and 3.4 years in the NHS II.

Those who sustained a vertebral fracture also had a higher risk of hearing loss in both studies (NHS: RR, 1.31; NHS II: RR, 1.39).

However, the increased risk of hearing loss was not observed with hip fracture.

“Our findings of up to a 40% higher risk among women with vertebral fracture, but not hip fracture, were intriguing and merit further study,” the authors noted.

“The discordant findings between these skeletal sites may reflect differences in composition and metabolism of bones in the spine and hip and could provide insight into the pathophysiological changes in the ear that may lead to hearing loss,” they added.
 

Audiometric subanalysis

In an analysis of a subcohort of 3,749 women looking at audiometric thresholds for a more precise measure of hearing loss, women with osteoporosis or low bone density continued to show significantly worse hearing loss when treated with bisphosphonates compared to those without osteoporosis or low bone density.

However, there were no significant hearing loss differences among those with osteoporosis who did not take bisphosphonates versus those without osteoporosis.

The authors speculate that the use of bisphosphonates could have been indicative of more severe osteoporosis, hence the poorer audiometric thresholds.

In an interview, Dr. Curhan said the details of bisphosphonate use, such as type and duration, and their role in hearing loss should be further evaluated.

“Possibly, a potential influence of bisphosphonates on the relation of osteoporosis and hearing loss in humans may depend on the type, dose, and timing of bisphosphonate administration,” she observed. “This is an important question for further study.”
 

Mechanisms: Bone loss may extend to ear structures

In terms of the mechanisms linking osteoporosis itself to hearing loss, the authors noted that bone loss, in addition to compromising more prominent skeletal sites, could logically extend to bone-related structures in the ear.

“Bone mass at peripheral sites is correlated with bone mass at central sites, such as hip and spine, with correlation coefficients between 0.6 and 0.7,” they explained. “Plausibly, systemic bone demineralization could involve the temporal bone, the otic capsule, and the middle ear ossicles.”

They noted that hearing loss has been linked to other pathologic bone disorders, including otosclerosis and Paget disease.

Furthermore, imbalances in bone formation and resorption in osteoporosis may lead to alterations in ionic metabolism, which can lead to hearing loss.

Looking ahead, Dr. Curhan and colleagues plan to further examine whether calcium and vitamin D, which are associated with the prevention of osteoporosis, have a role in preventing hearing loss.

In the meantime, the findings underscore that clinicians treating patients with osteoporosis should routinely check patients’ hearing, Dr. Curhan said.

“Undetected and untreated hearing loss can adversely impact social interactions, physical and mental well-being, and daily life,” she said.

“Early detection of hearing loss offers greater opportunity for successful management and to learn strategies for rehabilitation and prevention of further progression.”

The study received support from the National Institutes of Health.
 

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