Video

MUNICH – The “overwhelming impression” that Paul K. Whelton, MD, has of the newly revised hypertension diagnosis and management guidelines of the European Society of Cardiology is their similarity to hypertension guidelines released by the American College of Cardiology and American Heart Association in November 2017.

“We both recommend the same treatment target, of less than 130/80 mm Hg,” noted Dr. Whelton, professor at Tulane University in New Orleans, although the European guidelines (Euro J Cardiology. 2018 Sep 1; 39[33]:3021-104) put more qualifications on this target and specify treating to no lower than 130 mm Hg systolic pressure in patients who are at least 65 years old as well as in patients with chronic kidney disease at any age. In a video interview, Dr. Whelton also cited areas of disagreement, such as how patients with an untreated blood pressure of 130-139 mm Hg are classified (high normal in the European guidelines, stage 1 hypertension in the U.S. guidelines), and whether initial drug monotherapy is a reasonable treatment strategy (U.S. says yes, Europe says no).

Dr. Whelton noted that recent modeling studies have documented the potential public health benefits from following the diagnosis and management approaches set forth in the 2017 U.S. guidelines (J Am Coll Cardiol. 2018 May;71[19]:e127-e248). For example, an analysis based on data collected by the U.S. National Health and Nutrition Examination Survey during 2013-2016 showed that following the 2017 guidelines for diagnosing and treating hypertension would have resulted in prevention of more than twice the number of cardiovascular disease events nationally as compared with application of the prior, 2014 U.S. hypertension guideline (JAMA. 2014 Feb 5;311[5]:507-20): 610,000 events prevented, compared with 270,000 events prevented. The same study showed that the 2017 guidelines would have nearly doubled the number of all-cause deaths prevented, with 334,000 deaths prevented, compared with 177,000 prevented by applying the 2014 guidelines (JAMA Cardiology. 2018 July;3[7]:572-81).

Dr. Whelton had no commercial disclosures.

[email protected]

MUNICH – The “overwhelming impression” that Paul K. Whelton, MD, has of the newly revised hypertension diagnosis and management guidelines of the European Society of Cardiology is their similarity to hypertension guidelines released by the American College of Cardiology and American Heart Association in November 2017.

“We both recommend the same treatment target, of less than 130/80 mm Hg,” noted Dr. Whelton, professor at Tulane University in New Orleans, although the European guidelines (Euro J Cardiology. 2018 Sep 1; 39[33]:3021-104) put more qualifications on this target and specify treating to no lower than 130 mm Hg systolic pressure in patients who are at least 65 years old as well as in patients with chronic kidney disease at any age. In a video interview, Dr. Whelton also cited areas of disagreement, such as how patients with an untreated blood pressure of 130-139 mm Hg are classified (high normal in the European guidelines, stage 1 hypertension in the U.S. guidelines), and whether initial drug monotherapy is a reasonable treatment strategy (U.S. says yes, Europe says no).

Dr. Whelton noted that recent modeling studies have documented the potential public health benefits from following the diagnosis and management approaches set forth in the 2017 U.S. guidelines (J Am Coll Cardiol. 2018 May;71[19]:e127-e248). For example, an analysis based on data collected by the U.S. National Health and Nutrition Examination Survey during 2013-2016 showed that following the 2017 guidelines for diagnosing and treating hypertension would have resulted in prevention of more than twice the number of cardiovascular disease events nationally as compared with application of the prior, 2014 U.S. hypertension guideline (JAMA. 2014 Feb 5;311[5]:507-20): 610,000 events prevented, compared with 270,000 events prevented. The same study showed that the 2017 guidelines would have nearly doubled the number of all-cause deaths prevented, with 334,000 deaths prevented, compared with 177,000 prevented by applying the 2014 guidelines (JAMA Cardiology. 2018 July;3[7]:572-81).

Dr. Whelton had no commercial disclosures.

[email protected]

MUNICH – The “overwhelming impression” that Paul K. Whelton, MD, has of the newly revised hypertension diagnosis and management guidelines of the European Society of Cardiology is their similarity to hypertension guidelines released by the American College of Cardiology and American Heart Association in November 2017.

“We both recommend the same treatment target, of less than 130/80 mm Hg,” noted Dr. Whelton, professor at Tulane University in New Orleans, although the European guidelines (Euro J Cardiology. 2018 Sep 1; 39[33]:3021-104) put more qualifications on this target and specify treating to no lower than 130 mm Hg systolic pressure in patients who are at least 65 years old as well as in patients with chronic kidney disease at any age. In a video interview, Dr. Whelton also cited areas of disagreement, such as how patients with an untreated blood pressure of 130-139 mm Hg are classified (high normal in the European guidelines, stage 1 hypertension in the U.S. guidelines), and whether initial drug monotherapy is a reasonable treatment strategy (U.S. says yes, Europe says no).

Dr. Whelton noted that recent modeling studies have documented the potential public health benefits from following the diagnosis and management approaches set forth in the 2017 U.S. guidelines (J Am Coll Cardiol. 2018 May;71[19]:e127-e248). For example, an analysis based on data collected by the U.S. National Health and Nutrition Examination Survey during 2013-2016 showed that following the 2017 guidelines for diagnosing and treating hypertension would have resulted in prevention of more than twice the number of cardiovascular disease events nationally as compared with application of the prior, 2014 U.S. hypertension guideline (JAMA. 2014 Feb 5;311[5]:507-20): 610,000 events prevented, compared with 270,000 events prevented. The same study showed that the 2017 guidelines would have nearly doubled the number of all-cause deaths prevented, with 334,000 deaths prevented, compared with 177,000 prevented by applying the 2014 guidelines (JAMA Cardiology. 2018 July;3[7]:572-81).

Dr. Whelton had no commercial disclosures.

[email protected]

MUNICH – The European Society of Cardiology joined other international cardiology groups in endorsing lower targets for blood pressure treatment and lower pressure thresholds for starting drug treatment in its revised hypertension diagnosis and management guidelines released in August during the Society’s annual congress here.

“Provided that treatment is well tolerated, treated blood pressure should be targeted to 130/80 mm Hg or lower in most patients,” Giuseppe Mancia, MD, said as he and his colleagues presented the new guidelines at the annual congress of the European Society of Cardiology.

Although the new European guidelines further buttress this more aggressive approach to blood pressure management that first appeared almost a year ago in U.S. guidelines from the American College of Cardiology and the American Heart Association, an approach that remains controversial among U.S. primary care physicians, the European strategy (Eur Heart J. 2018 Sep 1;39[33]:3021-104) was generally more cautious than the broader endorsement of lower blood pressure goals advanced by the U.S. recommendations (J Am Coll Cardiol. 2018 May;71[19]:e127-e248).

In the European approach, “the first objective is to treat to less than 140/90 mm Hg. If this is well tolerated, then treat to less than 130/80 mm Hg in most patients,” said Dr. Mancia, cochair of the European writing panel. Further pressure reductions to less than 130/80 mm Hg are usually harder, the incremental benefit from further reduction is less than when pressures first fall below 140/90 mm Hg, and the evidence for incremental benefit of any size from further pressure reduction is less strong for certain key patient subgroups: people at least 80 years old, and patients with diabetes, chronic kidney disease, or coronary artery disease, said Dr. Mancia, an emeritus professor at the University of Milan.

“The consistency between two major guidelines is important, but there are differences that may look subtle but are not subtle,” he said in a video interview. “If a patient gets to less than 140 mm Hg, the doctor should not think that’s a failure; it’s a very important result.”

One striking example of how the two guidelines differ on treatment targets is for people at least 80 years old. The overall blood pressure threshold for starting drug treatment in patients this age in the European guidelines is 160/90 mm Hg, although it remains at 140/90 for people aged 65-79 years old “provided that treatment is well tolerated” and the patients are “fit.” The 2017 U.S. guidelines, by contrast, say that considering drug treatment for everyone with a pressure at or above 130/80 mm Hg is a class I recommendation regardless of age as long as the person is “noninstitutionalized, ambulatory, [and] community-dwelling.” Once an older patient of any age, 65 years or older, starts drug treatment to reduce blood pressure, the European guidelines allow for treating to a target systolic blood pressure of 130-139 mm Hg as long as the regimen is well tolerated, and the guidelines say that a diastolic pressure target of less than 80 mm Hg should be considered for all adults regardless of age.

Mitchel L. Zoler/MDedge News

The new European guidelines also define adults with an untreated pressure of 130-139/85-89 mm Hg as “high normal,” rather than the “stage 1 hypertension” designation given to people with pressures of 130-139/80-89 mm Hg in the U.S. guidelines. Robert M. Carey, MD, vice chair of the U.S. guidelines panel, minimized this as a “semantic” difference, and he highlighted that management of people with pressures in this range is roughly similar in the two sets of recommendations. “The name is different, but treatment is the same,” Dr. Carey said.

The European guidelines call for initial lifestyle interventions, followed by drug treatment “that may be considered” for patients who have “very-high” cardiovascular risk because of established cardiovascular disease, especially coronary artery disease, and detail the specific clinical conditions that fall into the very-high-risk category. The U.S. guidelines say that stage 1 hypertension patients should get lifestyle interventions, followed by drug treatment for the roughly 30% of patients in this category who score at least a 10% 10-year risk on the American College of Cardiology’s Atherosclerotic Cardiovascular Disease Risk Estimator Plus.The new European guidelines are a “validation” of the ACC/AHA 2017 guidelines, commented Dr. Carey, a professor of medicine at the University of Virginia in Charlottesville. “Overall, we’re delighted to have these two major groups” agree, he said in an interview. “There is a tremendous amount of concurrence.”

Other areas of agreement between the two guidelines include their emphasis on careful and repeated blood pressure measurement, including out-of-office measurement, before settling on a diagnosis of hypertension; systematic assessment of possible masked or white-coat hypertension in selected people; and frequent use of combined drug treatment including initiation of a dual-drug, single-pill regimen when starting drug treatment and aggressive follow-up by adding a third drug when needed. However, in another divergence the U.S. guidelines give a much stronger endorsement to starting treatment with monotherapy, a strategy the European guidelines scrapped.

Mitchel L. Zoler/MDedge News

Dr. Carey also noted that the European endorsement of three antihypertensives formulated into a single pill for patients who need more than two drugs would be difficult for American clinicians to follow as virtually no such formulations are approved for U.S. use.

Dr. Mancini has received honoraria from Boehringer Ingelheim, CVRx, Daiichi Sankyo, Ferrer, Medtronic, Menarini, Merck, Novartis, Recordati, and Servier. Dr. Williams has been a consultant to Novartis, Relypsa, and Vascular Dynamics, and he has spoken on behalf of Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Servier. Dr. Carey and Dr. Whelton had no commercial disclosures.
 

[email protected]

MUNICH – The European Society of Cardiology joined other international cardiology groups in endorsing lower targets for blood pressure treatment and lower pressure thresholds for starting drug treatment in its revised hypertension diagnosis and management guidelines released in August during the Society’s annual congress here.

“Provided that treatment is well tolerated, treated blood pressure should be targeted to 130/80 mm Hg or lower in most patients,” Giuseppe Mancia, MD, said as he and his colleagues presented the new guidelines at the annual congress of the European Society of Cardiology.

Although the new European guidelines further buttress this more aggressive approach to blood pressure management that first appeared almost a year ago in U.S. guidelines from the American College of Cardiology and the American Heart Association, an approach that remains controversial among U.S. primary care physicians, the European strategy (Eur Heart J. 2018 Sep 1;39[33]:3021-104) was generally more cautious than the broader endorsement of lower blood pressure goals advanced by the U.S. recommendations (J Am Coll Cardiol. 2018 May;71[19]:e127-e248).

In the European approach, “the first objective is to treat to less than 140/90 mm Hg. If this is well tolerated, then treat to less than 130/80 mm Hg in most patients,” said Dr. Mancia, cochair of the European writing panel. Further pressure reductions to less than 130/80 mm Hg are usually harder, the incremental benefit from further reduction is less than when pressures first fall below 140/90 mm Hg, and the evidence for incremental benefit of any size from further pressure reduction is less strong for certain key patient subgroups: people at least 80 years old, and patients with diabetes, chronic kidney disease, or coronary artery disease, said Dr. Mancia, an emeritus professor at the University of Milan.

“The consistency between two major guidelines is important, but there are differences that may look subtle but are not subtle,” he said in a video interview. “If a patient gets to less than 140 mm Hg, the doctor should not think that’s a failure; it’s a very important result.”

One striking example of how the two guidelines differ on treatment targets is for people at least 80 years old. The overall blood pressure threshold for starting drug treatment in patients this age in the European guidelines is 160/90 mm Hg, although it remains at 140/90 for people aged 65-79 years old “provided that treatment is well tolerated” and the patients are “fit.” The 2017 U.S. guidelines, by contrast, say that considering drug treatment for everyone with a pressure at or above 130/80 mm Hg is a class I recommendation regardless of age as long as the person is “noninstitutionalized, ambulatory, [and] community-dwelling.” Once an older patient of any age, 65 years or older, starts drug treatment to reduce blood pressure, the European guidelines allow for treating to a target systolic blood pressure of 130-139 mm Hg as long as the regimen is well tolerated, and the guidelines say that a diastolic pressure target of less than 80 mm Hg should be considered for all adults regardless of age.

Mitchel L. Zoler/MDedge News

The new European guidelines also define adults with an untreated pressure of 130-139/85-89 mm Hg as “high normal,” rather than the “stage 1 hypertension” designation given to people with pressures of 130-139/80-89 mm Hg in the U.S. guidelines. Robert M. Carey, MD, vice chair of the U.S. guidelines panel, minimized this as a “semantic” difference, and he highlighted that management of people with pressures in this range is roughly similar in the two sets of recommendations. “The name is different, but treatment is the same,” Dr. Carey said.

The European guidelines call for initial lifestyle interventions, followed by drug treatment “that may be considered” for patients who have “very-high” cardiovascular risk because of established cardiovascular disease, especially coronary artery disease, and detail the specific clinical conditions that fall into the very-high-risk category. The U.S. guidelines say that stage 1 hypertension patients should get lifestyle interventions, followed by drug treatment for the roughly 30% of patients in this category who score at least a 10% 10-year risk on the American College of Cardiology’s Atherosclerotic Cardiovascular Disease Risk Estimator Plus.The new European guidelines are a “validation” of the ACC/AHA 2017 guidelines, commented Dr. Carey, a professor of medicine at the University of Virginia in Charlottesville. “Overall, we’re delighted to have these two major groups” agree, he said in an interview. “There is a tremendous amount of concurrence.”

Other areas of agreement between the two guidelines include their emphasis on careful and repeated blood pressure measurement, including out-of-office measurement, before settling on a diagnosis of hypertension; systematic assessment of possible masked or white-coat hypertension in selected people; and frequent use of combined drug treatment including initiation of a dual-drug, single-pill regimen when starting drug treatment and aggressive follow-up by adding a third drug when needed. However, in another divergence the U.S. guidelines give a much stronger endorsement to starting treatment with monotherapy, a strategy the European guidelines scrapped.

Mitchel L. Zoler/MDedge News

Dr. Carey also noted that the European endorsement of three antihypertensives formulated into a single pill for patients who need more than two drugs would be difficult for American clinicians to follow as virtually no such formulations are approved for U.S. use.

Dr. Mancini has received honoraria from Boehringer Ingelheim, CVRx, Daiichi Sankyo, Ferrer, Medtronic, Menarini, Merck, Novartis, Recordati, and Servier. Dr. Williams has been a consultant to Novartis, Relypsa, and Vascular Dynamics, and he has spoken on behalf of Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Servier. Dr. Carey and Dr. Whelton had no commercial disclosures.
 

[email protected]

MUNICH – The European Society of Cardiology joined other international cardiology groups in endorsing lower targets for blood pressure treatment and lower pressure thresholds for starting drug treatment in its revised hypertension diagnosis and management guidelines released in August during the Society’s annual congress here.

“Provided that treatment is well tolerated, treated blood pressure should be targeted to 130/80 mm Hg or lower in most patients,” Giuseppe Mancia, MD, said as he and his colleagues presented the new guidelines at the annual congress of the European Society of Cardiology.

Although the new European guidelines further buttress this more aggressive approach to blood pressure management that first appeared almost a year ago in U.S. guidelines from the American College of Cardiology and the American Heart Association, an approach that remains controversial among U.S. primary care physicians, the European strategy (Eur Heart J. 2018 Sep 1;39[33]:3021-104) was generally more cautious than the broader endorsement of lower blood pressure goals advanced by the U.S. recommendations (J Am Coll Cardiol. 2018 May;71[19]:e127-e248).

In the European approach, “the first objective is to treat to less than 140/90 mm Hg. If this is well tolerated, then treat to less than 130/80 mm Hg in most patients,” said Dr. Mancia, cochair of the European writing panel. Further pressure reductions to less than 130/80 mm Hg are usually harder, the incremental benefit from further reduction is less than when pressures first fall below 140/90 mm Hg, and the evidence for incremental benefit of any size from further pressure reduction is less strong for certain key patient subgroups: people at least 80 years old, and patients with diabetes, chronic kidney disease, or coronary artery disease, said Dr. Mancia, an emeritus professor at the University of Milan.

“The consistency between two major guidelines is important, but there are differences that may look subtle but are not subtle,” he said in a video interview. “If a patient gets to less than 140 mm Hg, the doctor should not think that’s a failure; it’s a very important result.”

One striking example of how the two guidelines differ on treatment targets is for people at least 80 years old. The overall blood pressure threshold for starting drug treatment in patients this age in the European guidelines is 160/90 mm Hg, although it remains at 140/90 for people aged 65-79 years old “provided that treatment is well tolerated” and the patients are “fit.” The 2017 U.S. guidelines, by contrast, say that considering drug treatment for everyone with a pressure at or above 130/80 mm Hg is a class I recommendation regardless of age as long as the person is “noninstitutionalized, ambulatory, [and] community-dwelling.” Once an older patient of any age, 65 years or older, starts drug treatment to reduce blood pressure, the European guidelines allow for treating to a target systolic blood pressure of 130-139 mm Hg as long as the regimen is well tolerated, and the guidelines say that a diastolic pressure target of less than 80 mm Hg should be considered for all adults regardless of age.

Mitchel L. Zoler/MDedge News

The new European guidelines also define adults with an untreated pressure of 130-139/85-89 mm Hg as “high normal,” rather than the “stage 1 hypertension” designation given to people with pressures of 130-139/80-89 mm Hg in the U.S. guidelines. Robert M. Carey, MD, vice chair of the U.S. guidelines panel, minimized this as a “semantic” difference, and he highlighted that management of people with pressures in this range is roughly similar in the two sets of recommendations. “The name is different, but treatment is the same,” Dr. Carey said.

The European guidelines call for initial lifestyle interventions, followed by drug treatment “that may be considered” for patients who have “very-high” cardiovascular risk because of established cardiovascular disease, especially coronary artery disease, and detail the specific clinical conditions that fall into the very-high-risk category. The U.S. guidelines say that stage 1 hypertension patients should get lifestyle interventions, followed by drug treatment for the roughly 30% of patients in this category who score at least a 10% 10-year risk on the American College of Cardiology’s Atherosclerotic Cardiovascular Disease Risk Estimator Plus.The new European guidelines are a “validation” of the ACC/AHA 2017 guidelines, commented Dr. Carey, a professor of medicine at the University of Virginia in Charlottesville. “Overall, we’re delighted to have these two major groups” agree, he said in an interview. “There is a tremendous amount of concurrence.”

Other areas of agreement between the two guidelines include their emphasis on careful and repeated blood pressure measurement, including out-of-office measurement, before settling on a diagnosis of hypertension; systematic assessment of possible masked or white-coat hypertension in selected people; and frequent use of combined drug treatment including initiation of a dual-drug, single-pill regimen when starting drug treatment and aggressive follow-up by adding a third drug when needed. However, in another divergence the U.S. guidelines give a much stronger endorsement to starting treatment with monotherapy, a strategy the European guidelines scrapped.

Mitchel L. Zoler/MDedge News

Dr. Carey also noted that the European endorsement of three antihypertensives formulated into a single pill for patients who need more than two drugs would be difficult for American clinicians to follow as virtually no such formulations are approved for U.S. use.

Dr. Mancini has received honoraria from Boehringer Ingelheim, CVRx, Daiichi Sankyo, Ferrer, Medtronic, Menarini, Merck, Novartis, Recordati, and Servier. Dr. Williams has been a consultant to Novartis, Relypsa, and Vascular Dynamics, and he has spoken on behalf of Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Servier. Dr. Carey and Dr. Whelton had no commercial disclosures.
 

[email protected]

CHICAGO – There’s another reason to worry about hypertension in children: cognitive decline later in life.

In a pilot study, Marc Lande, MD, a professor of pediatric nephrology at the University of Rochester (N.Y.), and his colleagues found evidence of impaired white matter integrity on MRI in a handful of hypertensive children, similar to what’s found in adults with cognitive impairment from hypertension.

The work is ongoing, but it helps explain the subtle deficits on cognitive testing that have been previously demonstrated in children with hypertension.

“The fact that we are finding anything at this very early stage of disease is striking and somewhat bothersome. The hope is that, by improving blood pressure in children, you can improve subsequent cognition and maybe even delay the onset of dementia further down the road,” Dr. Lande said.

For now, the findings underscore the need to diagnose and manage hypertension in children, but there might be additional treatment implications in the future, especially if blood pressure targets are found that ameliorate the problem.

Dr. Lande explained the issues and the emerging evidence in a video interview at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

[email protected]

CHICAGO – There’s another reason to worry about hypertension in children: cognitive decline later in life.

In a pilot study, Marc Lande, MD, a professor of pediatric nephrology at the University of Rochester (N.Y.), and his colleagues found evidence of impaired white matter integrity on MRI in a handful of hypertensive children, similar to what’s found in adults with cognitive impairment from hypertension.

The work is ongoing, but it helps explain the subtle deficits on cognitive testing that have been previously demonstrated in children with hypertension.

“The fact that we are finding anything at this very early stage of disease is striking and somewhat bothersome. The hope is that, by improving blood pressure in children, you can improve subsequent cognition and maybe even delay the onset of dementia further down the road,” Dr. Lande said.

For now, the findings underscore the need to diagnose and manage hypertension in children, but there might be additional treatment implications in the future, especially if blood pressure targets are found that ameliorate the problem.

Dr. Lande explained the issues and the emerging evidence in a video interview at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

[email protected]

CHICAGO – There’s another reason to worry about hypertension in children: cognitive decline later in life.

In a pilot study, Marc Lande, MD, a professor of pediatric nephrology at the University of Rochester (N.Y.), and his colleagues found evidence of impaired white matter integrity on MRI in a handful of hypertensive children, similar to what’s found in adults with cognitive impairment from hypertension.

The work is ongoing, but it helps explain the subtle deficits on cognitive testing that have been previously demonstrated in children with hypertension.

“The fact that we are finding anything at this very early stage of disease is striking and somewhat bothersome. The hope is that, by improving blood pressure in children, you can improve subsequent cognition and maybe even delay the onset of dementia further down the road,” Dr. Lande said.

For now, the findings underscore the need to diagnose and manage hypertension in children, but there might be additional treatment implications in the future, especially if blood pressure targets are found that ameliorate the problem.

Dr. Lande explained the issues and the emerging evidence in a video interview at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

[email protected]

A new study finds that piperacillin-tazobactam doesn’t improve mortality compared to meropenem in patients with ceftriaxone-resistant blood poisoning caused by E. coli or K. pneumoniae. The findings were so striking that the study was ended early.

Vidyard Video

Courtesy: JAMA

“These findings do not support use of piperacillin-tazobactam in this setting,” wrote the authors. The report was published Sept. 11 in JAMA (2018;320[10]:984-94.)

According to the Centers for Disease Control and Prevention, an estimated 1,700 deaths in the United States in 2011 were caused by gram-negative bacteria that produce extended-spectrum beta-lactamase enzymes.

While carbapenems such as meropenem (Merrem) are “regarded as the treatment of choice for serious infections,” the MERINO trial (NCT02176122) authors wrote, their rising use could lead to drug resistance.

One alternate option is to embrace beta-lactam/beta-lactamase inhibitors such as piperacillin-tazobactam (Zosyn), the researchers noted, but research has produced conflicting results.

Piperacillin-tazobactam is an injected penicillin antibiotic used to treat conditions such as severe pneumonia, complicated urinary tract infections and complicated skin and soft tissue infections.

For the new study, researchers led by Patrick N. A. Harris, MBBS, of the University of Queensland, randomly assigned 188 patients to intravenous piperacillin-tazobactam (4.5 g every 6 hours) and 191 patients to meropenem (1 g every 8 hours) for 4-14 days, depending on clinician’s preference. (12 other patients did not continue with the study after initial randomization due to factors such as errors).

All patients were adults and had at least one blood test showing they were positive for E. coli or K. pneumoniae. They all had to be nonsusceptible to ceftriaxone (Rocephin) but susceptible to piperacillin-tazobactam.

The study was ceased prior to enrollment because of the risk of harm. Interim findings suggested the study was unlikely to show higher effectiveness for piperacillin-tazobactam

The primary analysis included 379 patients (mean age 67 years, 48% were women), and the primary outcome analysis included 378 patients.

A total of 23 (12.3%) of 187 patients in the piperacillin-tazobactam group died by 30 days compared to 7 (3.7%) of 191 in the meropenem group (risk difference: 8.6%, P = .90 for noninferiority).

By day 4, 68% of the piperacillin-tazobactam group and 75% of the meropenem group achieved clinical and microbiological resolution.

Serious adverse effects other than death were rare, occurring in around 3% of the piperacillin-tazobactam group and nearly 2% of the meropenem group.

The researchers note various limitations, including the unblinded nature of the study and the fact that it’s not known if extended or continuous infusions of piperacillin-tazobactam would boost the drug’s effectiveness. They also note that delays resulted in some patients initially receiving treatment with one of the study’s two drugs before being randomized to the other.

The study authors caution that it’s not clear if newer beta-lactam/beta-lactamase inhibitors agents such as ceftolozane-tazobactam or ceftazidime-avibactam may be effective in this population.

The study was funded by the University of Queensland, Australian Society for Antimicrobials, International Society for Chemotherapy, and National University Hospital Singapore. Various organizations funded the researchers and the study’s whole-genome sequencing. The study authors report various disclosures, including funding from drugmakers such as Pfizer, maker of Zosyn (through its subsidiary Wyeth) and Merrem.
 

SOURCE: Harris PNA et al. JAMA 2018 Sep 11;320[10]:984-94. doi: 10.1001/jama.2018.12163.

A new study finds that piperacillin-tazobactam doesn’t improve mortality compared to meropenem in patients with ceftriaxone-resistant blood poisoning caused by E. coli or K. pneumoniae. The findings were so striking that the study was ended early.

Vidyard Video

Courtesy: JAMA

“These findings do not support use of piperacillin-tazobactam in this setting,” wrote the authors. The report was published Sept. 11 in JAMA (2018;320[10]:984-94.)

According to the Centers for Disease Control and Prevention, an estimated 1,700 deaths in the United States in 2011 were caused by gram-negative bacteria that produce extended-spectrum beta-lactamase enzymes.

While carbapenems such as meropenem (Merrem) are “regarded as the treatment of choice for serious infections,” the MERINO trial (NCT02176122) authors wrote, their rising use could lead to drug resistance.

One alternate option is to embrace beta-lactam/beta-lactamase inhibitors such as piperacillin-tazobactam (Zosyn), the researchers noted, but research has produced conflicting results.

Piperacillin-tazobactam is an injected penicillin antibiotic used to treat conditions such as severe pneumonia, complicated urinary tract infections and complicated skin and soft tissue infections.

For the new study, researchers led by Patrick N. A. Harris, MBBS, of the University of Queensland, randomly assigned 188 patients to intravenous piperacillin-tazobactam (4.5 g every 6 hours) and 191 patients to meropenem (1 g every 8 hours) for 4-14 days, depending on clinician’s preference. (12 other patients did not continue with the study after initial randomization due to factors such as errors).

All patients were adults and had at least one blood test showing they were positive for E. coli or K. pneumoniae. They all had to be nonsusceptible to ceftriaxone (Rocephin) but susceptible to piperacillin-tazobactam.

The study was ceased prior to enrollment because of the risk of harm. Interim findings suggested the study was unlikely to show higher effectiveness for piperacillin-tazobactam

The primary analysis included 379 patients (mean age 67 years, 48% were women), and the primary outcome analysis included 378 patients.

A total of 23 (12.3%) of 187 patients in the piperacillin-tazobactam group died by 30 days compared to 7 (3.7%) of 191 in the meropenem group (risk difference: 8.6%, P = .90 for noninferiority).

By day 4, 68% of the piperacillin-tazobactam group and 75% of the meropenem group achieved clinical and microbiological resolution.

Serious adverse effects other than death were rare, occurring in around 3% of the piperacillin-tazobactam group and nearly 2% of the meropenem group.

The researchers note various limitations, including the unblinded nature of the study and the fact that it’s not known if extended or continuous infusions of piperacillin-tazobactam would boost the drug’s effectiveness. They also note that delays resulted in some patients initially receiving treatment with one of the study’s two drugs before being randomized to the other.

The study authors caution that it’s not clear if newer beta-lactam/beta-lactamase inhibitors agents such as ceftolozane-tazobactam or ceftazidime-avibactam may be effective in this population.

The study was funded by the University of Queensland, Australian Society for Antimicrobials, International Society for Chemotherapy, and National University Hospital Singapore. Various organizations funded the researchers and the study’s whole-genome sequencing. The study authors report various disclosures, including funding from drugmakers such as Pfizer, maker of Zosyn (through its subsidiary Wyeth) and Merrem.
 

SOURCE: Harris PNA et al. JAMA 2018 Sep 11;320[10]:984-94. doi: 10.1001/jama.2018.12163.

A new study finds that piperacillin-tazobactam doesn’t improve mortality compared to meropenem in patients with ceftriaxone-resistant blood poisoning caused by E. coli or K. pneumoniae. The findings were so striking that the study was ended early.

Vidyard Video

Courtesy: JAMA

“These findings do not support use of piperacillin-tazobactam in this setting,” wrote the authors. The report was published Sept. 11 in JAMA (2018;320[10]:984-94.)

According to the Centers for Disease Control and Prevention, an estimated 1,700 deaths in the United States in 2011 were caused by gram-negative bacteria that produce extended-spectrum beta-lactamase enzymes.

While carbapenems such as meropenem (Merrem) are “regarded as the treatment of choice for serious infections,” the MERINO trial (NCT02176122) authors wrote, their rising use could lead to drug resistance.

One alternate option is to embrace beta-lactam/beta-lactamase inhibitors such as piperacillin-tazobactam (Zosyn), the researchers noted, but research has produced conflicting results.

Piperacillin-tazobactam is an injected penicillin antibiotic used to treat conditions such as severe pneumonia, complicated urinary tract infections and complicated skin and soft tissue infections.

For the new study, researchers led by Patrick N. A. Harris, MBBS, of the University of Queensland, randomly assigned 188 patients to intravenous piperacillin-tazobactam (4.5 g every 6 hours) and 191 patients to meropenem (1 g every 8 hours) for 4-14 days, depending on clinician’s preference. (12 other patients did not continue with the study after initial randomization due to factors such as errors).

All patients were adults and had at least one blood test showing they were positive for E. coli or K. pneumoniae. They all had to be nonsusceptible to ceftriaxone (Rocephin) but susceptible to piperacillin-tazobactam.

The study was ceased prior to enrollment because of the risk of harm. Interim findings suggested the study was unlikely to show higher effectiveness for piperacillin-tazobactam

The primary analysis included 379 patients (mean age 67 years, 48% were women), and the primary outcome analysis included 378 patients.

A total of 23 (12.3%) of 187 patients in the piperacillin-tazobactam group died by 30 days compared to 7 (3.7%) of 191 in the meropenem group (risk difference: 8.6%, P = .90 for noninferiority).

By day 4, 68% of the piperacillin-tazobactam group and 75% of the meropenem group achieved clinical and microbiological resolution.

Serious adverse effects other than death were rare, occurring in around 3% of the piperacillin-tazobactam group and nearly 2% of the meropenem group.

The researchers note various limitations, including the unblinded nature of the study and the fact that it’s not known if extended or continuous infusions of piperacillin-tazobactam would boost the drug’s effectiveness. They also note that delays resulted in some patients initially receiving treatment with one of the study’s two drugs before being randomized to the other.

The study authors caution that it’s not clear if newer beta-lactam/beta-lactamase inhibitors agents such as ceftolozane-tazobactam or ceftazidime-avibactam may be effective in this population.

The study was funded by the University of Queensland, Australian Society for Antimicrobials, International Society for Chemotherapy, and National University Hospital Singapore. Various organizations funded the researchers and the study’s whole-genome sequencing. The study authors report various disclosures, including funding from drugmakers such as Pfizer, maker of Zosyn (through its subsidiary Wyeth) and Merrem.
 

SOURCE: Harris PNA et al. JAMA 2018 Sep 11;320[10]:984-94. doi: 10.1001/jama.2018.12163.

Don’t miss the CHEST Annual Meeting 2018 in San Antonio, Oct 6-10. Watch as CHEST 2018 Program Chair David A. Schulman, MD, MPH, FCCP, walks you through the vision of this year’s meeting. View complete details at chestmeeting.chestnet.org.

Don’t miss the CHEST Annual Meeting 2018 in San Antonio, Oct 6-10. Watch as CHEST 2018 Program Chair David A. Schulman, MD, MPH, FCCP, walks you through the vision of this year’s meeting. View complete details at chestmeeting.chestnet.org.

Don’t miss the CHEST Annual Meeting 2018 in San Antonio, Oct 6-10. Watch as CHEST 2018 Program Chair David A. Schulman, MD, MPH, FCCP, walks you through the vision of this year’s meeting. View complete details at chestmeeting.chestnet.org.

Once-daily treatment with the oral second-generation thrombopoietin agonist avatrombopag (Doptelet) significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures, according to the results of two international, randomized, double-blind, phase III, placebo-controlled trials reported in the September issue of Gastroenterology.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia, versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group, versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).

These results led the Food and Drug Administration to approve avatrombopag in May 2018 under its priority review process. The novel therapy “may be a safe and effective alternative to platelet transfusions” that could simplify the clinical management of patients with chronic liver disease and thrombocytopenia, Norah Terrault, MD, MPH, and her associates wrote in Gastroenterology.

The ADAPT-1 study included 231 patients, while ADAPT-2 included 204 patients. In each trial, patients were randomized on a 2:1 basis to receive oral avatrombopag or placebo once daily for 5 consecutive days. Patients in the intervention arms received 60 mg avatrombopag if their baseline platelet count was less than 40 x 10⁹ per liter, and 40 mg if their baseline platelet count was 40-50 x 10⁹ per liter. Procedures were scheduled for 10-13 days after treatment initiation.

“Platelet counts increased by [treatment] day 4, peaked at days 10-13, and then returned to baseline levels by day 35,” the researchers reported. Among ADAPT-1 patients with low baseline counts, 69% of avatrombopag recipients reached a prespecified target of at least 50 x 10⁹ platelets per liter on their procedure day, versus 4% of placebo recipients (P less than .0001). Corresponding proportions in ADAPT-2 were 67% and 7%, respectively (P less than .0001). Among patients with higher baseline counts, 88% and 20% achieved the target, respectively, in ADAPT-1 (P less than .0001), as did 93% versus 39%, respectively, in ADAPT-2 (P less than .0001).

Avatrombopag and placebo produced similar rates of treatment-emergent adverse events. These most often consisted of abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache. Only three avatrombopag patients developed platelet counts above 200 x 10⁹ per liter, and they all remained asymptomatic, the investigators said.

Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.

SOURCE: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.

Once-daily treatment with the oral second-generation thrombopoietin agonist avatrombopag (Doptelet) significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures, according to the results of two international, randomized, double-blind, phase III, placebo-controlled trials reported in the September issue of Gastroenterology.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia, versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group, versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).

These results led the Food and Drug Administration to approve avatrombopag in May 2018 under its priority review process. The novel therapy “may be a safe and effective alternative to platelet transfusions” that could simplify the clinical management of patients with chronic liver disease and thrombocytopenia, Norah Terrault, MD, MPH, and her associates wrote in Gastroenterology.

The ADAPT-1 study included 231 patients, while ADAPT-2 included 204 patients. In each trial, patients were randomized on a 2:1 basis to receive oral avatrombopag or placebo once daily for 5 consecutive days. Patients in the intervention arms received 60 mg avatrombopag if their baseline platelet count was less than 40 x 10⁹ per liter, and 40 mg if their baseline platelet count was 40-50 x 10⁹ per liter. Procedures were scheduled for 10-13 days after treatment initiation.

“Platelet counts increased by [treatment] day 4, peaked at days 10-13, and then returned to baseline levels by day 35,” the researchers reported. Among ADAPT-1 patients with low baseline counts, 69% of avatrombopag recipients reached a prespecified target of at least 50 x 10⁹ platelets per liter on their procedure day, versus 4% of placebo recipients (P less than .0001). Corresponding proportions in ADAPT-2 were 67% and 7%, respectively (P less than .0001). Among patients with higher baseline counts, 88% and 20% achieved the target, respectively, in ADAPT-1 (P less than .0001), as did 93% versus 39%, respectively, in ADAPT-2 (P less than .0001).

Avatrombopag and placebo produced similar rates of treatment-emergent adverse events. These most often consisted of abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache. Only three avatrombopag patients developed platelet counts above 200 x 10⁹ per liter, and they all remained asymptomatic, the investigators said.

Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.

SOURCE: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.

Once-daily treatment with the oral second-generation thrombopoietin agonist avatrombopag (Doptelet) significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures, according to the results of two international, randomized, double-blind, phase III, placebo-controlled trials reported in the September issue of Gastroenterology.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia, versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group, versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).

These results led the Food and Drug Administration to approve avatrombopag in May 2018 under its priority review process. The novel therapy “may be a safe and effective alternative to platelet transfusions” that could simplify the clinical management of patients with chronic liver disease and thrombocytopenia, Norah Terrault, MD, MPH, and her associates wrote in Gastroenterology.

The ADAPT-1 study included 231 patients, while ADAPT-2 included 204 patients. In each trial, patients were randomized on a 2:1 basis to receive oral avatrombopag or placebo once daily for 5 consecutive days. Patients in the intervention arms received 60 mg avatrombopag if their baseline platelet count was less than 40 x 10⁹ per liter, and 40 mg if their baseline platelet count was 40-50 x 10⁹ per liter. Procedures were scheduled for 10-13 days after treatment initiation.

“Platelet counts increased by [treatment] day 4, peaked at days 10-13, and then returned to baseline levels by day 35,” the researchers reported. Among ADAPT-1 patients with low baseline counts, 69% of avatrombopag recipients reached a prespecified target of at least 50 x 10⁹ platelets per liter on their procedure day, versus 4% of placebo recipients (P less than .0001). Corresponding proportions in ADAPT-2 were 67% and 7%, respectively (P less than .0001). Among patients with higher baseline counts, 88% and 20% achieved the target, respectively, in ADAPT-1 (P less than .0001), as did 93% versus 39%, respectively, in ADAPT-2 (P less than .0001).

Avatrombopag and placebo produced similar rates of treatment-emergent adverse events. These most often consisted of abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache. Only three avatrombopag patients developed platelet counts above 200 x 10⁹ per liter, and they all remained asymptomatic, the investigators said.

Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.

SOURCE: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.

MUNICH – In a double blow to the current, widespread routine use of low-dose aspirin and fish oil supplements for primary cardiovascular prevention in patients with diabetes, neither treatment provided any net clinical benefit in the massive, long-term ASCEND study, investigators reported at the annual congress of the European Society of Cardiology.

And, in yet another bitter pill to swallow, low-dose aspirin failed to reduce the incidence of GI cancer or any other type of cancer, compared with placebo in the study. Earlier, nondefinitive meta-analyses of much smaller randomized trials had raised the possibility of a roughly 30% reduction in the incidence of colorectal cancer in long-time users, said Jane Armitage, MD, professor of clinical trials and epidemiology at the University of Oxford (England).

“We saw no suggestion of an anticancer effect emerging over time,” Dr. Armitage said. “We did see a significant reduction in the risk of vascular events but also an increase in major bleeding such that the absolute benefits from avoiding a serious vascular event were largely counterbalanced by increased risk of bleeding. And there was no subgroup in which we could clearly define that the benefit outweighs the risk,” she added in a video interview.

ASCEND (A Study of Cardiovascular Events in Diabetes) was a randomized, blinded trial in which 15,480 U.K. patients with diabetes and no known cardiovascular disease were placed on 100 mg/day of enteric-coated aspirin or placebo and 1 g/day of omega-3 fatty acids in capsule form or placebo in a 2 x 2 factorial design and followed prospectively for a mean of 7.4 years.

The study was undertaken because, even though the value of low-dose aspirin for secondary prevention is supported by strong evidence, the medication’s value for primary prevention in patients with diabetes has long been uncertain. American Diabetes Association guidelines give a Grade C recommendation to consideration of low-dose aspirin as a primary prevention strategy in patients with diabetes having a 10-year cardiovascular risk estimated at 10% or greater.

The primary efficacy endpoint in ASCEND was the occurrence of a first serious vascular event, defined as MI, stroke, transient ischemic attack, or death from any vascular cause other than intracranial hemorrhage. The rate was 8.5% in the aspirin group and 9.6% with placebo, for a statistically significant 12% relative risk reduction. However, the rate of the primary composite safety endpoint, comprising intracranial hemorrhage, GI bleeding, sight-threatening bleeding in the eye, or other bleeding serious enough to entail a trip to the hospital, was 4.1% in the aspirin group and 3.2% with placebo, a 29% increase in risk.

Aspirin reduced the absolute risk of a serious vascular event by 1.1%, compared with placebo, while boosting the risk of major bleeding by an absolute 0.9% – essentially a wash. The number needed to treat to avoid a serious vascular event was 91 patients, with 112 being the number needed to cause a major bleeding event. The risk of major bleeding rose with increasing baseline 5-year vascular event risk.

ASCEND provided no support for a recent report suggesting the benefit of low-dose aspirin for cardioprotection is largely confined to individuals weighing less than 70 kg (Lancet. 2018; 392:387-99); in fact, the opposite appeared to be true, according to Dr. Armitage.

The incidence of cancer of the GI tract was 2.0% in both study arms. The overall cancer rate was 11.6% in the aspirin arm and 11.5% with placebo. Additional follow-up focused on cancer is planned for 5 and 10 years after the end of ASCEND in order to examine the possibility of a delayed anticancer effect, she added.

Dr. Armitage said one reason aspirin may have failed to show a significant net benefit was the high rate of background cardioprotective medication usage, especially statins and antihypertensive drugs.

“I think if your diabetes is well managed and you’ve got your other risk factors under control, you have to consider very carefully whether or not, for you, the benefits of aspirin outweigh the risks,” she concluded.

Cardiologists respond

ASCEND’s two designated discussants, both cardiologists, took a more positive view of the results than Dr. Armitage, who isn’t a cardiologist.

Bruce Jancin/MDedge News

Sigrun Halvorsen, MD, professor of cardiology at the University of Oslo, noted that most ASCEND participants were at relatively low cardiovascular risk, with an event rate of about 1.3% per year. She indicated that she’d like to see more data on higher-risk individuals before excluding any role for aspirin in primary cardiovascular prevention in patients with diabetes.

“Serious vascular events and bleeding are not necessarily equally weighted,” she added. “Most major bleeds in ASCEND were GI bleeds, and these can be largely prevented by PPIs [proton pump inhibitors], in contrast to death and stroke, which are irreversible events.”

“I think this study could be interpreted more favorably,” agreed Christopher P. Cannon, MD, professor of medicine at Harvard Medical School, Boston. “Bleeds are reversible, but MIs and whatnot are not.”

Fish oil flounders in ASCEND

Bruce Jancin/MDedge News

Louise Bowman, MD, also at the University of Oxford, presented the ASCEND fish oil findings. Over an average of 7.4 years, omega-3 fatty acid supplementation had no effect on the rate of serious vascular events, no effect on cancer, no impact on all-cause or cause-specific mortality, and raised no safety issues in patients with diabetes. She argued that current guidelines recommending fish oil supplements for cardiovascular prevention should be reconsidered.

“Certainly there doesn’t seem to be any justification for the use of this dose of omega-3 fatty acids – 1 g/day – for the prevention of cardiovascular disease,” Dr. Bowman said.

However, Dr. Cannon saw a sliver of hope within the ASCEND findings. One component of the serious vascular event composite endpoint – vascular death – occurred in 2.4% of the fish oil group and 2.9% of placebo-treated controls, for a statistically significant 19% relative risk reduction. It could be a fluke, given that none of the other vascular endpoints followed suit. But physicians and patients won’t have to wait long to find out. Another randomized trial of low-dose fish oil supplements for primary cardiovascular prevention – the nearly 26,000-patient VITAL trial – is due to report later in 2018.

In addition, two major, randomized trials of higher-dose fish oil supplementation for secondary prevention are ongoing. The roughly 8,000-patient REDUCE-IT trial is expected to report results later this year, and the STRENGTH trial, featuring more than 13,000 patients, should be completed in 2020. Both studies are heavily loaded with diabetes patients, Dr. Cannon noted.

Simultaneous with presentation of the ASCEND results at the ESC congress, the study was published online at the New England Journal of Medicine website (doi: 10.1056/NEJMoa1804988 and doi: 10.1056/NEJMoa1804989).

The ASCEND study was funded by the British Heart Foundation and the U.K. Medical Research Council with support provided by Abbott Laboratories, Bayer, Mylan, and Solvay. Dr. Armitage and Dr. Bowman reported receiving research grants from the Medicines Company, Bayer, and Mylan. Dr. Halvorsen reported no financial conflicts. Dr. Cannon reported serving as a consultant to roughly a dozen pharmaceutical companies, including the Amarin Corporation, which markets a fish oil supplement and sponsored the REDUCE-IT trial.

[email protected]

MUNICH – In a double blow to the current, widespread routine use of low-dose aspirin and fish oil supplements for primary cardiovascular prevention in patients with diabetes, neither treatment provided any net clinical benefit in the massive, long-term ASCEND study, investigators reported at the annual congress of the European Society of Cardiology.

And, in yet another bitter pill to swallow, low-dose aspirin failed to reduce the incidence of GI cancer or any other type of cancer, compared with placebo in the study. Earlier, nondefinitive meta-analyses of much smaller randomized trials had raised the possibility of a roughly 30% reduction in the incidence of colorectal cancer in long-time users, said Jane Armitage, MD, professor of clinical trials and epidemiology at the University of Oxford (England).

“We saw no suggestion of an anticancer effect emerging over time,” Dr. Armitage said. “We did see a significant reduction in the risk of vascular events but also an increase in major bleeding such that the absolute benefits from avoiding a serious vascular event were largely counterbalanced by increased risk of bleeding. And there was no subgroup in which we could clearly define that the benefit outweighs the risk,” she added in a video interview.

ASCEND (A Study of Cardiovascular Events in Diabetes) was a randomized, blinded trial in which 15,480 U.K. patients with diabetes and no known cardiovascular disease were placed on 100 mg/day of enteric-coated aspirin or placebo and 1 g/day of omega-3 fatty acids in capsule form or placebo in a 2 x 2 factorial design and followed prospectively for a mean of 7.4 years.

The study was undertaken because, even though the value of low-dose aspirin for secondary prevention is supported by strong evidence, the medication’s value for primary prevention in patients with diabetes has long been uncertain. American Diabetes Association guidelines give a Grade C recommendation to consideration of low-dose aspirin as a primary prevention strategy in patients with diabetes having a 10-year cardiovascular risk estimated at 10% or greater.

The primary efficacy endpoint in ASCEND was the occurrence of a first serious vascular event, defined as MI, stroke, transient ischemic attack, or death from any vascular cause other than intracranial hemorrhage. The rate was 8.5% in the aspirin group and 9.6% with placebo, for a statistically significant 12% relative risk reduction. However, the rate of the primary composite safety endpoint, comprising intracranial hemorrhage, GI bleeding, sight-threatening bleeding in the eye, or other bleeding serious enough to entail a trip to the hospital, was 4.1% in the aspirin group and 3.2% with placebo, a 29% increase in risk.

Aspirin reduced the absolute risk of a serious vascular event by 1.1%, compared with placebo, while boosting the risk of major bleeding by an absolute 0.9% – essentially a wash. The number needed to treat to avoid a serious vascular event was 91 patients, with 112 being the number needed to cause a major bleeding event. The risk of major bleeding rose with increasing baseline 5-year vascular event risk.

ASCEND provided no support for a recent report suggesting the benefit of low-dose aspirin for cardioprotection is largely confined to individuals weighing less than 70 kg (Lancet. 2018; 392:387-99); in fact, the opposite appeared to be true, according to Dr. Armitage.

The incidence of cancer of the GI tract was 2.0% in both study arms. The overall cancer rate was 11.6% in the aspirin arm and 11.5% with placebo. Additional follow-up focused on cancer is planned for 5 and 10 years after the end of ASCEND in order to examine the possibility of a delayed anticancer effect, she added.

Dr. Armitage said one reason aspirin may have failed to show a significant net benefit was the high rate of background cardioprotective medication usage, especially statins and antihypertensive drugs.

“I think if your diabetes is well managed and you’ve got your other risk factors under control, you have to consider very carefully whether or not, for you, the benefits of aspirin outweigh the risks,” she concluded.

Cardiologists respond

ASCEND’s two designated discussants, both cardiologists, took a more positive view of the results than Dr. Armitage, who isn’t a cardiologist.

Bruce Jancin/MDedge News

Sigrun Halvorsen, MD, professor of cardiology at the University of Oslo, noted that most ASCEND participants were at relatively low cardiovascular risk, with an event rate of about 1.3% per year. She indicated that she’d like to see more data on higher-risk individuals before excluding any role for aspirin in primary cardiovascular prevention in patients with diabetes.

“Serious vascular events and bleeding are not necessarily equally weighted,” she added. “Most major bleeds in ASCEND were GI bleeds, and these can be largely prevented by PPIs [proton pump inhibitors], in contrast to death and stroke, which are irreversible events.”

“I think this study could be interpreted more favorably,” agreed Christopher P. Cannon, MD, professor of medicine at Harvard Medical School, Boston. “Bleeds are reversible, but MIs and whatnot are not.”

Fish oil flounders in ASCEND

Bruce Jancin/MDedge News

Louise Bowman, MD, also at the University of Oxford, presented the ASCEND fish oil findings. Over an average of 7.4 years, omega-3 fatty acid supplementation had no effect on the rate of serious vascular events, no effect on cancer, no impact on all-cause or cause-specific mortality, and raised no safety issues in patients with diabetes. She argued that current guidelines recommending fish oil supplements for cardiovascular prevention should be reconsidered.

“Certainly there doesn’t seem to be any justification for the use of this dose of omega-3 fatty acids – 1 g/day – for the prevention of cardiovascular disease,” Dr. Bowman said.

However, Dr. Cannon saw a sliver of hope within the ASCEND findings. One component of the serious vascular event composite endpoint – vascular death – occurred in 2.4% of the fish oil group and 2.9% of placebo-treated controls, for a statistically significant 19% relative risk reduction. It could be a fluke, given that none of the other vascular endpoints followed suit. But physicians and patients won’t have to wait long to find out. Another randomized trial of low-dose fish oil supplements for primary cardiovascular prevention – the nearly 26,000-patient VITAL trial – is due to report later in 2018.

In addition, two major, randomized trials of higher-dose fish oil supplementation for secondary prevention are ongoing. The roughly 8,000-patient REDUCE-IT trial is expected to report results later this year, and the STRENGTH trial, featuring more than 13,000 patients, should be completed in 2020. Both studies are heavily loaded with diabetes patients, Dr. Cannon noted.

Simultaneous with presentation of the ASCEND results at the ESC congress, the study was published online at the New England Journal of Medicine website (doi: 10.1056/NEJMoa1804988 and doi: 10.1056/NEJMoa1804989).

The ASCEND study was funded by the British Heart Foundation and the U.K. Medical Research Council with support provided by Abbott Laboratories, Bayer, Mylan, and Solvay. Dr. Armitage and Dr. Bowman reported receiving research grants from the Medicines Company, Bayer, and Mylan. Dr. Halvorsen reported no financial conflicts. Dr. Cannon reported serving as a consultant to roughly a dozen pharmaceutical companies, including the Amarin Corporation, which markets a fish oil supplement and sponsored the REDUCE-IT trial.

[email protected]

MUNICH – In a double blow to the current, widespread routine use of low-dose aspirin and fish oil supplements for primary cardiovascular prevention in patients with diabetes, neither treatment provided any net clinical benefit in the massive, long-term ASCEND study, investigators reported at the annual congress of the European Society of Cardiology.

And, in yet another bitter pill to swallow, low-dose aspirin failed to reduce the incidence of GI cancer or any other type of cancer, compared with placebo in the study. Earlier, nondefinitive meta-analyses of much smaller randomized trials had raised the possibility of a roughly 30% reduction in the incidence of colorectal cancer in long-time users, said Jane Armitage, MD, professor of clinical trials and epidemiology at the University of Oxford (England).

“We saw no suggestion of an anticancer effect emerging over time,” Dr. Armitage said. “We did see a significant reduction in the risk of vascular events but also an increase in major bleeding such that the absolute benefits from avoiding a serious vascular event were largely counterbalanced by increased risk of bleeding. And there was no subgroup in which we could clearly define that the benefit outweighs the risk,” she added in a video interview.

ASCEND (A Study of Cardiovascular Events in Diabetes) was a randomized, blinded trial in which 15,480 U.K. patients with diabetes and no known cardiovascular disease were placed on 100 mg/day of enteric-coated aspirin or placebo and 1 g/day of omega-3 fatty acids in capsule form or placebo in a 2 x 2 factorial design and followed prospectively for a mean of 7.4 years.

The study was undertaken because, even though the value of low-dose aspirin for secondary prevention is supported by strong evidence, the medication’s value for primary prevention in patients with diabetes has long been uncertain. American Diabetes Association guidelines give a Grade C recommendation to consideration of low-dose aspirin as a primary prevention strategy in patients with diabetes having a 10-year cardiovascular risk estimated at 10% or greater.

The primary efficacy endpoint in ASCEND was the occurrence of a first serious vascular event, defined as MI, stroke, transient ischemic attack, or death from any vascular cause other than intracranial hemorrhage. The rate was 8.5% in the aspirin group and 9.6% with placebo, for a statistically significant 12% relative risk reduction. However, the rate of the primary composite safety endpoint, comprising intracranial hemorrhage, GI bleeding, sight-threatening bleeding in the eye, or other bleeding serious enough to entail a trip to the hospital, was 4.1% in the aspirin group and 3.2% with placebo, a 29% increase in risk.

Aspirin reduced the absolute risk of a serious vascular event by 1.1%, compared with placebo, while boosting the risk of major bleeding by an absolute 0.9% – essentially a wash. The number needed to treat to avoid a serious vascular event was 91 patients, with 112 being the number needed to cause a major bleeding event. The risk of major bleeding rose with increasing baseline 5-year vascular event risk.

ASCEND provided no support for a recent report suggesting the benefit of low-dose aspirin for cardioprotection is largely confined to individuals weighing less than 70 kg (Lancet. 2018; 392:387-99); in fact, the opposite appeared to be true, according to Dr. Armitage.

The incidence of cancer of the GI tract was 2.0% in both study arms. The overall cancer rate was 11.6% in the aspirin arm and 11.5% with placebo. Additional follow-up focused on cancer is planned for 5 and 10 years after the end of ASCEND in order to examine the possibility of a delayed anticancer effect, she added.

Dr. Armitage said one reason aspirin may have failed to show a significant net benefit was the high rate of background cardioprotective medication usage, especially statins and antihypertensive drugs.

“I think if your diabetes is well managed and you’ve got your other risk factors under control, you have to consider very carefully whether or not, for you, the benefits of aspirin outweigh the risks,” she concluded.

Cardiologists respond

ASCEND’s two designated discussants, both cardiologists, took a more positive view of the results than Dr. Armitage, who isn’t a cardiologist.

Bruce Jancin/MDedge News

Sigrun Halvorsen, MD, professor of cardiology at the University of Oslo, noted that most ASCEND participants were at relatively low cardiovascular risk, with an event rate of about 1.3% per year. She indicated that she’d like to see more data on higher-risk individuals before excluding any role for aspirin in primary cardiovascular prevention in patients with diabetes.

“Serious vascular events and bleeding are not necessarily equally weighted,” she added. “Most major bleeds in ASCEND were GI bleeds, and these can be largely prevented by PPIs [proton pump inhibitors], in contrast to death and stroke, which are irreversible events.”

“I think this study could be interpreted more favorably,” agreed Christopher P. Cannon, MD, professor of medicine at Harvard Medical School, Boston. “Bleeds are reversible, but MIs and whatnot are not.”

Fish oil flounders in ASCEND

Bruce Jancin/MDedge News

Louise Bowman, MD, also at the University of Oxford, presented the ASCEND fish oil findings. Over an average of 7.4 years, omega-3 fatty acid supplementation had no effect on the rate of serious vascular events, no effect on cancer, no impact on all-cause or cause-specific mortality, and raised no safety issues in patients with diabetes. She argued that current guidelines recommending fish oil supplements for cardiovascular prevention should be reconsidered.

“Certainly there doesn’t seem to be any justification for the use of this dose of omega-3 fatty acids – 1 g/day – for the prevention of cardiovascular disease,” Dr. Bowman said.

However, Dr. Cannon saw a sliver of hope within the ASCEND findings. One component of the serious vascular event composite endpoint – vascular death – occurred in 2.4% of the fish oil group and 2.9% of placebo-treated controls, for a statistically significant 19% relative risk reduction. It could be a fluke, given that none of the other vascular endpoints followed suit. But physicians and patients won’t have to wait long to find out. Another randomized trial of low-dose fish oil supplements for primary cardiovascular prevention – the nearly 26,000-patient VITAL trial – is due to report later in 2018.

In addition, two major, randomized trials of higher-dose fish oil supplementation for secondary prevention are ongoing. The roughly 8,000-patient REDUCE-IT trial is expected to report results later this year, and the STRENGTH trial, featuring more than 13,000 patients, should be completed in 2020. Both studies are heavily loaded with diabetes patients, Dr. Cannon noted.

Simultaneous with presentation of the ASCEND results at the ESC congress, the study was published online at the New England Journal of Medicine website (doi: 10.1056/NEJMoa1804988 and doi: 10.1056/NEJMoa1804989).

The ASCEND study was funded by the British Heart Foundation and the U.K. Medical Research Council with support provided by Abbott Laboratories, Bayer, Mylan, and Solvay. Dr. Armitage and Dr. Bowman reported receiving research grants from the Medicines Company, Bayer, and Mylan. Dr. Halvorsen reported no financial conflicts. Dr. Cannon reported serving as a consultant to roughly a dozen pharmaceutical companies, including the Amarin Corporation, which markets a fish oil supplement and sponsored the REDUCE-IT trial.

[email protected]

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”   

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

[email protected]

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”   

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

[email protected]

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”   

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

[email protected]

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

The AGA Obesity Practice Guide provides physicians with a comprehensive, multi-disciplinary process to guide and personalize innovative obesity care for safe and effective weight management. Learn more at https://www.gastro.org/practice-guidance/practice-updates/obesity-practice-guide.

[email protected]

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

The AGA Obesity Practice Guide provides physicians with a comprehensive, multi-disciplinary process to guide and personalize innovative obesity care for safe and effective weight management. Learn more at https://www.gastro.org/practice-guidance/practice-updates/obesity-practice-guide.

[email protected]

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

The AGA Obesity Practice Guide provides physicians with a comprehensive, multi-disciplinary process to guide and personalize innovative obesity care for safe and effective weight management. Learn more at https://www.gastro.org/practice-guidance/practice-updates/obesity-practice-guide.

[email protected]

AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.

The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.

Mitchel L. Zoler/MDedge News

Rise of the INSTIs

The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.

Mitchel L. Zoler/MDedge News

Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).

Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.

Mitchel L. Zoler/MDedge News

One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.

Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.

The NTD data

The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.

Mitchel L. Zoler/MDedge News

A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).

When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.

During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.

Modeling the risks and benefits

Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.

Mitchel L. Zoler/MDedge News

The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.

Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”

“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.

The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.

Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”

Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
 

[email protected]

AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.

The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.

Mitchel L. Zoler/MDedge News

Rise of the INSTIs

The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.

Mitchel L. Zoler/MDedge News

Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).

Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.

Mitchel L. Zoler/MDedge News

One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.

Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.

The NTD data

The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.

Mitchel L. Zoler/MDedge News

A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).

When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.

During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.

Modeling the risks and benefits

Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.

Mitchel L. Zoler/MDedge News

The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.

Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”

“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.

The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.

Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”

Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
 

[email protected]

AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.

The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.

Mitchel L. Zoler/MDedge News

Rise of the INSTIs

The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.

Mitchel L. Zoler/MDedge News

Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).

Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.

Mitchel L. Zoler/MDedge News

One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.

Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.

The NTD data

The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.

Mitchel L. Zoler/MDedge News

A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).

When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.

During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.

Modeling the risks and benefits

Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.

Mitchel L. Zoler/MDedge News

The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.

Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”

“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.

The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.

Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”

Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
 

[email protected]