Mitchel L. Zoler, PhD

WASHINGTON – Although severe, community-acquired sepsis in previously healthy U.S. adults is relatively uncommon, it occurs often enough to strike about 40,000 people annually, and when previously healthy people are hospitalized for severe sepsis, their rate of in-hospital mortality was double the rate in people with one or more comorbidities who have severe, community-acquired sepsis, based on a review of almost 7 million Americans hospitalized for sepsis.

The findings “underscore the importance of improving public awareness of sepsis and emphasizing early sepsis recognition and treatment in all patients,” including those without comorbidities, Chanu Rhee, MD, said at an annual scientific meeting on infectious diseases. He hypothesized that the increased sepsis mortality among previously healthy patients may have stemmed from factors such as delayed sepsis recognition resulting in hospitalization at a more advanced stage and less aggressive management.

In addition, “the findings provide context for high-profile reports about sepsis death in previously healthy people,” said Dr. Rhee, an infectious diseases and critical care physician at Brigham and Women’s Hospital in Boston. Dr. Rhee and associates found that, among patients hospitalized with what the researchers defined as “community-acquired” sepsis, 3% were judged previously healthy by having no identified major or minor comorbidity or pregnancy at the time of hospitalization, a percentage that – while small – still translates into roughly 40,000 such cases annually in the United States. That helps explain why every so often a headline appears about a famous person who died suddenly and unexpectedly from sepsis, he noted.

The study used data collected on hospitalized U.S. patients in the Cerner Health Facts, HCA Healthcare, and Institute for Health Metrics and Evaluation databases, which included about 6.7 million people total including 337,983 identified as having community-acquired sepsis, defined as patients who met the criteria for adult sepsis advanced by the Centers for Disease Control and Prevention within 2 days of their hospital admission. The researchers looked further into the hospital records of these patients and divided them into patients with one or more major comorbidities (96% of the cohort), patients who were pregnant or had a “minor” comorbidity such as a lipid disorder, benign neoplasm, or obesity (1% of the study group), or those with no chronic comorbidity (3%; the subgroup the researchers deemed previously healthy).

In a multivariate analysis that adjusted for patients’ age, sex, race, infection site, and illness severity at the time of hospital admission the researchers found that the rate of in-hospital death among the previously healthy patients was exactly twice the rate of those who had at least one major chronic comorbidity, Dr. Rhee reported. Differences in the treatment received by the previously-healthy patients or in their medical status compared with patients with a major comorbidity suggested that the previously health patients were sicker. They had a higher rate of mechanical ventilation, 30%, compared with about 18% for those with a comorbidity; a higher rate of acute kidney injury, about 43% in those previously healthy and 28% in those with a comorbidity; and a higher percentage had an elevated lactate level, about 41% among the previously healthy patients and about 22% among those with a comorbidity.

[email protected]

SOURCE: Alrawashdeh M et al. Open Forum Infect Dis. 2019 Oct 23;6. Abstract 891.

WASHINGTON – Although severe, community-acquired sepsis in previously healthy U.S. adults is relatively uncommon, it occurs often enough to strike about 40,000 people annually, and when previously healthy people are hospitalized for severe sepsis, their rate of in-hospital mortality was double the rate in people with one or more comorbidities who have severe, community-acquired sepsis, based on a review of almost 7 million Americans hospitalized for sepsis.

The findings “underscore the importance of improving public awareness of sepsis and emphasizing early sepsis recognition and treatment in all patients,” including those without comorbidities, Chanu Rhee, MD, said at an annual scientific meeting on infectious diseases. He hypothesized that the increased sepsis mortality among previously healthy patients may have stemmed from factors such as delayed sepsis recognition resulting in hospitalization at a more advanced stage and less aggressive management.

In addition, “the findings provide context for high-profile reports about sepsis death in previously healthy people,” said Dr. Rhee, an infectious diseases and critical care physician at Brigham and Women’s Hospital in Boston. Dr. Rhee and associates found that, among patients hospitalized with what the researchers defined as “community-acquired” sepsis, 3% were judged previously healthy by having no identified major or minor comorbidity or pregnancy at the time of hospitalization, a percentage that – while small – still translates into roughly 40,000 such cases annually in the United States. That helps explain why every so often a headline appears about a famous person who died suddenly and unexpectedly from sepsis, he noted.

The study used data collected on hospitalized U.S. patients in the Cerner Health Facts, HCA Healthcare, and Institute for Health Metrics and Evaluation databases, which included about 6.7 million people total including 337,983 identified as having community-acquired sepsis, defined as patients who met the criteria for adult sepsis advanced by the Centers for Disease Control and Prevention within 2 days of their hospital admission. The researchers looked further into the hospital records of these patients and divided them into patients with one or more major comorbidities (96% of the cohort), patients who were pregnant or had a “minor” comorbidity such as a lipid disorder, benign neoplasm, or obesity (1% of the study group), or those with no chronic comorbidity (3%; the subgroup the researchers deemed previously healthy).

In a multivariate analysis that adjusted for patients’ age, sex, race, infection site, and illness severity at the time of hospital admission the researchers found that the rate of in-hospital death among the previously healthy patients was exactly twice the rate of those who had at least one major chronic comorbidity, Dr. Rhee reported. Differences in the treatment received by the previously-healthy patients or in their medical status compared with patients with a major comorbidity suggested that the previously health patients were sicker. They had a higher rate of mechanical ventilation, 30%, compared with about 18% for those with a comorbidity; a higher rate of acute kidney injury, about 43% in those previously healthy and 28% in those with a comorbidity; and a higher percentage had an elevated lactate level, about 41% among the previously healthy patients and about 22% among those with a comorbidity.

[email protected]

SOURCE: Alrawashdeh M et al. Open Forum Infect Dis. 2019 Oct 23;6. Abstract 891.

WASHINGTON – Although severe, community-acquired sepsis in previously healthy U.S. adults is relatively uncommon, it occurs often enough to strike about 40,000 people annually, and when previously healthy people are hospitalized for severe sepsis, their rate of in-hospital mortality was double the rate in people with one or more comorbidities who have severe, community-acquired sepsis, based on a review of almost 7 million Americans hospitalized for sepsis.

The findings “underscore the importance of improving public awareness of sepsis and emphasizing early sepsis recognition and treatment in all patients,” including those without comorbidities, Chanu Rhee, MD, said at an annual scientific meeting on infectious diseases. He hypothesized that the increased sepsis mortality among previously healthy patients may have stemmed from factors such as delayed sepsis recognition resulting in hospitalization at a more advanced stage and less aggressive management.

In addition, “the findings provide context for high-profile reports about sepsis death in previously healthy people,” said Dr. Rhee, an infectious diseases and critical care physician at Brigham and Women’s Hospital in Boston. Dr. Rhee and associates found that, among patients hospitalized with what the researchers defined as “community-acquired” sepsis, 3% were judged previously healthy by having no identified major or minor comorbidity or pregnancy at the time of hospitalization, a percentage that – while small – still translates into roughly 40,000 such cases annually in the United States. That helps explain why every so often a headline appears about a famous person who died suddenly and unexpectedly from sepsis, he noted.

The study used data collected on hospitalized U.S. patients in the Cerner Health Facts, HCA Healthcare, and Institute for Health Metrics and Evaluation databases, which included about 6.7 million people total including 337,983 identified as having community-acquired sepsis, defined as patients who met the criteria for adult sepsis advanced by the Centers for Disease Control and Prevention within 2 days of their hospital admission. The researchers looked further into the hospital records of these patients and divided them into patients with one or more major comorbidities (96% of the cohort), patients who were pregnant or had a “minor” comorbidity such as a lipid disorder, benign neoplasm, or obesity (1% of the study group), or those with no chronic comorbidity (3%; the subgroup the researchers deemed previously healthy).

In a multivariate analysis that adjusted for patients’ age, sex, race, infection site, and illness severity at the time of hospital admission the researchers found that the rate of in-hospital death among the previously healthy patients was exactly twice the rate of those who had at least one major chronic comorbidity, Dr. Rhee reported. Differences in the treatment received by the previously-healthy patients or in their medical status compared with patients with a major comorbidity suggested that the previously health patients were sicker. They had a higher rate of mechanical ventilation, 30%, compared with about 18% for those with a comorbidity; a higher rate of acute kidney injury, about 43% in those previously healthy and 28% in those with a comorbidity; and a higher percentage had an elevated lactate level, about 41% among the previously healthy patients and about 22% among those with a comorbidity.

[email protected]

SOURCE: Alrawashdeh M et al. Open Forum Infect Dis. 2019 Oct 23;6. Abstract 891.

PARIS – The primary endpoint of PARAGON-HF was neutral in patients with heart failure with preserved ejection fraction, but that didn’t stop some experts from seeing a practice-changing message in its findings.

Mitchel L. Zoler/MDedge News

The results of PARAGON-HF, a major trial of sacubitril/valsartan – a compound already approved for treating heart failure with reduced left ventricular ejection fraction – in patients with heart failure with preserved ejection fraction (HFpEF), showed a statistically neutral result for the study’s primary endpoint, but with an excruciatingly close near miss for statistical significance and clear benefit in a subgroup of HFpEF patients with a modestly reduced left ventricular ejection fraction. These findings seemed to convince some experts to soon try using sacubitril/valsartan (Entresto) to treat selected patients with HFpEF, driven in large part by the lack of any other agent clearly proven to benefit the large number of patients with this form of heart failure.

HFpEF is “a huge unmet need,” and data from the PARAGON-HF trial “suggest that sacubitril/valsartan may be beneficial in some patients with HFpEF, particularly those with a left ventricular ejection fraction that is not frankly reduced, but less than normal,” specifically patients with a left ventricular ejection fraction of 45%-57%, Scott D. Solomon, MD, said at the annual congress of the European Society of Cardiology as he reported the primary PARAGON-HF results.

“I’m not speaking for regulators or for guidelines, but I suspect that in this group of patients [with HFpEF and a left ventricular ejection fraction of 45%-57%] there is at least some rationale to use this treatment,” said Dr. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, both in Boston.

His suggestion, which cut against the standard rules that govern the interpretation of trial results, met a substantial level of receptivity at the congress.

Trial results “are not black and white, where a P value of .049 means the trial was totally positive, and a P of .051 means it’s totally neutral. That’s misleading, and it’s why the field is moving to different types of [statistical] analysis that give us more leeway in interpreting data,” commented Philippe Gabriel Steg, MD, professor of cardiology at the University of Paris.

“Everything in this trial points to substantial potential benefit. I’m not impressed by the P value that just missed significance. I think this is a very important advance,” said Dr. Steg, who had no involvement in the study, during a press conference at the congress.

Mitchel L. Zoler/MDedge News

“I agree. I look at the totality of evidence, and to me the PARAGON-HF results were positive in patients with an ejection fraction of 50%, which is not a normal level. The way I interpret the results is, the treatment works in patients with an ejection fraction that is ‘lowish,’ but not at the conventional level of reduced ejection fraction,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School, who also had no involvement with PARAGON-HF.

Stuart J. Connolly, MD, designated discussant for the report at the congress and professor of medicine at McMaster University, Hamilton, Ont., struck similar notes during his discussion of the report, and called the subgroup analysis by baseline ejection fraction “compelling,” and supported by several secondary findings of the study, the biological plausibility of a link between ejection fraction and treatment response, and by suggestions of a similar effect caused by related drugs in prior studies.

The argument in favor of sacubitril/valsartan’s efficacy in a subgroup of PARAGON-HF patients was also taken up by Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas. “I think it’s legitimate to say that there are HFpEF subgroups that might benefit” from sacubitril/valsartan, such as women. “I think it’s appropriate in this disease to look at subgroups because we have to find something that works for these patients,” she added in a video interview.

But Dr. Jessup also urged caution in interpreting the link between modestly reduced ejection fraction and response to sacubitril/valsartan in HFpEF patients because ejection fraction measurements by echocardiography, as done in the trial, are notoriously unreliable. “We need more precise markers of who responds to this drug and who does not,” she said.

PARAGON-HF randomized 4,796 patients at 848 sites in 43 countries who were aged at least 50 years, had signs and symptoms of heart failure with a left ventricular ejection fraction of at least 45%, had evidence on echocardiography of either left atrial enlargement or left ventricular hypertrophy, and had an elevated blood level of natriuretic peptides.

The study’s primary endpoint was the composite rate of total (both first and recurrent) hospitalizations for heart failure and cardiovascular death. That outcome occurred at a rate of 12.8 events/100 patient-years in patients treated with sacubitril/valsartan and a rate of 14.6 events/100 patient-years in control patients treated with the angiotensin receptor blocking drug valsartan alone. Those results yielded a relative risk reduction by sacubitril/valsartan of 13% with a P value of .059, just missing statistical significance. Concurrently with Dr. Solomon’s report the results appeared in an article online and then subsequently in print (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The primary endpoint was driven primarily by a 15% relative risk reduction in hospitalizations for heart failure; the two treatment arms showed nearly identical rates of cardiovascular disease death.

Notable secondary findings that reached statistical significance included a 16% relative decrease in total heart failure hospitalizations, cardiovascular deaths, and urgent heart failure visits with sacubitril/valsartan treatment, as well as a 16% reduction in all investigator-reported events. Other significant benefits linked with sacubitril/valsartan treatment were a 45% relative improvement in functional class, a 30% relative improvement in patients achieving a meaningful increase in a quality of life measure, and a halving of the incidence of worsening renal function with sacubitril/valsartan.

The safety profile of sacubitril/valsartan in the study matched previous reports on the drug in patients with heart failure with reduced ejection fraction, an approved indication since 2015.

The key subgroup analysis detailed by Dr. Solomon was the incidence of the primary endpoint by baseline ejection fraction. Among the 2,495 patients (52% of the study population) with a left ventricular ejection fraction of 57% or less when they entered the study, treatment with sacubitril/valsartan cut the primary endpoint incidence by 22%, compared with valsartan alone, a statistically significant difference. Among patients with a baseline ejection fraction of 58% or greater, treatment with sacubitril/valsartan had no effect on the primary endpoint, compared with control patients. Dr. Solomon also reported a statistically significant 22% relative improvement in the primary endpoint among the 2,479 women in the study (52% of the total study cohort) while the drug had no discernible impact among men, but he did not highlight any immediate implication of this finding.

Despite how suggestive the finding related to ejection fraction may be for practice, a major impediment to prescribing sacubitril/valsartan to HFpEF patients may come from pharmacy managers, suggested Douglas L. Mann, MD, a heart failure specialist and professor of medicine at Washington University, St. Louis.

“The study did not hit its primary endpoint, so pharmacy managers will face no moral issue by withholding the drug” from HFpEF patients, Dr. Mann said in an interview. Because sacubitril/valsartan is substantially costlier than other renin-angiotensin system inhibitor drugs, which are mostly generic, patients may often find it difficult to pay for sacubitril/valsartan themselves if it receives no insurance coverage.

“It’s heartbreaking that the endpoint missed for a disease with no proven treatment. The study may have narrowly missed, but it still missed, and a lot of us had hoped it would be positive. It’s a slippery slope” when investigators try to qualify a trial result that failed to meet the study’s prespecified definition of a statistically significant effect. “The primary endpoint is the primary endpoint, and we should not overinterpret the data,” Dr. Mann warned.

PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). Dr. Solomon has been a consultant to and has received research funding from Novartis and from several other companies. Dr. Steg has received personal fees from Novartis and has received personal fees and research funding from several other companies. Dr. Bhatt has been a consultant to and received research funding from several companies but has had no recent relationship with Novartis. Dr. Connolly and Dr. Jessup had no disclosures. Dr. Mann has been a consultant to Novartis, as well as Bristol-Myers Squibb, LivaNova, and Tenaya Therapeutics.

[email protected]

PARIS – The primary endpoint of PARAGON-HF was neutral in patients with heart failure with preserved ejection fraction, but that didn’t stop some experts from seeing a practice-changing message in its findings.

Mitchel L. Zoler/MDedge News

The results of PARAGON-HF, a major trial of sacubitril/valsartan – a compound already approved for treating heart failure with reduced left ventricular ejection fraction – in patients with heart failure with preserved ejection fraction (HFpEF), showed a statistically neutral result for the study’s primary endpoint, but with an excruciatingly close near miss for statistical significance and clear benefit in a subgroup of HFpEF patients with a modestly reduced left ventricular ejection fraction. These findings seemed to convince some experts to soon try using sacubitril/valsartan (Entresto) to treat selected patients with HFpEF, driven in large part by the lack of any other agent clearly proven to benefit the large number of patients with this form of heart failure.

HFpEF is “a huge unmet need,” and data from the PARAGON-HF trial “suggest that sacubitril/valsartan may be beneficial in some patients with HFpEF, particularly those with a left ventricular ejection fraction that is not frankly reduced, but less than normal,” specifically patients with a left ventricular ejection fraction of 45%-57%, Scott D. Solomon, MD, said at the annual congress of the European Society of Cardiology as he reported the primary PARAGON-HF results.

“I’m not speaking for regulators or for guidelines, but I suspect that in this group of patients [with HFpEF and a left ventricular ejection fraction of 45%-57%] there is at least some rationale to use this treatment,” said Dr. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, both in Boston.

His suggestion, which cut against the standard rules that govern the interpretation of trial results, met a substantial level of receptivity at the congress.

Trial results “are not black and white, where a P value of .049 means the trial was totally positive, and a P of .051 means it’s totally neutral. That’s misleading, and it’s why the field is moving to different types of [statistical] analysis that give us more leeway in interpreting data,” commented Philippe Gabriel Steg, MD, professor of cardiology at the University of Paris.

“Everything in this trial points to substantial potential benefit. I’m not impressed by the P value that just missed significance. I think this is a very important advance,” said Dr. Steg, who had no involvement in the study, during a press conference at the congress.

Mitchel L. Zoler/MDedge News

“I agree. I look at the totality of evidence, and to me the PARAGON-HF results were positive in patients with an ejection fraction of 50%, which is not a normal level. The way I interpret the results is, the treatment works in patients with an ejection fraction that is ‘lowish,’ but not at the conventional level of reduced ejection fraction,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School, who also had no involvement with PARAGON-HF.

Stuart J. Connolly, MD, designated discussant for the report at the congress and professor of medicine at McMaster University, Hamilton, Ont., struck similar notes during his discussion of the report, and called the subgroup analysis by baseline ejection fraction “compelling,” and supported by several secondary findings of the study, the biological plausibility of a link between ejection fraction and treatment response, and by suggestions of a similar effect caused by related drugs in prior studies.

The argument in favor of sacubitril/valsartan’s efficacy in a subgroup of PARAGON-HF patients was also taken up by Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas. “I think it’s legitimate to say that there are HFpEF subgroups that might benefit” from sacubitril/valsartan, such as women. “I think it’s appropriate in this disease to look at subgroups because we have to find something that works for these patients,” she added in a video interview.

But Dr. Jessup also urged caution in interpreting the link between modestly reduced ejection fraction and response to sacubitril/valsartan in HFpEF patients because ejection fraction measurements by echocardiography, as done in the trial, are notoriously unreliable. “We need more precise markers of who responds to this drug and who does not,” she said.

PARAGON-HF randomized 4,796 patients at 848 sites in 43 countries who were aged at least 50 years, had signs and symptoms of heart failure with a left ventricular ejection fraction of at least 45%, had evidence on echocardiography of either left atrial enlargement or left ventricular hypertrophy, and had an elevated blood level of natriuretic peptides.

The study’s primary endpoint was the composite rate of total (both first and recurrent) hospitalizations for heart failure and cardiovascular death. That outcome occurred at a rate of 12.8 events/100 patient-years in patients treated with sacubitril/valsartan and a rate of 14.6 events/100 patient-years in control patients treated with the angiotensin receptor blocking drug valsartan alone. Those results yielded a relative risk reduction by sacubitril/valsartan of 13% with a P value of .059, just missing statistical significance. Concurrently with Dr. Solomon’s report the results appeared in an article online and then subsequently in print (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The primary endpoint was driven primarily by a 15% relative risk reduction in hospitalizations for heart failure; the two treatment arms showed nearly identical rates of cardiovascular disease death.

Notable secondary findings that reached statistical significance included a 16% relative decrease in total heart failure hospitalizations, cardiovascular deaths, and urgent heart failure visits with sacubitril/valsartan treatment, as well as a 16% reduction in all investigator-reported events. Other significant benefits linked with sacubitril/valsartan treatment were a 45% relative improvement in functional class, a 30% relative improvement in patients achieving a meaningful increase in a quality of life measure, and a halving of the incidence of worsening renal function with sacubitril/valsartan.

The safety profile of sacubitril/valsartan in the study matched previous reports on the drug in patients with heart failure with reduced ejection fraction, an approved indication since 2015.

The key subgroup analysis detailed by Dr. Solomon was the incidence of the primary endpoint by baseline ejection fraction. Among the 2,495 patients (52% of the study population) with a left ventricular ejection fraction of 57% or less when they entered the study, treatment with sacubitril/valsartan cut the primary endpoint incidence by 22%, compared with valsartan alone, a statistically significant difference. Among patients with a baseline ejection fraction of 58% or greater, treatment with sacubitril/valsartan had no effect on the primary endpoint, compared with control patients. Dr. Solomon also reported a statistically significant 22% relative improvement in the primary endpoint among the 2,479 women in the study (52% of the total study cohort) while the drug had no discernible impact among men, but he did not highlight any immediate implication of this finding.

Despite how suggestive the finding related to ejection fraction may be for practice, a major impediment to prescribing sacubitril/valsartan to HFpEF patients may come from pharmacy managers, suggested Douglas L. Mann, MD, a heart failure specialist and professor of medicine at Washington University, St. Louis.

“The study did not hit its primary endpoint, so pharmacy managers will face no moral issue by withholding the drug” from HFpEF patients, Dr. Mann said in an interview. Because sacubitril/valsartan is substantially costlier than other renin-angiotensin system inhibitor drugs, which are mostly generic, patients may often find it difficult to pay for sacubitril/valsartan themselves if it receives no insurance coverage.

“It’s heartbreaking that the endpoint missed for a disease with no proven treatment. The study may have narrowly missed, but it still missed, and a lot of us had hoped it would be positive. It’s a slippery slope” when investigators try to qualify a trial result that failed to meet the study’s prespecified definition of a statistically significant effect. “The primary endpoint is the primary endpoint, and we should not overinterpret the data,” Dr. Mann warned.

PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). Dr. Solomon has been a consultant to and has received research funding from Novartis and from several other companies. Dr. Steg has received personal fees from Novartis and has received personal fees and research funding from several other companies. Dr. Bhatt has been a consultant to and received research funding from several companies but has had no recent relationship with Novartis. Dr. Connolly and Dr. Jessup had no disclosures. Dr. Mann has been a consultant to Novartis, as well as Bristol-Myers Squibb, LivaNova, and Tenaya Therapeutics.

[email protected]

PARIS – The primary endpoint of PARAGON-HF was neutral in patients with heart failure with preserved ejection fraction, but that didn’t stop some experts from seeing a practice-changing message in its findings.

Mitchel L. Zoler/MDedge News

The results of PARAGON-HF, a major trial of sacubitril/valsartan – a compound already approved for treating heart failure with reduced left ventricular ejection fraction – in patients with heart failure with preserved ejection fraction (HFpEF), showed a statistically neutral result for the study’s primary endpoint, but with an excruciatingly close near miss for statistical significance and clear benefit in a subgroup of HFpEF patients with a modestly reduced left ventricular ejection fraction. These findings seemed to convince some experts to soon try using sacubitril/valsartan (Entresto) to treat selected patients with HFpEF, driven in large part by the lack of any other agent clearly proven to benefit the large number of patients with this form of heart failure.

HFpEF is “a huge unmet need,” and data from the PARAGON-HF trial “suggest that sacubitril/valsartan may be beneficial in some patients with HFpEF, particularly those with a left ventricular ejection fraction that is not frankly reduced, but less than normal,” specifically patients with a left ventricular ejection fraction of 45%-57%, Scott D. Solomon, MD, said at the annual congress of the European Society of Cardiology as he reported the primary PARAGON-HF results.

“I’m not speaking for regulators or for guidelines, but I suspect that in this group of patients [with HFpEF and a left ventricular ejection fraction of 45%-57%] there is at least some rationale to use this treatment,” said Dr. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, both in Boston.

His suggestion, which cut against the standard rules that govern the interpretation of trial results, met a substantial level of receptivity at the congress.

Trial results “are not black and white, where a P value of .049 means the trial was totally positive, and a P of .051 means it’s totally neutral. That’s misleading, and it’s why the field is moving to different types of [statistical] analysis that give us more leeway in interpreting data,” commented Philippe Gabriel Steg, MD, professor of cardiology at the University of Paris.

“Everything in this trial points to substantial potential benefit. I’m not impressed by the P value that just missed significance. I think this is a very important advance,” said Dr. Steg, who had no involvement in the study, during a press conference at the congress.

Mitchel L. Zoler/MDedge News

“I agree. I look at the totality of evidence, and to me the PARAGON-HF results were positive in patients with an ejection fraction of 50%, which is not a normal level. The way I interpret the results is, the treatment works in patients with an ejection fraction that is ‘lowish,’ but not at the conventional level of reduced ejection fraction,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School, who also had no involvement with PARAGON-HF.

Stuart J. Connolly, MD, designated discussant for the report at the congress and professor of medicine at McMaster University, Hamilton, Ont., struck similar notes during his discussion of the report, and called the subgroup analysis by baseline ejection fraction “compelling,” and supported by several secondary findings of the study, the biological plausibility of a link between ejection fraction and treatment response, and by suggestions of a similar effect caused by related drugs in prior studies.

The argument in favor of sacubitril/valsartan’s efficacy in a subgroup of PARAGON-HF patients was also taken up by Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas. “I think it’s legitimate to say that there are HFpEF subgroups that might benefit” from sacubitril/valsartan, such as women. “I think it’s appropriate in this disease to look at subgroups because we have to find something that works for these patients,” she added in a video interview.

But Dr. Jessup also urged caution in interpreting the link between modestly reduced ejection fraction and response to sacubitril/valsartan in HFpEF patients because ejection fraction measurements by echocardiography, as done in the trial, are notoriously unreliable. “We need more precise markers of who responds to this drug and who does not,” she said.

PARAGON-HF randomized 4,796 patients at 848 sites in 43 countries who were aged at least 50 years, had signs and symptoms of heart failure with a left ventricular ejection fraction of at least 45%, had evidence on echocardiography of either left atrial enlargement or left ventricular hypertrophy, and had an elevated blood level of natriuretic peptides.

The study’s primary endpoint was the composite rate of total (both first and recurrent) hospitalizations for heart failure and cardiovascular death. That outcome occurred at a rate of 12.8 events/100 patient-years in patients treated with sacubitril/valsartan and a rate of 14.6 events/100 patient-years in control patients treated with the angiotensin receptor blocking drug valsartan alone. Those results yielded a relative risk reduction by sacubitril/valsartan of 13% with a P value of .059, just missing statistical significance. Concurrently with Dr. Solomon’s report the results appeared in an article online and then subsequently in print (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The primary endpoint was driven primarily by a 15% relative risk reduction in hospitalizations for heart failure; the two treatment arms showed nearly identical rates of cardiovascular disease death.

Notable secondary findings that reached statistical significance included a 16% relative decrease in total heart failure hospitalizations, cardiovascular deaths, and urgent heart failure visits with sacubitril/valsartan treatment, as well as a 16% reduction in all investigator-reported events. Other significant benefits linked with sacubitril/valsartan treatment were a 45% relative improvement in functional class, a 30% relative improvement in patients achieving a meaningful increase in a quality of life measure, and a halving of the incidence of worsening renal function with sacubitril/valsartan.

The safety profile of sacubitril/valsartan in the study matched previous reports on the drug in patients with heart failure with reduced ejection fraction, an approved indication since 2015.

The key subgroup analysis detailed by Dr. Solomon was the incidence of the primary endpoint by baseline ejection fraction. Among the 2,495 patients (52% of the study population) with a left ventricular ejection fraction of 57% or less when they entered the study, treatment with sacubitril/valsartan cut the primary endpoint incidence by 22%, compared with valsartan alone, a statistically significant difference. Among patients with a baseline ejection fraction of 58% or greater, treatment with sacubitril/valsartan had no effect on the primary endpoint, compared with control patients. Dr. Solomon also reported a statistically significant 22% relative improvement in the primary endpoint among the 2,479 women in the study (52% of the total study cohort) while the drug had no discernible impact among men, but he did not highlight any immediate implication of this finding.

Despite how suggestive the finding related to ejection fraction may be for practice, a major impediment to prescribing sacubitril/valsartan to HFpEF patients may come from pharmacy managers, suggested Douglas L. Mann, MD, a heart failure specialist and professor of medicine at Washington University, St. Louis.

“The study did not hit its primary endpoint, so pharmacy managers will face no moral issue by withholding the drug” from HFpEF patients, Dr. Mann said in an interview. Because sacubitril/valsartan is substantially costlier than other renin-angiotensin system inhibitor drugs, which are mostly generic, patients may often find it difficult to pay for sacubitril/valsartan themselves if it receives no insurance coverage.

“It’s heartbreaking that the endpoint missed for a disease with no proven treatment. The study may have narrowly missed, but it still missed, and a lot of us had hoped it would be positive. It’s a slippery slope” when investigators try to qualify a trial result that failed to meet the study’s prespecified definition of a statistically significant effect. “The primary endpoint is the primary endpoint, and we should not overinterpret the data,” Dr. Mann warned.

PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). Dr. Solomon has been a consultant to and has received research funding from Novartis and from several other companies. Dr. Steg has received personal fees from Novartis and has received personal fees and research funding from several other companies. Dr. Bhatt has been a consultant to and received research funding from several companies but has had no recent relationship with Novartis. Dr. Connolly and Dr. Jessup had no disclosures. Dr. Mann has been a consultant to Novartis, as well as Bristol-Myers Squibb, LivaNova, and Tenaya Therapeutics.

[email protected]

WASHINGTON – People may differ in their susceptibility to different influenza subtypes based in part on the year when they were born and the flu strains that circulated during their birth year, according to infection patterns during a recent U.S. flu season.

“Our findings may indicate protection against H1 [influenza] viruses in age groups with early exposure to H1N1pdm09 during the 2009 pandemic or to older, antigenically similar H1N1 viruses,” Shikha Garg, MD, said at an annual scientific meeting on infectious diseases. If results from further studies confirm this relationship it could have implications for flu vaccine effectiveness in various age groups and influence the composition of flu vaccines based on the ages of the people who will receive them, said Dr. Garg, a medical epidemiologist with the Centers for Disease Control and Prevention in Atlanta.

The analysis she reported using data collected by the CDC’s Influenza Hospitalization Surveillance Network on 18,699 people hospitalized for influenza infection during the 2018-2019 season, Oct. 1, 2018–April 30, 2019. The database provides a representative sampling of patients hospitalized for influenza at more than 250 acute care hospitals in 13 states. During the season studied, both the H1N1 and H3N2 subtypes circulated and caused similar cumulative rates of infections, with H1N1 causing about 32 confirmed cases per 100,000 people and H3N2 causing about 29 cases/100,000.

But a more granular analysis that divided the hospitalized patients by their birth year showed an excess of H1N1 infections in two demographic slices: those born during 2010-2019 (corresponding to children 0-9 years old), in whom H1N1 accounted for roughly 60% of cases; and also in those born during 1948-1995 (people aged 24-70 years old) in whom H1N1 caused roughly 70% or more of all infections in some for some birth-year groups in this demographic range. In contrast, infection with the circulating H3N2 strain in the 2018-2019 season dominated among those born during 1996-2009 (people aged 10-23), as well as in those born in 1947 or earlier (those who were at least 71 years old). Some age groups within those born in 1996-2009 had H3N2 infection rates that made up 70% or more of all flu infections, and among nonagenarians well over three-quarters of flu infection were by the H3N2 subtype.

Dr. Garg also showed a similar pattern of predominant flu subtype by age using U.S. influenza hospitalization data for the 2017-2018 season, as well as for all types of 2018-2019 U.S. influenza infections that underwent strain typing including outpatients as well as in patients. All of these findings support the hypothesis and extend the data published earlier this year by Dr. Garg and several of her CDC colleagues that described a pattern of “antigen imprinting” that appeared caused by influenza exposure during the first year of life (J Infect Dis. 2019 Sep 1;220[5]:820-9). However, more data are needed to better assess time trends for children who were first exposed to H1N1 influenza during the 2009 pandemic, Dr. Garg said.

[email protected]

SOURCE: Garg S. ID Week 2019, Abstract LB19.

WASHINGTON – People may differ in their susceptibility to different influenza subtypes based in part on the year when they were born and the flu strains that circulated during their birth year, according to infection patterns during a recent U.S. flu season.

“Our findings may indicate protection against H1 [influenza] viruses in age groups with early exposure to H1N1pdm09 during the 2009 pandemic or to older, antigenically similar H1N1 viruses,” Shikha Garg, MD, said at an annual scientific meeting on infectious diseases. If results from further studies confirm this relationship it could have implications for flu vaccine effectiveness in various age groups and influence the composition of flu vaccines based on the ages of the people who will receive them, said Dr. Garg, a medical epidemiologist with the Centers for Disease Control and Prevention in Atlanta.

The analysis she reported using data collected by the CDC’s Influenza Hospitalization Surveillance Network on 18,699 people hospitalized for influenza infection during the 2018-2019 season, Oct. 1, 2018–April 30, 2019. The database provides a representative sampling of patients hospitalized for influenza at more than 250 acute care hospitals in 13 states. During the season studied, both the H1N1 and H3N2 subtypes circulated and caused similar cumulative rates of infections, with H1N1 causing about 32 confirmed cases per 100,000 people and H3N2 causing about 29 cases/100,000.

But a more granular analysis that divided the hospitalized patients by their birth year showed an excess of H1N1 infections in two demographic slices: those born during 2010-2019 (corresponding to children 0-9 years old), in whom H1N1 accounted for roughly 60% of cases; and also in those born during 1948-1995 (people aged 24-70 years old) in whom H1N1 caused roughly 70% or more of all infections in some for some birth-year groups in this demographic range. In contrast, infection with the circulating H3N2 strain in the 2018-2019 season dominated among those born during 1996-2009 (people aged 10-23), as well as in those born in 1947 or earlier (those who were at least 71 years old). Some age groups within those born in 1996-2009 had H3N2 infection rates that made up 70% or more of all flu infections, and among nonagenarians well over three-quarters of flu infection were by the H3N2 subtype.

Dr. Garg also showed a similar pattern of predominant flu subtype by age using U.S. influenza hospitalization data for the 2017-2018 season, as well as for all types of 2018-2019 U.S. influenza infections that underwent strain typing including outpatients as well as in patients. All of these findings support the hypothesis and extend the data published earlier this year by Dr. Garg and several of her CDC colleagues that described a pattern of “antigen imprinting” that appeared caused by influenza exposure during the first year of life (J Infect Dis. 2019 Sep 1;220[5]:820-9). However, more data are needed to better assess time trends for children who were first exposed to H1N1 influenza during the 2009 pandemic, Dr. Garg said.

[email protected]

SOURCE: Garg S. ID Week 2019, Abstract LB19.

WASHINGTON – People may differ in their susceptibility to different influenza subtypes based in part on the year when they were born and the flu strains that circulated during their birth year, according to infection patterns during a recent U.S. flu season.

“Our findings may indicate protection against H1 [influenza] viruses in age groups with early exposure to H1N1pdm09 during the 2009 pandemic or to older, antigenically similar H1N1 viruses,” Shikha Garg, MD, said at an annual scientific meeting on infectious diseases. If results from further studies confirm this relationship it could have implications for flu vaccine effectiveness in various age groups and influence the composition of flu vaccines based on the ages of the people who will receive them, said Dr. Garg, a medical epidemiologist with the Centers for Disease Control and Prevention in Atlanta.

The analysis she reported using data collected by the CDC’s Influenza Hospitalization Surveillance Network on 18,699 people hospitalized for influenza infection during the 2018-2019 season, Oct. 1, 2018–April 30, 2019. The database provides a representative sampling of patients hospitalized for influenza at more than 250 acute care hospitals in 13 states. During the season studied, both the H1N1 and H3N2 subtypes circulated and caused similar cumulative rates of infections, with H1N1 causing about 32 confirmed cases per 100,000 people and H3N2 causing about 29 cases/100,000.

But a more granular analysis that divided the hospitalized patients by their birth year showed an excess of H1N1 infections in two demographic slices: those born during 2010-2019 (corresponding to children 0-9 years old), in whom H1N1 accounted for roughly 60% of cases; and also in those born during 1948-1995 (people aged 24-70 years old) in whom H1N1 caused roughly 70% or more of all infections in some for some birth-year groups in this demographic range. In contrast, infection with the circulating H3N2 strain in the 2018-2019 season dominated among those born during 1996-2009 (people aged 10-23), as well as in those born in 1947 or earlier (those who were at least 71 years old). Some age groups within those born in 1996-2009 had H3N2 infection rates that made up 70% or more of all flu infections, and among nonagenarians well over three-quarters of flu infection were by the H3N2 subtype.

Dr. Garg also showed a similar pattern of predominant flu subtype by age using U.S. influenza hospitalization data for the 2017-2018 season, as well as for all types of 2018-2019 U.S. influenza infections that underwent strain typing including outpatients as well as in patients. All of these findings support the hypothesis and extend the data published earlier this year by Dr. Garg and several of her CDC colleagues that described a pattern of “antigen imprinting” that appeared caused by influenza exposure during the first year of life (J Infect Dis. 2019 Sep 1;220[5]:820-9). However, more data are needed to better assess time trends for children who were first exposed to H1N1 influenza during the 2009 pandemic, Dr. Garg said.

[email protected]

SOURCE: Garg S. ID Week 2019, Abstract LB19.

Breast implants sold in the United States may soon require a boxed warning in their label, along with other label changes proposed by the Food and Drug Administration aimed at better informing prospective patients and clinicians of the potential risks from breast implants.

Mitchel L. Zoler/MDedge News

Other elements of the proposed labeling changes include creation of a patient-decision checklist, new recommendations for follow-up imaging to monitor for implant rupture, inclusion of detailed and understandable information about materials in the device, and provision of a device card to each patient with details on the specific implant they received.

These labeling changes all stemmed from a breast implant hearing held by the agency’s General and Plastic Surgery Devices Panel in March 2019, according to the draft guidance document officially released by the FDA on Oct. 24.

The proposed labeling changes were generally welcomed by patient advocates and by clinicians as a reasonable response to the concerns discussed at the March hearing. In an earlier move to address issues brought up at the hearing, the FDA in July arranged for a recall for certain Allergan models of textured breast implants because of their link with the development of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL).

The boxed warning proposed by the FDA would highlight four specific facts that patients, physicians, and surgeons should know about breast implants: They are not considered lifetime devices, the chance of developing complications from implants increases over time, some complications require additional surgery, and placement of breast implants has been associated with development of BIA-ALCL and may also be associated with certain systemic symptoms.

The FDA also proposed four other notable labeling changes:

• Creation of a patient-decision checklist to better systematize the informed consent process and make sure that certain aspects of breast implant placement are clearly brought to patients’ attention. The FDA proposed that patients sign their checklist attesting to having read and understood the information and that patients receive a take-home copy for their future reference. Proposed elements of the checklist include situations to not use breast implants; considerations for successful implant recipients; the risks of breast implant surgery; the importance of appropriate physician education, training, and experience; the risk for developing BIA-ALCL or systemic symptoms; and discussion of options other than breast implants.
• A new scheme for systematically and serially using imaging to screen for implant rupture that designates for the first time that ultrasound is an acceptable alternative to MRI and relies on a schedule by which either method initially screens the implant 5-6 years post operatively and then every 2 years thereafter.
• Detailed and understandable information about each material component of the implant with further information on possible adverse health effects of these compounds.
• A device card that patients should receive after their surgery with the implant’s name, serial number, and other identifiers; the boxed warning information; and a web link for accessing more up-to-date information.

The patient group Breast Implant Victim Advocacy praised the draft guidance. “The March Advisory Committee meeting seems to have prompted a shift by the FDA, surgeons, and industry,” said Jamee Cook, cofounder of the group. “We are definitely seeing a change in patient engagement. The FDA has been cooperating with patients and listening to our concerns. We still have a long way to go in raising public awareness of breast implant issues, but progress over the past 1-2 years has been amazing.”

Diana Zuckerman, PhD, president of the National Center for Health Research in Washington, gave the draft guidance a mixed review. “The FDA’s draft includes the types of information that we had proposed to the FDA in recent months in our work with patient advocates and plastic surgeons,” she said. “However, it is not as informative as it should be in describing well-designed studies indicating a risk of systemic illnesses. Patients deserve to make better-informed decisions in the future than most women considering breast implants have been able to make” in the past.

Patricia McGuire, MD, a St. Louis plastic surgeon who specializes in breast surgery and has studied breast implant illness, declared the guidance to be “reasonable.”

“I think the changes address the concerns expressed by patients during the [March] hearing; I agree with everything the FDA proposed in the guidance document,” Dr. McGuire said. “The boxed warning is reasonable and needs to be part of the informed consent process. I also agree with the changes in screening implants postoperatively. Most patients do not get MRI examinations. High-resolution ultrasound is more convenient and cost effective.”

The boxed warning was rated as “reasonably strong” and “the most serious step the FDA can take short of taking a device off the market,” but in the case of breast implants, a wider recall of textured implants than what the FDA arranged last July would be even more appropriate, commented Sidney M. Wolfe, MD, founder and senior adviser to Public Citizen. He also faulted the agency for not taking quicker action in mandating inclusion of the proposed boxed warning.

Issuing the labeling changes as draft guidance “is a ministep forward,” but also a process that “guarantees delay” and “creeps along at a dangerously slow pace,” Dr. Wolfe said. “The FDA is delaying what should be inevitable. The agency could put the boxed warning in place right now if they had the guts to do it.”

Dr. McGuire has been a consultant to Allergan, Establishment Labs, and Hans Biomed. Ms. Cook, Dr. Zuckerman, and Dr. Wolfe reported having no commercial disclosures.

[email protected]

Breast implants sold in the United States may soon require a boxed warning in their label, along with other label changes proposed by the Food and Drug Administration aimed at better informing prospective patients and clinicians of the potential risks from breast implants.

Mitchel L. Zoler/MDedge News

Other elements of the proposed labeling changes include creation of a patient-decision checklist, new recommendations for follow-up imaging to monitor for implant rupture, inclusion of detailed and understandable information about materials in the device, and provision of a device card to each patient with details on the specific implant they received.

These labeling changes all stemmed from a breast implant hearing held by the agency’s General and Plastic Surgery Devices Panel in March 2019, according to the draft guidance document officially released by the FDA on Oct. 24.

The proposed labeling changes were generally welcomed by patient advocates and by clinicians as a reasonable response to the concerns discussed at the March hearing. In an earlier move to address issues brought up at the hearing, the FDA in July arranged for a recall for certain Allergan models of textured breast implants because of their link with the development of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL).

The boxed warning proposed by the FDA would highlight four specific facts that patients, physicians, and surgeons should know about breast implants: They are not considered lifetime devices, the chance of developing complications from implants increases over time, some complications require additional surgery, and placement of breast implants has been associated with development of BIA-ALCL and may also be associated with certain systemic symptoms.

The FDA also proposed four other notable labeling changes:

• Creation of a patient-decision checklist to better systematize the informed consent process and make sure that certain aspects of breast implant placement are clearly brought to patients’ attention. The FDA proposed that patients sign their checklist attesting to having read and understood the information and that patients receive a take-home copy for their future reference. Proposed elements of the checklist include situations to not use breast implants; considerations for successful implant recipients; the risks of breast implant surgery; the importance of appropriate physician education, training, and experience; the risk for developing BIA-ALCL or systemic symptoms; and discussion of options other than breast implants.
• A new scheme for systematically and serially using imaging to screen for implant rupture that designates for the first time that ultrasound is an acceptable alternative to MRI and relies on a schedule by which either method initially screens the implant 5-6 years post operatively and then every 2 years thereafter.
• Detailed and understandable information about each material component of the implant with further information on possible adverse health effects of these compounds.
• A device card that patients should receive after their surgery with the implant’s name, serial number, and other identifiers; the boxed warning information; and a web link for accessing more up-to-date information.

The patient group Breast Implant Victim Advocacy praised the draft guidance. “The March Advisory Committee meeting seems to have prompted a shift by the FDA, surgeons, and industry,” said Jamee Cook, cofounder of the group. “We are definitely seeing a change in patient engagement. The FDA has been cooperating with patients and listening to our concerns. We still have a long way to go in raising public awareness of breast implant issues, but progress over the past 1-2 years has been amazing.”

Diana Zuckerman, PhD, president of the National Center for Health Research in Washington, gave the draft guidance a mixed review. “The FDA’s draft includes the types of information that we had proposed to the FDA in recent months in our work with patient advocates and plastic surgeons,” she said. “However, it is not as informative as it should be in describing well-designed studies indicating a risk of systemic illnesses. Patients deserve to make better-informed decisions in the future than most women considering breast implants have been able to make” in the past.

Patricia McGuire, MD, a St. Louis plastic surgeon who specializes in breast surgery and has studied breast implant illness, declared the guidance to be “reasonable.”

“I think the changes address the concerns expressed by patients during the [March] hearing; I agree with everything the FDA proposed in the guidance document,” Dr. McGuire said. “The boxed warning is reasonable and needs to be part of the informed consent process. I also agree with the changes in screening implants postoperatively. Most patients do not get MRI examinations. High-resolution ultrasound is more convenient and cost effective.”

The boxed warning was rated as “reasonably strong” and “the most serious step the FDA can take short of taking a device off the market,” but in the case of breast implants, a wider recall of textured implants than what the FDA arranged last July would be even more appropriate, commented Sidney M. Wolfe, MD, founder and senior adviser to Public Citizen. He also faulted the agency for not taking quicker action in mandating inclusion of the proposed boxed warning.

Issuing the labeling changes as draft guidance “is a ministep forward,” but also a process that “guarantees delay” and “creeps along at a dangerously slow pace,” Dr. Wolfe said. “The FDA is delaying what should be inevitable. The agency could put the boxed warning in place right now if they had the guts to do it.”

Dr. McGuire has been a consultant to Allergan, Establishment Labs, and Hans Biomed. Ms. Cook, Dr. Zuckerman, and Dr. Wolfe reported having no commercial disclosures.

[email protected]

Breast implants sold in the United States may soon require a boxed warning in their label, along with other label changes proposed by the Food and Drug Administration aimed at better informing prospective patients and clinicians of the potential risks from breast implants.

Mitchel L. Zoler/MDedge News

Other elements of the proposed labeling changes include creation of a patient-decision checklist, new recommendations for follow-up imaging to monitor for implant rupture, inclusion of detailed and understandable information about materials in the device, and provision of a device card to each patient with details on the specific implant they received.

These labeling changes all stemmed from a breast implant hearing held by the agency’s General and Plastic Surgery Devices Panel in March 2019, according to the draft guidance document officially released by the FDA on Oct. 24.

The proposed labeling changes were generally welcomed by patient advocates and by clinicians as a reasonable response to the concerns discussed at the March hearing. In an earlier move to address issues brought up at the hearing, the FDA in July arranged for a recall for certain Allergan models of textured breast implants because of their link with the development of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL).

The boxed warning proposed by the FDA would highlight four specific facts that patients, physicians, and surgeons should know about breast implants: They are not considered lifetime devices, the chance of developing complications from implants increases over time, some complications require additional surgery, and placement of breast implants has been associated with development of BIA-ALCL and may also be associated with certain systemic symptoms.

The FDA also proposed four other notable labeling changes:

• Creation of a patient-decision checklist to better systematize the informed consent process and make sure that certain aspects of breast implant placement are clearly brought to patients’ attention. The FDA proposed that patients sign their checklist attesting to having read and understood the information and that patients receive a take-home copy for their future reference. Proposed elements of the checklist include situations to not use breast implants; considerations for successful implant recipients; the risks of breast implant surgery; the importance of appropriate physician education, training, and experience; the risk for developing BIA-ALCL or systemic symptoms; and discussion of options other than breast implants.
• A new scheme for systematically and serially using imaging to screen for implant rupture that designates for the first time that ultrasound is an acceptable alternative to MRI and relies on a schedule by which either method initially screens the implant 5-6 years post operatively and then every 2 years thereafter.
• Detailed and understandable information about each material component of the implant with further information on possible adverse health effects of these compounds.
• A device card that patients should receive after their surgery with the implant’s name, serial number, and other identifiers; the boxed warning information; and a web link for accessing more up-to-date information.

The patient group Breast Implant Victim Advocacy praised the draft guidance. “The March Advisory Committee meeting seems to have prompted a shift by the FDA, surgeons, and industry,” said Jamee Cook, cofounder of the group. “We are definitely seeing a change in patient engagement. The FDA has been cooperating with patients and listening to our concerns. We still have a long way to go in raising public awareness of breast implant issues, but progress over the past 1-2 years has been amazing.”

Diana Zuckerman, PhD, president of the National Center for Health Research in Washington, gave the draft guidance a mixed review. “The FDA’s draft includes the types of information that we had proposed to the FDA in recent months in our work with patient advocates and plastic surgeons,” she said. “However, it is not as informative as it should be in describing well-designed studies indicating a risk of systemic illnesses. Patients deserve to make better-informed decisions in the future than most women considering breast implants have been able to make” in the past.

Patricia McGuire, MD, a St. Louis plastic surgeon who specializes in breast surgery and has studied breast implant illness, declared the guidance to be “reasonable.”

“I think the changes address the concerns expressed by patients during the [March] hearing; I agree with everything the FDA proposed in the guidance document,” Dr. McGuire said. “The boxed warning is reasonable and needs to be part of the informed consent process. I also agree with the changes in screening implants postoperatively. Most patients do not get MRI examinations. High-resolution ultrasound is more convenient and cost effective.”

The boxed warning was rated as “reasonably strong” and “the most serious step the FDA can take short of taking a device off the market,” but in the case of breast implants, a wider recall of textured implants than what the FDA arranged last July would be even more appropriate, commented Sidney M. Wolfe, MD, founder and senior adviser to Public Citizen. He also faulted the agency for not taking quicker action in mandating inclusion of the proposed boxed warning.

Issuing the labeling changes as draft guidance “is a ministep forward,” but also a process that “guarantees delay” and “creeps along at a dangerously slow pace,” Dr. Wolfe said. “The FDA is delaying what should be inevitable. The agency could put the boxed warning in place right now if they had the guts to do it.”

Dr. McGuire has been a consultant to Allergan, Establishment Labs, and Hans Biomed. Ms. Cook, Dr. Zuckerman, and Dr. Wolfe reported having no commercial disclosures.

[email protected]

WASHINGTON – A single dose of a novel monoclonal antibody against a respiratory syncytial virus surface protein safely protected preterm infants against severe infections for 150 days during their first winter season in a randomized trial with more than 1,400 children.

copyright DesignPics/Thinkstock

One intramuscular injection of nirsevimab (also known as MEDI8897) administered to infants born at 29-35 weeks’ gestation at the start of the local respiratory syncytial virus (RSV) season (November in the Northern hemisphere) led to a 70% relative reduction in the rate of medically attended lower respiratory tract infections with RSV during the subsequent 150 days, compared with placebo, the study’s primary efficacy outcome, M. Pamela Griffin, MD, said at an annual scientific meeting on infectious diseases.

In a secondary efficacy measure, the rate of hospitalizations for RSV-caused lower respiratory tract infections, a single injection of nirsevimab dropped the incidence by 78%, relative to placebo. Both effects were statistically significant. The rate of total adverse events and serious adverse events was similar in the two treatment arms, reported Dr. Griffin, a clinical development lead with AstraZeneca.

These positive results for a single intramuscular injection of nirsevimab are the first findings from a series of studies aimed at getting the monoclonal antibody onto the U.S. market as a superior alternative to palivizumab (Synagis), which acts in a similar way to block RSV infection (albeit by targeting a different viral surface protein) but which requires administration every 30 days. This need for serial dosing of palivizumab in children younger than 1 year old for complete seasonal protection against RSV is probably a reason why the American Academy of Pediatrics, as well as other medical societies, have targeted using palivizumab only on certain types of high-risk infants: those born before 29 weeks’ gestational age, with chronic lung disease of prematurity, or with hemodynamically significant congenital heart disease (Pediatrics. 2014 Aug;134[2]:415-20). “It’s not feasible for most infants to come for five treatments during RSV season,” Dr. Griffin noted. A tweak in the structure of nirsevimab gives it a much longer blood half-life than palivizumab and allows a single dose to maintain efficacy for 5 months, the duration of RSV season.

“The big advantage of nirsevimab is one dose instead of five,” she said in an interview.

The study randomized 969 preterm infants to nirsevimab and 484 to placebo when the children averaged 3 months old and 4.5 kg. The incidence of the primary endpoint was 2.6% in the nirsevimab-treated infants and 9.5% in those who received placebo. The incidence of hospitalizations associated with an RSV lower respiratory tract infection was 0.8% in the nirsevimab group and 4.1% on placebo. Nirsevimab was equally effective regardless of RSV subtype, infant age, or sex. The rate of hypersensitivity reactions was low, less than 1%, and similar in the two treatment arms, as was the rate of detection of antidrug antibody, 3.8% with placebo and 5.6% with nirsevimab.

Two other large trials are underway to document the performance of nirsevimab in other types of infants. One study is examining the drug’s performance compared with placebo in term infants with a gestational age of at least 36 weeks, while another is comparing nirsevimab against a five-dose regimen of palivizumab in high-risk infants who are recommended to receive palivizumab by local medical societies. In the United States, this would be infants born at less than 29 weeks’ gestation, and those with either hemodynamically significant congenital heart disease or chronic lung disease of prematurity. In these studies, the researchers also will assess the cost effectiveness of nirsevimab relative to the costs for medical care needed by infants who receive comparator treatments, Dr. Griffin said.

The study was funded by AstraZeneca, the company developing nirsevimab. Dr. Griffin is an employee of and shareholder in AstraZeneca.

[email protected]

SOURCE: ClinicalTrials.gov identifier: NCT02878330.

WASHINGTON – A single dose of a novel monoclonal antibody against a respiratory syncytial virus surface protein safely protected preterm infants against severe infections for 150 days during their first winter season in a randomized trial with more than 1,400 children.

copyright DesignPics/Thinkstock

One intramuscular injection of nirsevimab (also known as MEDI8897) administered to infants born at 29-35 weeks’ gestation at the start of the local respiratory syncytial virus (RSV) season (November in the Northern hemisphere) led to a 70% relative reduction in the rate of medically attended lower respiratory tract infections with RSV during the subsequent 150 days, compared with placebo, the study’s primary efficacy outcome, M. Pamela Griffin, MD, said at an annual scientific meeting on infectious diseases.

In a secondary efficacy measure, the rate of hospitalizations for RSV-caused lower respiratory tract infections, a single injection of nirsevimab dropped the incidence by 78%, relative to placebo. Both effects were statistically significant. The rate of total adverse events and serious adverse events was similar in the two treatment arms, reported Dr. Griffin, a clinical development lead with AstraZeneca.

These positive results for a single intramuscular injection of nirsevimab are the first findings from a series of studies aimed at getting the monoclonal antibody onto the U.S. market as a superior alternative to palivizumab (Synagis), which acts in a similar way to block RSV infection (albeit by targeting a different viral surface protein) but which requires administration every 30 days. This need for serial dosing of palivizumab in children younger than 1 year old for complete seasonal protection against RSV is probably a reason why the American Academy of Pediatrics, as well as other medical societies, have targeted using palivizumab only on certain types of high-risk infants: those born before 29 weeks’ gestational age, with chronic lung disease of prematurity, or with hemodynamically significant congenital heart disease (Pediatrics. 2014 Aug;134[2]:415-20). “It’s not feasible for most infants to come for five treatments during RSV season,” Dr. Griffin noted. A tweak in the structure of nirsevimab gives it a much longer blood half-life than palivizumab and allows a single dose to maintain efficacy for 5 months, the duration of RSV season.

“The big advantage of nirsevimab is one dose instead of five,” she said in an interview.

The study randomized 969 preterm infants to nirsevimab and 484 to placebo when the children averaged 3 months old and 4.5 kg. The incidence of the primary endpoint was 2.6% in the nirsevimab-treated infants and 9.5% in those who received placebo. The incidence of hospitalizations associated with an RSV lower respiratory tract infection was 0.8% in the nirsevimab group and 4.1% on placebo. Nirsevimab was equally effective regardless of RSV subtype, infant age, or sex. The rate of hypersensitivity reactions was low, less than 1%, and similar in the two treatment arms, as was the rate of detection of antidrug antibody, 3.8% with placebo and 5.6% with nirsevimab.

Two other large trials are underway to document the performance of nirsevimab in other types of infants. One study is examining the drug’s performance compared with placebo in term infants with a gestational age of at least 36 weeks, while another is comparing nirsevimab against a five-dose regimen of palivizumab in high-risk infants who are recommended to receive palivizumab by local medical societies. In the United States, this would be infants born at less than 29 weeks’ gestation, and those with either hemodynamically significant congenital heart disease or chronic lung disease of prematurity. In these studies, the researchers also will assess the cost effectiveness of nirsevimab relative to the costs for medical care needed by infants who receive comparator treatments, Dr. Griffin said.

The study was funded by AstraZeneca, the company developing nirsevimab. Dr. Griffin is an employee of and shareholder in AstraZeneca.

[email protected]

SOURCE: ClinicalTrials.gov identifier: NCT02878330.

WASHINGTON – A single dose of a novel monoclonal antibody against a respiratory syncytial virus surface protein safely protected preterm infants against severe infections for 150 days during their first winter season in a randomized trial with more than 1,400 children.

copyright DesignPics/Thinkstock

One intramuscular injection of nirsevimab (also known as MEDI8897) administered to infants born at 29-35 weeks’ gestation at the start of the local respiratory syncytial virus (RSV) season (November in the Northern hemisphere) led to a 70% relative reduction in the rate of medically attended lower respiratory tract infections with RSV during the subsequent 150 days, compared with placebo, the study’s primary efficacy outcome, M. Pamela Griffin, MD, said at an annual scientific meeting on infectious diseases.

In a secondary efficacy measure, the rate of hospitalizations for RSV-caused lower respiratory tract infections, a single injection of nirsevimab dropped the incidence by 78%, relative to placebo. Both effects were statistically significant. The rate of total adverse events and serious adverse events was similar in the two treatment arms, reported Dr. Griffin, a clinical development lead with AstraZeneca.

These positive results for a single intramuscular injection of nirsevimab are the first findings from a series of studies aimed at getting the monoclonal antibody onto the U.S. market as a superior alternative to palivizumab (Synagis), which acts in a similar way to block RSV infection (albeit by targeting a different viral surface protein) but which requires administration every 30 days. This need for serial dosing of palivizumab in children younger than 1 year old for complete seasonal protection against RSV is probably a reason why the American Academy of Pediatrics, as well as other medical societies, have targeted using palivizumab only on certain types of high-risk infants: those born before 29 weeks’ gestational age, with chronic lung disease of prematurity, or with hemodynamically significant congenital heart disease (Pediatrics. 2014 Aug;134[2]:415-20). “It’s not feasible for most infants to come for five treatments during RSV season,” Dr. Griffin noted. A tweak in the structure of nirsevimab gives it a much longer blood half-life than palivizumab and allows a single dose to maintain efficacy for 5 months, the duration of RSV season.

“The big advantage of nirsevimab is one dose instead of five,” she said in an interview.

The study randomized 969 preterm infants to nirsevimab and 484 to placebo when the children averaged 3 months old and 4.5 kg. The incidence of the primary endpoint was 2.6% in the nirsevimab-treated infants and 9.5% in those who received placebo. The incidence of hospitalizations associated with an RSV lower respiratory tract infection was 0.8% in the nirsevimab group and 4.1% on placebo. Nirsevimab was equally effective regardless of RSV subtype, infant age, or sex. The rate of hypersensitivity reactions was low, less than 1%, and similar in the two treatment arms, as was the rate of detection of antidrug antibody, 3.8% with placebo and 5.6% with nirsevimab.

Two other large trials are underway to document the performance of nirsevimab in other types of infants. One study is examining the drug’s performance compared with placebo in term infants with a gestational age of at least 36 weeks, while another is comparing nirsevimab against a five-dose regimen of palivizumab in high-risk infants who are recommended to receive palivizumab by local medical societies. In the United States, this would be infants born at less than 29 weeks’ gestation, and those with either hemodynamically significant congenital heart disease or chronic lung disease of prematurity. In these studies, the researchers also will assess the cost effectiveness of nirsevimab relative to the costs for medical care needed by infants who receive comparator treatments, Dr. Griffin said.

The study was funded by AstraZeneca, the company developing nirsevimab. Dr. Griffin is an employee of and shareholder in AstraZeneca.

[email protected]

SOURCE: ClinicalTrials.gov identifier: NCT02878330.

WASHINGTON – Influenza vaccines that substitute flu grown in cell-culture for the standard formulation of flu grown in eggs recently came onto the U.S. market, and new evidence confirmed that cell-grown flu works at least as well as its egg-grown counterpart for triggering immune responses.

Results from a randomized study with 148 evaluable subjects that directly compared the immune response of individuals aged 4-20 years old to the 2018-2019 commercial formulation of a mostly cell-based influenza vaccine with a commercially marketed, fully egg-based vaccine from the same vintage showed “no difference” between the two vaccines for inducing serologic titers on both the hemagluttination inhibition assay and by microneutralization, Richard K. Zimmerman, MD, said at an annual scientific meeting on infectious diseases.

The question addressed by the study was whether the primarily cell culture–grown vaccine would perform differently in children than a standard, egg-grown vaccine. “We thought that we might find something different, but we didn’t,” said Dr. Zimmerman, a professor of family medicine at the University of Pittsburgh who studies vaccines. The finding gave further support to using flu vaccines made without eggs because of their advantages over egg-based vaccines, he said in an interview.

Dr. Zimmerman cited two major, potential problems with egg-grown influenza vaccines. First, they require a big supply of eggs to manufacture, which can pose logistical challenges that are absent with cell culture–grown vaccine once the bioreactor capacity exists to produce the necessary amount of cells. This means that egg-free vaccine production can ramp up faster when a pandemic starts, he noted.

Second, over time, egg-grown vaccine strains of influenza have become increasingly adapted to grow in eggs with the result that “in some years the egg-grown virus is so different as to not work as well [Proc Natl Acad Sci. 2017 Nov;114[44]:12578-83]. With cell culture you bypass” issues of glycosylation mismatch or other antigenic problems caused by egg passage, he explained.

Dr. Zimmerman feels so strongly about the superiority of the cell-culture vaccine that “I am personally going to get a vaccine that’s not egg based,” and he advised the University of Pittsburgh Medical Center to focus its 2019-2020 flu vaccine purchase primarily on formulations made by cell culture. For the 2019-2020 season, that specifically is Flucelvax, an inactivated influenza vaccine licensed for people aged at least 4 years old, and Flublok, a recombinant flu vaccine also produced entirely in cell culture and licensed for people aged at least 18 years old. The 2019-2020 season is the first one during which the quadravalent Flucelvax vaccine has all four component strains (one H1N1, one H3N2, and two B strains) grown in cell culture.

The study run by Dr. Zimmerman and associates at the start of the 2018-2019 season used that season’s formulation of Flucelvax, which had only three of its four component strains grown in cell culture plus one strain (H1N1) grown in eggs. The Pittsburgh researchers randomized 168 individuals to receive the 2018-2019 Flucelvax vaccine or Fluzone, an entirely egg-made quadravelent vaccine, and they had analyzable results from 148 of the enrolled participants, more than 85% of whom were 9-20 years old. The study’s primary endpoint was the extent of seropositivity and seroconversion 28 days after immunization measured with both a hemagglutination inhibition assay and by a microneutralization assay. The results showed similar rates in the 75 children who received Flucelvax and the 73 who received Fluzone. For example, seropositivity against B Victoria lineage strains by the hemagglutination inhibition assay 28 days after vaccination was 76% in children who received Flucelvax, and it was 79% among those who got Fluzone, with a seroconversion rate of 34% in each of the two study subgroups.

“These findings do not say that egg-free is better, but it was certainly no worse. My guess is that in some years vaccines that are egg-free will make a big difference. In other years it may not. But you don’t know ahead of time,” Dr. Zimmerman said.

The study received no commercial funding but received free Fluzone vaccine from Sanofi Pasteur. Dr. Zimmerman had no disclosures.

[email protected]

WASHINGTON – Influenza vaccines that substitute flu grown in cell-culture for the standard formulation of flu grown in eggs recently came onto the U.S. market, and new evidence confirmed that cell-grown flu works at least as well as its egg-grown counterpart for triggering immune responses.

Results from a randomized study with 148 evaluable subjects that directly compared the immune response of individuals aged 4-20 years old to the 2018-2019 commercial formulation of a mostly cell-based influenza vaccine with a commercially marketed, fully egg-based vaccine from the same vintage showed “no difference” between the two vaccines for inducing serologic titers on both the hemagluttination inhibition assay and by microneutralization, Richard K. Zimmerman, MD, said at an annual scientific meeting on infectious diseases.

The question addressed by the study was whether the primarily cell culture–grown vaccine would perform differently in children than a standard, egg-grown vaccine. “We thought that we might find something different, but we didn’t,” said Dr. Zimmerman, a professor of family medicine at the University of Pittsburgh who studies vaccines. The finding gave further support to using flu vaccines made without eggs because of their advantages over egg-based vaccines, he said in an interview.

Dr. Zimmerman cited two major, potential problems with egg-grown influenza vaccines. First, they require a big supply of eggs to manufacture, which can pose logistical challenges that are absent with cell culture–grown vaccine once the bioreactor capacity exists to produce the necessary amount of cells. This means that egg-free vaccine production can ramp up faster when a pandemic starts, he noted.

Second, over time, egg-grown vaccine strains of influenza have become increasingly adapted to grow in eggs with the result that “in some years the egg-grown virus is so different as to not work as well [Proc Natl Acad Sci. 2017 Nov;114[44]:12578-83]. With cell culture you bypass” issues of glycosylation mismatch or other antigenic problems caused by egg passage, he explained.

Dr. Zimmerman feels so strongly about the superiority of the cell-culture vaccine that “I am personally going to get a vaccine that’s not egg based,” and he advised the University of Pittsburgh Medical Center to focus its 2019-2020 flu vaccine purchase primarily on formulations made by cell culture. For the 2019-2020 season, that specifically is Flucelvax, an inactivated influenza vaccine licensed for people aged at least 4 years old, and Flublok, a recombinant flu vaccine also produced entirely in cell culture and licensed for people aged at least 18 years old. The 2019-2020 season is the first one during which the quadravalent Flucelvax vaccine has all four component strains (one H1N1, one H3N2, and two B strains) grown in cell culture.

The study run by Dr. Zimmerman and associates at the start of the 2018-2019 season used that season’s formulation of Flucelvax, which had only three of its four component strains grown in cell culture plus one strain (H1N1) grown in eggs. The Pittsburgh researchers randomized 168 individuals to receive the 2018-2019 Flucelvax vaccine or Fluzone, an entirely egg-made quadravelent vaccine, and they had analyzable results from 148 of the enrolled participants, more than 85% of whom were 9-20 years old. The study’s primary endpoint was the extent of seropositivity and seroconversion 28 days after immunization measured with both a hemagglutination inhibition assay and by a microneutralization assay. The results showed similar rates in the 75 children who received Flucelvax and the 73 who received Fluzone. For example, seropositivity against B Victoria lineage strains by the hemagglutination inhibition assay 28 days after vaccination was 76% in children who received Flucelvax, and it was 79% among those who got Fluzone, with a seroconversion rate of 34% in each of the two study subgroups.

“These findings do not say that egg-free is better, but it was certainly no worse. My guess is that in some years vaccines that are egg-free will make a big difference. In other years it may not. But you don’t know ahead of time,” Dr. Zimmerman said.

The study received no commercial funding but received free Fluzone vaccine from Sanofi Pasteur. Dr. Zimmerman had no disclosures.

[email protected]

WASHINGTON – Influenza vaccines that substitute flu grown in cell-culture for the standard formulation of flu grown in eggs recently came onto the U.S. market, and new evidence confirmed that cell-grown flu works at least as well as its egg-grown counterpart for triggering immune responses.

Results from a randomized study with 148 evaluable subjects that directly compared the immune response of individuals aged 4-20 years old to the 2018-2019 commercial formulation of a mostly cell-based influenza vaccine with a commercially marketed, fully egg-based vaccine from the same vintage showed “no difference” between the two vaccines for inducing serologic titers on both the hemagluttination inhibition assay and by microneutralization, Richard K. Zimmerman, MD, said at an annual scientific meeting on infectious diseases.

The question addressed by the study was whether the primarily cell culture–grown vaccine would perform differently in children than a standard, egg-grown vaccine. “We thought that we might find something different, but we didn’t,” said Dr. Zimmerman, a professor of family medicine at the University of Pittsburgh who studies vaccines. The finding gave further support to using flu vaccines made without eggs because of their advantages over egg-based vaccines, he said in an interview.

Dr. Zimmerman cited two major, potential problems with egg-grown influenza vaccines. First, they require a big supply of eggs to manufacture, which can pose logistical challenges that are absent with cell culture–grown vaccine once the bioreactor capacity exists to produce the necessary amount of cells. This means that egg-free vaccine production can ramp up faster when a pandemic starts, he noted.

Second, over time, egg-grown vaccine strains of influenza have become increasingly adapted to grow in eggs with the result that “in some years the egg-grown virus is so different as to not work as well [Proc Natl Acad Sci. 2017 Nov;114[44]:12578-83]. With cell culture you bypass” issues of glycosylation mismatch or other antigenic problems caused by egg passage, he explained.

Dr. Zimmerman feels so strongly about the superiority of the cell-culture vaccine that “I am personally going to get a vaccine that’s not egg based,” and he advised the University of Pittsburgh Medical Center to focus its 2019-2020 flu vaccine purchase primarily on formulations made by cell culture. For the 2019-2020 season, that specifically is Flucelvax, an inactivated influenza vaccine licensed for people aged at least 4 years old, and Flublok, a recombinant flu vaccine also produced entirely in cell culture and licensed for people aged at least 18 years old. The 2019-2020 season is the first one during which the quadravalent Flucelvax vaccine has all four component strains (one H1N1, one H3N2, and two B strains) grown in cell culture.

The study run by Dr. Zimmerman and associates at the start of the 2018-2019 season used that season’s formulation of Flucelvax, which had only three of its four component strains grown in cell culture plus one strain (H1N1) grown in eggs. The Pittsburgh researchers randomized 168 individuals to receive the 2018-2019 Flucelvax vaccine or Fluzone, an entirely egg-made quadravelent vaccine, and they had analyzable results from 148 of the enrolled participants, more than 85% of whom were 9-20 years old. The study’s primary endpoint was the extent of seropositivity and seroconversion 28 days after immunization measured with both a hemagglutination inhibition assay and by a microneutralization assay. The results showed similar rates in the 75 children who received Flucelvax and the 73 who received Fluzone. For example, seropositivity against B Victoria lineage strains by the hemagglutination inhibition assay 28 days after vaccination was 76% in children who received Flucelvax, and it was 79% among those who got Fluzone, with a seroconversion rate of 34% in each of the two study subgroups.

“These findings do not say that egg-free is better, but it was certainly no worse. My guess is that in some years vaccines that are egg-free will make a big difference. In other years it may not. But you don’t know ahead of time,” Dr. Zimmerman said.

The study received no commercial funding but received free Fluzone vaccine from Sanofi Pasteur. Dr. Zimmerman had no disclosures.

[email protected]

WASHINGTON – Evidence continues to mount that infants born to moms infected with Zika virus during pregnancy can have neurodevelopmental abnormalities as they age even if they showed no defects at birth, based on follow-up of 890 Colombian children tracked by epidemiologists from the U.S. Centers for Disease Control and Prevention.

Among the 890 neonates born to mothers apparently infected with Zika during pregnancy and followed for up to 2 years, 40 of the 852 (5%) without a detectable birth defect at delivery went on to show some type of neurodevelopmental sequelae during up to 24 months of age, Margaret Honein, PhD, said at an annual scientific meeting on infectious diseases.

In addition, among the children without birth defects at delivery who received follow-up examinations out to about 2 years, the incidence of “alerts” for possible neurodevelopmental issues was 15%-20% for each of the four domains studied (gross motor, fine motor, hearing and language, and personal and social functions), said Dr. Honein, an epidemiologist and chief of the birth defects branch of the CDC. In contrast, 17 of the 38 children (45%) followed who had identifiable birth defects at delivery also showed neurodevelopmental abnormalities when reexamined as long as 2 years after birth. These possible neurodevelopmental abnormalities, designated as alerts, were identified in comparison with a contemporaneous cohort of children born to uninfected mothers in the same regions of Colombia and assessed by the CDC researchers.

This cohort of children born to mothers who became infected with Zika virus during the 2016 Colombian epidemic will not undergo any planned, additional follow-up beyond the initial 2 years, Dr. Honein noted.

The findings she reported were consistent with observations from a much smaller cohort of 70 infants born to Colombian mothers infected with Zika virus while pregnant who had a normal head circumference and a normal clinical examination at delivery. When assessed once or twice 4-18 months after birth, these 70 infants showed an overall greater than one standard deviation (z-score) drop in their scores on the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA) metric by 12 months after birth and continuing out to 18 months, said Sarah B. Mulkey, MD, a fetal-neonatal neurologist at Children’s National Health System in Washington. These deficits were especially pronounced in the mobility and social cognition domains of the four-domain WIDEA metric. The social cognition domain is an important predictor of later problems with executive function and other neurologic disorders, Dr. Mulkey said while reporting her findings in a separate talk at the meeting. She acknowledged that the analysis was flawed by comparing the WIDEA outcomes of the Zika virus–exposed children to healthy children from either inner-city Chicago or Canada. Dr. Mulkey said that she and her associates plan to characterize a population of Zika virus–unexposed children in Colombia to use for future comparisons.

The study reported by Dr. Honein involved an enhanced surveillance program launched by the CDC in 2016 in three regions of Colombia and included 1,190 pregnancies accompanied by Zika symptoms in the mother and with a reported pregnancy outcome, including 1,185 live births. Nearly half of the Zika infections occurred during the first trimester, and 34% occurred during the second trimester. However, fewer than a third of the pregnant women underwent some type of laboratory testing to confirm their infection, either by serology or by a DNA-based assay, and of these 28% had a positive finding. Dr. Honein cautioned that many of the specimens that tested negative for Zika virus may have been false negatives.

The birth defects identified among the infants born from an apparently affected pregnancy included brain abnormalities, eye anomalies, and microcephaly, with 5% of the 1,185 live births showing one or more of these outcomes. The neurodevelopmental deficits identified during follow-up of 890 of the children out to 2 years included seizures; abnormalities of tone, movement, or swallowing; and impairments of vision or hearing.

[email protected]

WASHINGTON – Evidence continues to mount that infants born to moms infected with Zika virus during pregnancy can have neurodevelopmental abnormalities as they age even if they showed no defects at birth, based on follow-up of 890 Colombian children tracked by epidemiologists from the U.S. Centers for Disease Control and Prevention.

Among the 890 neonates born to mothers apparently infected with Zika during pregnancy and followed for up to 2 years, 40 of the 852 (5%) without a detectable birth defect at delivery went on to show some type of neurodevelopmental sequelae during up to 24 months of age, Margaret Honein, PhD, said at an annual scientific meeting on infectious diseases.

In addition, among the children without birth defects at delivery who received follow-up examinations out to about 2 years, the incidence of “alerts” for possible neurodevelopmental issues was 15%-20% for each of the four domains studied (gross motor, fine motor, hearing and language, and personal and social functions), said Dr. Honein, an epidemiologist and chief of the birth defects branch of the CDC. In contrast, 17 of the 38 children (45%) followed who had identifiable birth defects at delivery also showed neurodevelopmental abnormalities when reexamined as long as 2 years after birth. These possible neurodevelopmental abnormalities, designated as alerts, were identified in comparison with a contemporaneous cohort of children born to uninfected mothers in the same regions of Colombia and assessed by the CDC researchers.

This cohort of children born to mothers who became infected with Zika virus during the 2016 Colombian epidemic will not undergo any planned, additional follow-up beyond the initial 2 years, Dr. Honein noted.

The findings she reported were consistent with observations from a much smaller cohort of 70 infants born to Colombian mothers infected with Zika virus while pregnant who had a normal head circumference and a normal clinical examination at delivery. When assessed once or twice 4-18 months after birth, these 70 infants showed an overall greater than one standard deviation (z-score) drop in their scores on the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA) metric by 12 months after birth and continuing out to 18 months, said Sarah B. Mulkey, MD, a fetal-neonatal neurologist at Children’s National Health System in Washington. These deficits were especially pronounced in the mobility and social cognition domains of the four-domain WIDEA metric. The social cognition domain is an important predictor of later problems with executive function and other neurologic disorders, Dr. Mulkey said while reporting her findings in a separate talk at the meeting. She acknowledged that the analysis was flawed by comparing the WIDEA outcomes of the Zika virus–exposed children to healthy children from either inner-city Chicago or Canada. Dr. Mulkey said that she and her associates plan to characterize a population of Zika virus–unexposed children in Colombia to use for future comparisons.

The study reported by Dr. Honein involved an enhanced surveillance program launched by the CDC in 2016 in three regions of Colombia and included 1,190 pregnancies accompanied by Zika symptoms in the mother and with a reported pregnancy outcome, including 1,185 live births. Nearly half of the Zika infections occurred during the first trimester, and 34% occurred during the second trimester. However, fewer than a third of the pregnant women underwent some type of laboratory testing to confirm their infection, either by serology or by a DNA-based assay, and of these 28% had a positive finding. Dr. Honein cautioned that many of the specimens that tested negative for Zika virus may have been false negatives.

The birth defects identified among the infants born from an apparently affected pregnancy included brain abnormalities, eye anomalies, and microcephaly, with 5% of the 1,185 live births showing one or more of these outcomes. The neurodevelopmental deficits identified during follow-up of 890 of the children out to 2 years included seizures; abnormalities of tone, movement, or swallowing; and impairments of vision or hearing.

[email protected]

WASHINGTON – Evidence continues to mount that infants born to moms infected with Zika virus during pregnancy can have neurodevelopmental abnormalities as they age even if they showed no defects at birth, based on follow-up of 890 Colombian children tracked by epidemiologists from the U.S. Centers for Disease Control and Prevention.

Among the 890 neonates born to mothers apparently infected with Zika during pregnancy and followed for up to 2 years, 40 of the 852 (5%) without a detectable birth defect at delivery went on to show some type of neurodevelopmental sequelae during up to 24 months of age, Margaret Honein, PhD, said at an annual scientific meeting on infectious diseases.

In addition, among the children without birth defects at delivery who received follow-up examinations out to about 2 years, the incidence of “alerts” for possible neurodevelopmental issues was 15%-20% for each of the four domains studied (gross motor, fine motor, hearing and language, and personal and social functions), said Dr. Honein, an epidemiologist and chief of the birth defects branch of the CDC. In contrast, 17 of the 38 children (45%) followed who had identifiable birth defects at delivery also showed neurodevelopmental abnormalities when reexamined as long as 2 years after birth. These possible neurodevelopmental abnormalities, designated as alerts, were identified in comparison with a contemporaneous cohort of children born to uninfected mothers in the same regions of Colombia and assessed by the CDC researchers.

This cohort of children born to mothers who became infected with Zika virus during the 2016 Colombian epidemic will not undergo any planned, additional follow-up beyond the initial 2 years, Dr. Honein noted.

The findings she reported were consistent with observations from a much smaller cohort of 70 infants born to Colombian mothers infected with Zika virus while pregnant who had a normal head circumference and a normal clinical examination at delivery. When assessed once or twice 4-18 months after birth, these 70 infants showed an overall greater than one standard deviation (z-score) drop in their scores on the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA) metric by 12 months after birth and continuing out to 18 months, said Sarah B. Mulkey, MD, a fetal-neonatal neurologist at Children’s National Health System in Washington. These deficits were especially pronounced in the mobility and social cognition domains of the four-domain WIDEA metric. The social cognition domain is an important predictor of later problems with executive function and other neurologic disorders, Dr. Mulkey said while reporting her findings in a separate talk at the meeting. She acknowledged that the analysis was flawed by comparing the WIDEA outcomes of the Zika virus–exposed children to healthy children from either inner-city Chicago or Canada. Dr. Mulkey said that she and her associates plan to characterize a population of Zika virus–unexposed children in Colombia to use for future comparisons.

The study reported by Dr. Honein involved an enhanced surveillance program launched by the CDC in 2016 in three regions of Colombia and included 1,190 pregnancies accompanied by Zika symptoms in the mother and with a reported pregnancy outcome, including 1,185 live births. Nearly half of the Zika infections occurred during the first trimester, and 34% occurred during the second trimester. However, fewer than a third of the pregnant women underwent some type of laboratory testing to confirm their infection, either by serology or by a DNA-based assay, and of these 28% had a positive finding. Dr. Honein cautioned that many of the specimens that tested negative for Zika virus may have been false negatives.

The birth defects identified among the infants born from an apparently affected pregnancy included brain abnormalities, eye anomalies, and microcephaly, with 5% of the 1,185 live births showing one or more of these outcomes. The neurodevelopmental deficits identified during follow-up of 890 of the children out to 2 years included seizures; abnormalities of tone, movement, or swallowing; and impairments of vision or hearing.

[email protected]

WASHINGTON – Daily treatment with valacyclovir for at least 6 weeks safely cut the cytomegalovirus (CMV) vertical transmission rate from mothers to fetuses in women with a primary CMV infection during the three weeks before conception through their first trimester. That finding emerged from a randomized, controlled, single-center Israeli study with 92 women.

The rate of congenital fetal infection with CMV was 11% among neonates born to 45 women treated with 8 g/day of valacyclovir, compared with a 30% rate among the infants born to 47 women who received placebo, a statistically significant difference, Keren Shahar-Nissan, MD, said at an annual scientific meeting on infectious diseases. The results also showed that the valacyclovir regimen was well tolerated, with no increase compared with placebo in adverse events and with no need for dosage adjustment regardless of a 16 pill/day regimen to deliver the 8 g/day of valacyclovir or placebo that participants received.

Dr. Shahar-Nissan said that she and her associates felt comfortable administering this amount of valacyclovir to pregnant woman given previous reports of the safety of this dosage for both women and their fetuses. These reports included 20 pregnant women safely treated for 7 weeks with 8 g/day during the late second or early third trimester (BJOG. 2007 Sept;114[9]:1113-21); more than 600 women in a Danish nationwide study treated with any dosage of valacyclovir during preconception, the first trimester, or the second or third trimesters with a prevalence of births defects not significantly different from unexposed pregnancies (JAMA. 2010 Aug 25;304[8]:859-66); and a prospective, open-label study of 8 g/day valacyclovir to treat 43 women carrying CMV-infected fetuses starting at a median 26 weeks gestation and continuing through delivery (Am J Obstet Gynecol. 2016 Oct;215[4]:462.e1-462.e10).

The study she ran enrolled women seen at Helen Schneider Hospital for Women in Petah Tikva, Israel, during November 2015-October 2018 who had a serologically-proven primary CMV infection that began at any time from 3 weeks before conception through the first trimester, excluding patients with renal dysfunction, liver disease, bone-marrow suppression, or acyclovir sensitivity. Screening for active CMV infection is common among newly-pregnant Israeli women, usually at the time of their first obstetrical consultation for a suspected pregnancy, noted Dr. Shahar-Nissan, a pediatrician at Schneider Children’s Medical Center of Israel in Petah Tikva. About a quarter of the enrolled women became infected during the 3 weeks prior to conception, and nearly two-thirds became infected during the first 8 weeks of pregnancy.

The valacyclovir intervention appeared to be effective specifically for preventing vertical transmission of infection acquired early during pregnancy. In this subgroup the transmission rate was 11% with valacyclovir treatment and 48% on placebo. Valacyclovir seemed to have no effect on vertical transmission of infections that began before conception, likely because treatment began too late to prevent transmission.

“I think this study is enough” to convince the U.S. Food and Drug Administration to add this treatment indication to the labeling of valacyclovir, a drug that has been available in generic formulations for many years, Dr. Shahar-Nissan said in an interview. Before approaching the FDA, her first goal is publishing the findings, she added.

[email protected]

On Twitter @mitchelzoler

WASHINGTON – Daily treatment with valacyclovir for at least 6 weeks safely cut the cytomegalovirus (CMV) vertical transmission rate from mothers to fetuses in women with a primary CMV infection during the three weeks before conception through their first trimester. That finding emerged from a randomized, controlled, single-center Israeli study with 92 women.

The rate of congenital fetal infection with CMV was 11% among neonates born to 45 women treated with 8 g/day of valacyclovir, compared with a 30% rate among the infants born to 47 women who received placebo, a statistically significant difference, Keren Shahar-Nissan, MD, said at an annual scientific meeting on infectious diseases. The results also showed that the valacyclovir regimen was well tolerated, with no increase compared with placebo in adverse events and with no need for dosage adjustment regardless of a 16 pill/day regimen to deliver the 8 g/day of valacyclovir or placebo that participants received.

Dr. Shahar-Nissan said that she and her associates felt comfortable administering this amount of valacyclovir to pregnant woman given previous reports of the safety of this dosage for both women and their fetuses. These reports included 20 pregnant women safely treated for 7 weeks with 8 g/day during the late second or early third trimester (BJOG. 2007 Sept;114[9]:1113-21); more than 600 women in a Danish nationwide study treated with any dosage of valacyclovir during preconception, the first trimester, or the second or third trimesters with a prevalence of births defects not significantly different from unexposed pregnancies (JAMA. 2010 Aug 25;304[8]:859-66); and a prospective, open-label study of 8 g/day valacyclovir to treat 43 women carrying CMV-infected fetuses starting at a median 26 weeks gestation and continuing through delivery (Am J Obstet Gynecol. 2016 Oct;215[4]:462.e1-462.e10).

The study she ran enrolled women seen at Helen Schneider Hospital for Women in Petah Tikva, Israel, during November 2015-October 2018 who had a serologically-proven primary CMV infection that began at any time from 3 weeks before conception through the first trimester, excluding patients with renal dysfunction, liver disease, bone-marrow suppression, or acyclovir sensitivity. Screening for active CMV infection is common among newly-pregnant Israeli women, usually at the time of their first obstetrical consultation for a suspected pregnancy, noted Dr. Shahar-Nissan, a pediatrician at Schneider Children’s Medical Center of Israel in Petah Tikva. About a quarter of the enrolled women became infected during the 3 weeks prior to conception, and nearly two-thirds became infected during the first 8 weeks of pregnancy.

The valacyclovir intervention appeared to be effective specifically for preventing vertical transmission of infection acquired early during pregnancy. In this subgroup the transmission rate was 11% with valacyclovir treatment and 48% on placebo. Valacyclovir seemed to have no effect on vertical transmission of infections that began before conception, likely because treatment began too late to prevent transmission.

“I think this study is enough” to convince the U.S. Food and Drug Administration to add this treatment indication to the labeling of valacyclovir, a drug that has been available in generic formulations for many years, Dr. Shahar-Nissan said in an interview. Before approaching the FDA, her first goal is publishing the findings, she added.

[email protected]

On Twitter @mitchelzoler

WASHINGTON – Daily treatment with valacyclovir for at least 6 weeks safely cut the cytomegalovirus (CMV) vertical transmission rate from mothers to fetuses in women with a primary CMV infection during the three weeks before conception through their first trimester. That finding emerged from a randomized, controlled, single-center Israeli study with 92 women.

The rate of congenital fetal infection with CMV was 11% among neonates born to 45 women treated with 8 g/day of valacyclovir, compared with a 30% rate among the infants born to 47 women who received placebo, a statistically significant difference, Keren Shahar-Nissan, MD, said at an annual scientific meeting on infectious diseases. The results also showed that the valacyclovir regimen was well tolerated, with no increase compared with placebo in adverse events and with no need for dosage adjustment regardless of a 16 pill/day regimen to deliver the 8 g/day of valacyclovir or placebo that participants received.

Dr. Shahar-Nissan said that she and her associates felt comfortable administering this amount of valacyclovir to pregnant woman given previous reports of the safety of this dosage for both women and their fetuses. These reports included 20 pregnant women safely treated for 7 weeks with 8 g/day during the late second or early third trimester (BJOG. 2007 Sept;114[9]:1113-21); more than 600 women in a Danish nationwide study treated with any dosage of valacyclovir during preconception, the first trimester, or the second or third trimesters with a prevalence of births defects not significantly different from unexposed pregnancies (JAMA. 2010 Aug 25;304[8]:859-66); and a prospective, open-label study of 8 g/day valacyclovir to treat 43 women carrying CMV-infected fetuses starting at a median 26 weeks gestation and continuing through delivery (Am J Obstet Gynecol. 2016 Oct;215[4]:462.e1-462.e10).

The study she ran enrolled women seen at Helen Schneider Hospital for Women in Petah Tikva, Israel, during November 2015-October 2018 who had a serologically-proven primary CMV infection that began at any time from 3 weeks before conception through the first trimester, excluding patients with renal dysfunction, liver disease, bone-marrow suppression, or acyclovir sensitivity. Screening for active CMV infection is common among newly-pregnant Israeli women, usually at the time of their first obstetrical consultation for a suspected pregnancy, noted Dr. Shahar-Nissan, a pediatrician at Schneider Children’s Medical Center of Israel in Petah Tikva. About a quarter of the enrolled women became infected during the 3 weeks prior to conception, and nearly two-thirds became infected during the first 8 weeks of pregnancy.

The valacyclovir intervention appeared to be effective specifically for preventing vertical transmission of infection acquired early during pregnancy. In this subgroup the transmission rate was 11% with valacyclovir treatment and 48% on placebo. Valacyclovir seemed to have no effect on vertical transmission of infections that began before conception, likely because treatment began too late to prevent transmission.

“I think this study is enough” to convince the U.S. Food and Drug Administration to add this treatment indication to the labeling of valacyclovir, a drug that has been available in generic formulations for many years, Dr. Shahar-Nissan said in an interview. Before approaching the FDA, her first goal is publishing the findings, she added.

[email protected]

On Twitter @mitchelzoler

WASHINGTON – An investigational, oral, small molecule designed to boost innate antiviral immunity safely cut the incidence of various viral respiratory infections in elderly people during a winter season by nearly a third when administered once daily in a placebo-controlled, multicenter, phase 2 study of 952 patients. Based on these and other findings the drug, RTB101, is now undergoing testing in a phase 3 study, Joan Mannick, MD, said at an annual scientific meeting on infectious diseases.

Mitchel L. Zoler/MDedge News

At a dosage of 10 mg once daily, RTB101 was “well tolerated, upregulated innate antiviral gene expression, and reduced the incidence” of laboratory-confirmed respiratory tract infections caused by several different viruses, said Dr. Mannick, who disclosed that she is a cofounder and chief medical officer of resTORbio, a Boston-based company that’s developing the drug.

During 16 weeks of treatment during the winter virus season, once-daily dosing led to cuts in the rates of respiratory infections compared with placebo by rhinovirus and enterovirus, respiratory syncytial virus, coronavirus, influenza virus, metapneuomovirus, and parainfluenza virus, especially in patients whom the results identified as having the best drug responses: those who were at least 85 years old, and those who were at least 65 years old and also had asthma. Enrolled patients who were at least 65 years old and had other risk factors – current smoking, chronic obstructive pulmonary disease, or diabetes – had notably less robust responses to treatment, and the phase 3 study is not enrolling elderly people who currently smoke or have chronic obstructive pulmonary disease, Dr. Mannick said in an interview.

RTB101 inhibits the active site of the “mechanistic target of rapamycin” (mTOR) protein, the key player of the TORC1 protein complex that appears to downregulate innate antiviral immunity when active. Hence inhibiting mTOR and TORC1 activity should boost innate antiviral immunity. Once-daily dosing with 10 mg of RTB101 appears to mimic the normal daily cycle of high and low levels of TORC1 activity seen in younger adults but which is missing the elderly who generally have persistently elevated levels of TORC1 activity, Dr. Mannick explained.

The study she reported enrolled a total of 952 people at any of 10 sites in the Southern Hemisphere or 17 Northern Hemisphere study sites. The researchers randomized patients to receive either RTB101 or placebo at either of two once-daily dosages or either of two twice-daily regimens. The best drug performance was among the 356 patients treated with 10 mg once daily or placebo. Those who received the active drug at this level had a 19% incidence of any laboratory-confirmed respiratory tract infection, while those who received placebo had a 28% incidence, a 30.6% relative risk reduction with RTB101 treatment that was statistically significant.

The actively-treated patients showed upregulation for 19 of 20 “antiviral” genes assessed in the study compared with upregulation of just five of these genes in the those who received placebo. Two post hoc analyses showed that the people who received 10 mg once daily had about half the rate of all-cause hospitalizations compared with those on placebo, and among those who had respiratory infections treated patients had alleviation of their moderate or severe symptoms in about half the time compared with patients on placebo.

The 10-mg daily dosage of RTB101 is less than 1% of the maximum-tolerated dose in people, and the safety data collected in the current study showed adverse events occurring at similar rates in the patients who received the active drug and those who got placebo. Discontinuations because of adverse events occurred in 5% of people who received RTB101 and in 6% of those on placebo.

The researchers are planning to run a cost-effectiveness study to see whether the observed prevention of respiratory tract infections and their consequences can offset the cost of taking RTB101 daily for 16 weeks, Dr. Mannick said.

[email protected]

WASHINGTON – An investigational, oral, small molecule designed to boost innate antiviral immunity safely cut the incidence of various viral respiratory infections in elderly people during a winter season by nearly a third when administered once daily in a placebo-controlled, multicenter, phase 2 study of 952 patients. Based on these and other findings the drug, RTB101, is now undergoing testing in a phase 3 study, Joan Mannick, MD, said at an annual scientific meeting on infectious diseases.

Mitchel L. Zoler/MDedge News

At a dosage of 10 mg once daily, RTB101 was “well tolerated, upregulated innate antiviral gene expression, and reduced the incidence” of laboratory-confirmed respiratory tract infections caused by several different viruses, said Dr. Mannick, who disclosed that she is a cofounder and chief medical officer of resTORbio, a Boston-based company that’s developing the drug.

During 16 weeks of treatment during the winter virus season, once-daily dosing led to cuts in the rates of respiratory infections compared with placebo by rhinovirus and enterovirus, respiratory syncytial virus, coronavirus, influenza virus, metapneuomovirus, and parainfluenza virus, especially in patients whom the results identified as having the best drug responses: those who were at least 85 years old, and those who were at least 65 years old and also had asthma. Enrolled patients who were at least 65 years old and had other risk factors – current smoking, chronic obstructive pulmonary disease, or diabetes – had notably less robust responses to treatment, and the phase 3 study is not enrolling elderly people who currently smoke or have chronic obstructive pulmonary disease, Dr. Mannick said in an interview.

RTB101 inhibits the active site of the “mechanistic target of rapamycin” (mTOR) protein, the key player of the TORC1 protein complex that appears to downregulate innate antiviral immunity when active. Hence inhibiting mTOR and TORC1 activity should boost innate antiviral immunity. Once-daily dosing with 10 mg of RTB101 appears to mimic the normal daily cycle of high and low levels of TORC1 activity seen in younger adults but which is missing the elderly who generally have persistently elevated levels of TORC1 activity, Dr. Mannick explained.

The study she reported enrolled a total of 952 people at any of 10 sites in the Southern Hemisphere or 17 Northern Hemisphere study sites. The researchers randomized patients to receive either RTB101 or placebo at either of two once-daily dosages or either of two twice-daily regimens. The best drug performance was among the 356 patients treated with 10 mg once daily or placebo. Those who received the active drug at this level had a 19% incidence of any laboratory-confirmed respiratory tract infection, while those who received placebo had a 28% incidence, a 30.6% relative risk reduction with RTB101 treatment that was statistically significant.

The actively-treated patients showed upregulation for 19 of 20 “antiviral” genes assessed in the study compared with upregulation of just five of these genes in the those who received placebo. Two post hoc analyses showed that the people who received 10 mg once daily had about half the rate of all-cause hospitalizations compared with those on placebo, and among those who had respiratory infections treated patients had alleviation of their moderate or severe symptoms in about half the time compared with patients on placebo.

The 10-mg daily dosage of RTB101 is less than 1% of the maximum-tolerated dose in people, and the safety data collected in the current study showed adverse events occurring at similar rates in the patients who received the active drug and those who got placebo. Discontinuations because of adverse events occurred in 5% of people who received RTB101 and in 6% of those on placebo.

The researchers are planning to run a cost-effectiveness study to see whether the observed prevention of respiratory tract infections and their consequences can offset the cost of taking RTB101 daily for 16 weeks, Dr. Mannick said.

[email protected]

WASHINGTON – An investigational, oral, small molecule designed to boost innate antiviral immunity safely cut the incidence of various viral respiratory infections in elderly people during a winter season by nearly a third when administered once daily in a placebo-controlled, multicenter, phase 2 study of 952 patients. Based on these and other findings the drug, RTB101, is now undergoing testing in a phase 3 study, Joan Mannick, MD, said at an annual scientific meeting on infectious diseases.

Mitchel L. Zoler/MDedge News

At a dosage of 10 mg once daily, RTB101 was “well tolerated, upregulated innate antiviral gene expression, and reduced the incidence” of laboratory-confirmed respiratory tract infections caused by several different viruses, said Dr. Mannick, who disclosed that she is a cofounder and chief medical officer of resTORbio, a Boston-based company that’s developing the drug.

During 16 weeks of treatment during the winter virus season, once-daily dosing led to cuts in the rates of respiratory infections compared with placebo by rhinovirus and enterovirus, respiratory syncytial virus, coronavirus, influenza virus, metapneuomovirus, and parainfluenza virus, especially in patients whom the results identified as having the best drug responses: those who were at least 85 years old, and those who were at least 65 years old and also had asthma. Enrolled patients who were at least 65 years old and had other risk factors – current smoking, chronic obstructive pulmonary disease, or diabetes – had notably less robust responses to treatment, and the phase 3 study is not enrolling elderly people who currently smoke or have chronic obstructive pulmonary disease, Dr. Mannick said in an interview.

RTB101 inhibits the active site of the “mechanistic target of rapamycin” (mTOR) protein, the key player of the TORC1 protein complex that appears to downregulate innate antiviral immunity when active. Hence inhibiting mTOR and TORC1 activity should boost innate antiviral immunity. Once-daily dosing with 10 mg of RTB101 appears to mimic the normal daily cycle of high and low levels of TORC1 activity seen in younger adults but which is missing the elderly who generally have persistently elevated levels of TORC1 activity, Dr. Mannick explained.

The study she reported enrolled a total of 952 people at any of 10 sites in the Southern Hemisphere or 17 Northern Hemisphere study sites. The researchers randomized patients to receive either RTB101 or placebo at either of two once-daily dosages or either of two twice-daily regimens. The best drug performance was among the 356 patients treated with 10 mg once daily or placebo. Those who received the active drug at this level had a 19% incidence of any laboratory-confirmed respiratory tract infection, while those who received placebo had a 28% incidence, a 30.6% relative risk reduction with RTB101 treatment that was statistically significant.

The actively-treated patients showed upregulation for 19 of 20 “antiviral” genes assessed in the study compared with upregulation of just five of these genes in the those who received placebo. Two post hoc analyses showed that the people who received 10 mg once daily had about half the rate of all-cause hospitalizations compared with those on placebo, and among those who had respiratory infections treated patients had alleviation of their moderate or severe symptoms in about half the time compared with patients on placebo.

The 10-mg daily dosage of RTB101 is less than 1% of the maximum-tolerated dose in people, and the safety data collected in the current study showed adverse events occurring at similar rates in the patients who received the active drug and those who got placebo. Discontinuations because of adverse events occurred in 5% of people who received RTB101 and in 6% of those on placebo.

The researchers are planning to run a cost-effectiveness study to see whether the observed prevention of respiratory tract infections and their consequences can offset the cost of taking RTB101 daily for 16 weeks, Dr. Mannick said.

[email protected]

PARIS – Beta-blocking drugs were as effective for improving survival in patients with moderately severe renal dysfunction as they were in patients with normal renal function in a meta-analysis of more than 13,000 patients, a finding that seemed to solidify the role for this drug class for essentially all similar heart failure patients, regardless of their renal function.

Mitchel L. Zoler/MDedge News

This evidence could reshape usual care because “renal impairment is often considered a barrier in clinical practice” for starting a beta-blocker drug in patients with heart failure with reduced ejection fraction (HFrEF), Dipak Kotecha, MBChB, said at the annual congress of the European Society of Cardiology.

“We have shown with sufficient sample size that beta-blockers are effective in reducing mortality in patient with HFrEF and in sinus rhythm, even in those with an eGFR [estimated glomerular filtration rate] of 30-44 mL/min per 1.73 m²,” said Dr. Kotecha, a cardiologist at the University of Birmingham (England). “The results suggest that renal impairment should not obstruct the prescription and maintenance of beta-blockers in patients with HFrEF.”

“This important study was a novel attempt to look at [HFrEF] patients with renal insufficiency to see whether they received the same benefit from beta-blockers as other patients, and they did. So renal insufficiency is not a reason to withhold beta-blockers” from these patients, commented Mariell Jessup, MD, a heart failure physician and chief science and medical officer for the American Heart Association in Dallas. “The onus is on clinicians to find a reason not to give a beta-blocker to a patient with HFrEF because they are generally well tolerated and they can have enormous benefit, as we saw in this study,” she said in a video interview.

The analysis run by Dr. Kotecha and associates used data collected in 11 of the pivotal randomized, controlled trial run for beta-blockers during the 1990s and early 2000s, with each study comparing bucindolol, bisoprolol, carvedilol, metoprolol XL, or nebivolol against placebo. The studies collectively enrolled 18,637 patients, which the investigators whittled down in their analysis to 17,433 after excluding patients with a left ventricular ejection fraction below 50% or who were undocumented. The subgroup with HFrEF included 13,861 patient in sinus rhythm at entry, 2,879 with atrial fibrillation, and 693 with an unknown atrial status. The main analysis ran in the 13,861 patients with HFrEF and in sinus rhythm; 14% of this cohort had an eGFR of 30-44 mL/min per 1.73 m² and 27% had an eGFR of 45-59 mL/min per 1.73 m². The median age of all patients in the main analysis was 65 years, 23% were women, and their median left ventricular ejection fraction was 27%.

During follow-up of about 3 years, the impact of beta-blocker treatment on survival, compared with placebo, was “substantial” for all strata of patients by renal function, except for those with eGFRs below 30 mL/min per 1.73 m². (Survival was similar regardless of beta-blocker treatment in the small number of patients with severe renal dysfunction.) The number needed to treat to prevent 1 death in patients with an eGFR of 30-44 mL/min per 1.73 m² was 21, the same as among patients with an eGFR of 90 mL/min per 1.73 m² or more, Dr. Kotecha said.

Among the subgroup of patients with atrial fibrillation, beta-blockers appeared to exert no survival benefit, compared with placebo. The investigators did not assess the survival benefits exerted by any individual beta-blocker, compared with the others, and Dr. Kotecha stressed that “my belief is that this is a class effect” and is roughly similar across all the beta-blockers used in the studies.

The analysis also showed good safety and tolerability of the beta-blockers in patients with renal dysfunction. The incidence of adverse events leading to treatment termination was very similar in the beta-blocker and placebo arms, and more than three-quarters of patients in each of the two subgroups with renal dysfunction were maintained on more than 50% of their target beta-blocker dosage.

Dr. Kotecha has been an advisor to Bayer, a speaker on behalf of Atricure, and has received research funding from GlaxoSmithKline and Menarini. Dr. Jessup had no disclosures.

[email protected]

PARIS – Beta-blocking drugs were as effective for improving survival in patients with moderately severe renal dysfunction as they were in patients with normal renal function in a meta-analysis of more than 13,000 patients, a finding that seemed to solidify the role for this drug class for essentially all similar heart failure patients, regardless of their renal function.

Mitchel L. Zoler/MDedge News

This evidence could reshape usual care because “renal impairment is often considered a barrier in clinical practice” for starting a beta-blocker drug in patients with heart failure with reduced ejection fraction (HFrEF), Dipak Kotecha, MBChB, said at the annual congress of the European Society of Cardiology.

“We have shown with sufficient sample size that beta-blockers are effective in reducing mortality in patient with HFrEF and in sinus rhythm, even in those with an eGFR [estimated glomerular filtration rate] of 30-44 mL/min per 1.73 m²,” said Dr. Kotecha, a cardiologist at the University of Birmingham (England). “The results suggest that renal impairment should not obstruct the prescription and maintenance of beta-blockers in patients with HFrEF.”

“This important study was a novel attempt to look at [HFrEF] patients with renal insufficiency to see whether they received the same benefit from beta-blockers as other patients, and they did. So renal insufficiency is not a reason to withhold beta-blockers” from these patients, commented Mariell Jessup, MD, a heart failure physician and chief science and medical officer for the American Heart Association in Dallas. “The onus is on clinicians to find a reason not to give a beta-blocker to a patient with HFrEF because they are generally well tolerated and they can have enormous benefit, as we saw in this study,” she said in a video interview.

The analysis run by Dr. Kotecha and associates used data collected in 11 of the pivotal randomized, controlled trial run for beta-blockers during the 1990s and early 2000s, with each study comparing bucindolol, bisoprolol, carvedilol, metoprolol XL, or nebivolol against placebo. The studies collectively enrolled 18,637 patients, which the investigators whittled down in their analysis to 17,433 after excluding patients with a left ventricular ejection fraction below 50% or who were undocumented. The subgroup with HFrEF included 13,861 patient in sinus rhythm at entry, 2,879 with atrial fibrillation, and 693 with an unknown atrial status. The main analysis ran in the 13,861 patients with HFrEF and in sinus rhythm; 14% of this cohort had an eGFR of 30-44 mL/min per 1.73 m² and 27% had an eGFR of 45-59 mL/min per 1.73 m². The median age of all patients in the main analysis was 65 years, 23% were women, and their median left ventricular ejection fraction was 27%.

During follow-up of about 3 years, the impact of beta-blocker treatment on survival, compared with placebo, was “substantial” for all strata of patients by renal function, except for those with eGFRs below 30 mL/min per 1.73 m². (Survival was similar regardless of beta-blocker treatment in the small number of patients with severe renal dysfunction.) The number needed to treat to prevent 1 death in patients with an eGFR of 30-44 mL/min per 1.73 m² was 21, the same as among patients with an eGFR of 90 mL/min per 1.73 m² or more, Dr. Kotecha said.

Among the subgroup of patients with atrial fibrillation, beta-blockers appeared to exert no survival benefit, compared with placebo. The investigators did not assess the survival benefits exerted by any individual beta-blocker, compared with the others, and Dr. Kotecha stressed that “my belief is that this is a class effect” and is roughly similar across all the beta-blockers used in the studies.

The analysis also showed good safety and tolerability of the beta-blockers in patients with renal dysfunction. The incidence of adverse events leading to treatment termination was very similar in the beta-blocker and placebo arms, and more than three-quarters of patients in each of the two subgroups with renal dysfunction were maintained on more than 50% of their target beta-blocker dosage.

Dr. Kotecha has been an advisor to Bayer, a speaker on behalf of Atricure, and has received research funding from GlaxoSmithKline and Menarini. Dr. Jessup had no disclosures.

[email protected]

PARIS – Beta-blocking drugs were as effective for improving survival in patients with moderately severe renal dysfunction as they were in patients with normal renal function in a meta-analysis of more than 13,000 patients, a finding that seemed to solidify the role for this drug class for essentially all similar heart failure patients, regardless of their renal function.

Mitchel L. Zoler/MDedge News

This evidence could reshape usual care because “renal impairment is often considered a barrier in clinical practice” for starting a beta-blocker drug in patients with heart failure with reduced ejection fraction (HFrEF), Dipak Kotecha, MBChB, said at the annual congress of the European Society of Cardiology.

“We have shown with sufficient sample size that beta-blockers are effective in reducing mortality in patient with HFrEF and in sinus rhythm, even in those with an eGFR [estimated glomerular filtration rate] of 30-44 mL/min per 1.73 m²,” said Dr. Kotecha, a cardiologist at the University of Birmingham (England). “The results suggest that renal impairment should not obstruct the prescription and maintenance of beta-blockers in patients with HFrEF.”

“This important study was a novel attempt to look at [HFrEF] patients with renal insufficiency to see whether they received the same benefit from beta-blockers as other patients, and they did. So renal insufficiency is not a reason to withhold beta-blockers” from these patients, commented Mariell Jessup, MD, a heart failure physician and chief science and medical officer for the American Heart Association in Dallas. “The onus is on clinicians to find a reason not to give a beta-blocker to a patient with HFrEF because they are generally well tolerated and they can have enormous benefit, as we saw in this study,” she said in a video interview.

The analysis run by Dr. Kotecha and associates used data collected in 11 of the pivotal randomized, controlled trial run for beta-blockers during the 1990s and early 2000s, with each study comparing bucindolol, bisoprolol, carvedilol, metoprolol XL, or nebivolol against placebo. The studies collectively enrolled 18,637 patients, which the investigators whittled down in their analysis to 17,433 after excluding patients with a left ventricular ejection fraction below 50% or who were undocumented. The subgroup with HFrEF included 13,861 patient in sinus rhythm at entry, 2,879 with atrial fibrillation, and 693 with an unknown atrial status. The main analysis ran in the 13,861 patients with HFrEF and in sinus rhythm; 14% of this cohort had an eGFR of 30-44 mL/min per 1.73 m² and 27% had an eGFR of 45-59 mL/min per 1.73 m². The median age of all patients in the main analysis was 65 years, 23% were women, and their median left ventricular ejection fraction was 27%.

During follow-up of about 3 years, the impact of beta-blocker treatment on survival, compared with placebo, was “substantial” for all strata of patients by renal function, except for those with eGFRs below 30 mL/min per 1.73 m². (Survival was similar regardless of beta-blocker treatment in the small number of patients with severe renal dysfunction.) The number needed to treat to prevent 1 death in patients with an eGFR of 30-44 mL/min per 1.73 m² was 21, the same as among patients with an eGFR of 90 mL/min per 1.73 m² or more, Dr. Kotecha said.

Among the subgroup of patients with atrial fibrillation, beta-blockers appeared to exert no survival benefit, compared with placebo. The investigators did not assess the survival benefits exerted by any individual beta-blocker, compared with the others, and Dr. Kotecha stressed that “my belief is that this is a class effect” and is roughly similar across all the beta-blockers used in the studies.

The analysis also showed good safety and tolerability of the beta-blockers in patients with renal dysfunction. The incidence of adverse events leading to treatment termination was very similar in the beta-blocker and placebo arms, and more than three-quarters of patients in each of the two subgroups with renal dysfunction were maintained on more than 50% of their target beta-blocker dosage.

Dr. Kotecha has been an advisor to Bayer, a speaker on behalf of Atricure, and has received research funding from GlaxoSmithKline and Menarini. Dr. Jessup had no disclosures.

[email protected]