The 2022-2023 Term of the Supreme Court illustrates how important the Court has become to health-related matters, including decisions regarding the selection and training of new professionals, the daily practice of medicine, and the future availability of new drugs. The importance of several cases is reinforced by the fact that major medical organizations filed amicus curiae (“friend of the court”) briefs in those cases.

Amicus briefs are filed by individuals or organizations with something significant to say about a case to the court—most often to present a point of view, make an argument, or provide information that the parties to the case may not have communicated. Amicus briefs are burdensome in terms of the time, energy, and cost of preparing and filing. Thus, they are not undertaken lightly. Medical organizations submitted amicus briefs in the first 3 cases we consider.

Admissions, race, and diversity

The case: Students for Fair Admissions v President and Fellows of Harvard College

The American College of Obstetricians and Gynecologists (ACOG) joined an amici curiae brief in Students for Fair Admissions v President and Fellows of Harvard College (and the University of North Carolina [UNC]).¹ This case challenged the use of racial preferences in college admissions. The Association of American Medical Colleges (AAMC) was the lead organization; nearly 40 other health-related organizations joined the brief.

The legal claim. Those filing the suits asserted that racial preferences by public colleges violate the 14th Amendment’s Equal Protection Clause (“no state shall deny to any person … the equal protection of the law”). That is, if a state university gives racial preferences in selective admissions, it denies some other applicant the equal protection of the law. As for private schools (in this case, Harvard), Title VI of the Civil Rights Act of 1964 has the same standards as the Equal Protection Clause. Thus, the Court consolidated the cases and used the same legal standard in considering public and private colleges (with “colleges” including professional and graduate programs as well as undergraduate institutions).

Background. For nearly 50 years, the Supreme Court has allowed limited racial preferences in college admissions. Those preferences could only operate as a plus, however, and not a negative for applicants and be narrowly tailored. The measure was instituted temporarily; in a 2003 case, the Court said, “We expect that 25 years from now, the use of racial preferences will no longer be necessary.”²

Decision. In a 6-3 decision, the Court held (in the UNC case) that racial preferences generally violate the Constitution, and by a 6-2 decision (in the Harvard case) these preferences violate the Civil Rights Act of 1964. (Justice Jackson was recused in the Harvard case because of a conflict.) The opinion covered 237 pages in the US Reports, so any summary is incomplete.

The majority concluded, “The Harvard and UNC admissions programs cannot be reconciled with the guarantees of the Equal Protection Clause. Both programs lack sufficiently focused and measurable objectives warranting the use of race, unavoidably employ race in a negative manner, involve racial stereotyping, and lack meaningful end points. We have never permitted admissions programs to work in that way, and we will not do so today.”³

There were 3 concurring opinions and 2 dissents in the case. The concurrences reviewed the history of the Equal Protection Clause and the Civil Rights Act, the damage racial preferences can do, and the explicit limits the Court said there must be on racial preferences in higher education. The dissents had a different view of the legal history of the 14th Amendment. They said the majority was turning a blind eye to segregation in society and the race-based gap in America.

As a practical matter, this case means that colleges, including professional schools, cannot use racial preferences. The Court said that universities may consider essays and the like in which applicants describe how their own experiences as an individual (including race) have affected their own lives. However, the Court cautioned that “universities may not simply establish through application essays or other means the regime we hold unlawful today.”³

Continue to: The amici brief...

ACOG joined 40 other health-related organizations in filing an amici brief (multiple “friends”) in Students for Fair Admission. The AAMC led the brief, with the others signing as amici.⁴ The brief made 3 essential points: diversity in medical education “markedly improves health outcomes,” and a loss of diversity “threaten[s] patients’ health; medical schools engage in an intense “holistic” review of applicants for admission; and medical schools must consider applicants’ “full background” (including race) to achieve their educational and professional goals.⁴

A powerful part of the brief described the medical school admissions process, particularly the very “holistic” review that is not entirely dependent on admissions scores. The brief effectively weaves the consideration of race into this process, mentioning race (on page 22) only after discussing many other admissions factors.

Child custody decisions related to the Indian Child Welfare Act

The case: Haaland v Brackeen

The American Medical Association (AMA) and the American Academy of Pediatrics filed a brief in Haaland v Brackeen⁵ involving the constitutionality of the 1978 Indian Child Welfare Act (ICWA). The statute followed a terrible history of Indian children being removed from their families inappropriately, as detailed in a concurring opinion by Justice Gorsuch.⁵ The two purposes of the act were to promote raising Native American children in their culture and stem the downward trend in tribal membership.

The legal claim. The Court consolidated several cases. Essentially, a 10-month-old child (A.L.M.) was placed in foster care with the Brackeens in Texas. After more than 1 year, the Brackeens sought adoption; the biological father, mother, and grandparents all supported it. The Navajo and Cherokee Nations objected and informed the Texas court that they had found alternative placement with (nonrelative) tribal members in New Mexico. The “court-appointed guardian and a psychological expert … described the strong emotional bond between A.L.M. and his foster parents.” The court denied the adoption petition based on ICWA’s preference for tribe custody, and the Brackeens filed a lawsuit. The Court noted that the act “requires a state court to place an Indian child with an Indian caretaker, if one is available, even if the child is already living with a non-Indian family and the state court thinks it in the child’s best interest to stay there.” That is, the ICWA may require a placement that the court believes is not in the child’s best interest.⁵

Decision. The constitutional claim in the case was that Congress lacked the authority to impose these substantial rules on states in making child custody decisions. The Supreme Court, in a 7-2 decision, upheld the constitutionality of the ICWA. The Court found the authority primarily in Article 1, Section 8, giving Congress the power to “regulate Commerce with foreign Nations, and among the several States, and with the Indian Tribes.” In addition, the Court suggested that the treaty power and “principles inherent in the Constitution’s structure may empower Congress to act in the field of Indian affairs.”

The amici brief

The joint amici brief of the American Academy of Pediatrics (AAP) and the AMA argued that tribes are “extended families” of Native American children.⁶ It noted the destructive history of removing Native American children from their families and suggested that kinship care improves children’s health. To its credit, the brief also honestly noted the serious mental health and suicide rates in some tribes, which suggest issues that might arise in child custody and adoption cases.

The Court did not, in this case, take up another constitutional issue that the parties raised—whether the strong preference for Native American over non ̶ Native American custody violates the Equal Protection Clause of the 14th Amendment. The Court said the parties to this case did not have standing to raise the issue. Justice Kavanaugh, concurring, said it was a “serious” issue and invited it to be raised in another case.⁵

False Claims Act cases

The case: Costs for SuperValu prescriptions

For physicians and health care organizations, False Claims Act (FCA) cases are an ongoing burden and, some would say, threat. (There are also state FCAs, but here we are discussing the federal act.) The federal government has recovered more than $70 billion since 1986, most from health care entities.⁷The Justice Department identifies “health care fraud” as the largest area of FCA recovery and provides annual details on frauds resulting in liability.⁸

The legal claim. One FCA case this Term involved billings SuperValu made for outpatient prescriptions in Medicare-Medicaid programs. As its “usual and customary” costs, it essentially reported a list price that did not include the substantial discounts it commonly gave.⁹ The charge was that it “knowingly” made a false claim regarding the price of prescriptions. The question was what state of mind, or “scienter,” is required for “knowingly.” Should it be objective (what a reasonable person would know) or subjective (the defendant’s “knowledge and subjective beliefs”)?

Background. Subjective knowledge (what the defendant actually knows) may seem impossible to prove—the defendant could just say, “I did not know I was doing wrong.” Over time the law has developed several ways of demonstrating “knowing.” Justice Thomas, writing for a unanimous Court, held that whistleblowers or the government might prove “knowing” in 3 ways:

1. defendants “actually knew that their reported prices were not their ‘usual and customary’ prices when they reported them”

2. were aware of a substantial risk that their higher, retail prices were not their “usual and customary” prices and intentionally avoided learning whether their reports were accurate

3. were aware of such a substantial and unjustifiable risk but submitted the claims anyway.⁹

Of course, records of the company, information from the whistleblower, and circumstantial evidence may be used to prove any of these; it does not require the company’s admission.

The Court said that if the government or whistleblowers make a showing of any of these 3 things, it is enough.

Decision. The case was returned to the lower court to apply these rules.

The amici brief

The American Hospital Association and America’s Health Insurance Plans filed an amici brief.¹⁰ It reminded the Court that many reimbursement regulations are unclear. Therefore, it is inappropriate to impose FCA liability for guessing incorrectly what the regulations mean. Having to check on every possible ambiguity was unworkable. The Court declined, however, the suggestion that defendants should be able to use any one of many “objectively” reasonable interpretations of regulations.

Continue to: The case: Polansky v Executive Health Resources...

The case: Polansky v Executive Health Resources

Health care providers who dislike the FCA may find solace this Term in this second FCA case.¹¹

The legal claim. Polansky, a physician employed by a medical billing company, became an “intervenor” in a suit claiming the company assisted hospitals in false billing (inpatient claims for outpatient services). The government sought to dismiss the case, but Polansky refused.

Decision. The case eventually reached the Supreme Court, which held that the government may enter an FCA case at any time and move to dismiss the case even over the objection of a whistleblower. The government does not seek to enter a case in order to file dismissal motions often. When it does so, whistleblowers are protected by the fact that the dismissal motion requires a hearing before the federal court.

An important part of this case has escaped much attention. Justices Thomas, Kavanaugh, and Barrett invited litigation to determine if allowing private whistleblowers to represent the government’s interest is consistent with Article II of the Constitution.¹¹ The invitation will likely be accepted. We expect to see cases challenging the place of “intervenors” pursuing claims when the government has declined to take up the case. The private intervenor is a crucial provision of the current FCA, and if such a challenge were successful, it could substantially reduce FCA cases.

Criminal false claims

Another case this Term is cautionary about the consequences of health care misbilling. It resulted in a criminal charge. More importantly, in addition to a basic fraud charge, the government added a charge of aggravated identity theft,¹² which carries a mandatory 2-year prison sentence.

Dubin overbilled Medicaid for psychological testing by saying the testing was done by a licensed psychologist rather than an assistant. The government claimed the “identity theft” was using the patient’s (actual) Medicaid number in submitting the bill.¹² The Court unanimously held the overbilling was not aggravated identity theft as defined in federal law. Dubin could be convicted of fraudulent billing but not aggravated identity theft, thereby avoiding the mandatory prison term.

Patents of “genus” targets

The case: Amgen v Sanofi

This case, which corrected an error of the patent office, received little attention but was likely a turning point in the next generation of pharmaceuticals.¹³

Background. “Genus” patents allow a single pharmaceutical company to patent every antibody that binds to a specific amino acid on a naturally occurring protein. In this case, the patent office had granted a “genus” patent on “all antibodies” that bind to the naturally occurring protein PCSK9 and block it from hindering the body’s mechanism for removing low-density lipoprotein (LDL) cholesterol from the bloodstream,¹³ helping to reduce LDL cholesterol levels. These patents could involve millions of antibodies—and Amgen was claiming a patent on all of them. Amgen and Sanofi marketed their products, each with their own unique amino acid sequence.¹³ Amgen sued Sanofi for violating its patent rights.

Decision. The Court unanimously held that Amgen did not have a valid patent on all antibodies targeting PCSK9, only those that it had explicitly described in its patent application—a ruling based on a 150-year-old technical requirement for receiving a patent. An applicant for a patent must include “a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art…to make and use the same.”¹³ Amgen’s patent provided the description for only a few of the antibodies, but from the description in its application others could not “make and use” all of the antibodies targeting PCSK9.

While the decision was vital for future pharmaceuticals, the patent principle on which it was based has an interesting history. The Court noted that it affected the telegraph (Morse lost part of his patent), electric lights (Edison won his case against other inventors), and the glue for wood veneering (Perkins Glue Company lost).¹³

Continue to: Other notable decisions...

Student loans

The Court struck down the Biden Administration’s student loan forgiveness program, which would have cost approximately $430 billion.¹⁴ The central issue was whether the administration had the authority for such massive loan forgiveness; that is, whether Congress had authorized the broad loan forgiveness. The administration claimed authority from the post ̶ 9/11 HEROES Act, which allows the Secretary of Education to “waive or modify” loan provisions during national emergencies. The temporary hold on loan payments during COVID was based on this provision. However, in a 6-3 decision, the Court held that the act did not allow the secretary to cancel $430 billion in loans. “The Act allows the Secretary to ‘waive or modify’ existing statutory or regulatory provisions applicable to financial assistance programs under the Education Act, not to rewrite that statute from the ground up.”¹⁴

Free speech and the wedding web designer

303 Creative v Elenis involved a creative website designer who did not want to be required to create a website for a gay wedding.¹⁵ The designer had strong beliefs against same-sex marriages, but Colorado sought to force her to do so under the state “public accommodations” law. In a 6-3 decision, the Court held that the designer had a “free speech” right. That is, the state could not compel her to undertake speech expressing things she did not believe. This was because the website design was an expressive, creative activity and therefore was “speech” under the First Amendment.

Wetlands and the Clean Water Act

The essential issue in Sackett v Environmental Protection Agency (EPA) was the definitions of waters of the United States and related wetlands. The broad definition the EPA used meant it had jurisdiction to regulate an extraordinary amount of territory. It had, for example, prevented the Sacketts from building a modest house claiming it was part of the “waters of the United States because they were near a ditch that fed into a creek, which fed into Priest Lake, a navigable, intrastate lake.” The Court held that the EPA exceeded its statutory authority to define “wetlands.”¹⁶

The Court held that under the Clean Water Act, for the EPA to establish jurisdiction over adjacent wetlands, it must demonstrate that¹⁶:

1. “the adjacent body of water constitutes waters of the United States (ie, a relatively permanent body of water connected to traditional interstate navigable waters)…”

2. “…the wetland has a continuous surface connection with that water, making it difficult to determine where the water ends, and the wetland begins.”

Under this definition, the Sacketts could build their house. This was a statutory interpretation case. Therefore, Congress can expand or otherwise change the EPA’s authority under the Clean Water Act and other legislation.

Conclusions: A new justice, “shadow docket,” and ethics rules

SCOTUS’ newest member. When the Marshall called the Court into session on October 3, 2022, it had a new member, Justice Ketanji Brown Jackson. She was sworn in on June 30, 2022, when her predecessor (Justice Breyer) officially retired. She had been a law clerk for Justice Breyer in 1999, as well as a district court judge and court of appeals judge. Those who count such things described her as the “chattiest justice.”¹⁷ She spoke more than any other justice—by one count, a total of 75,632 words (an average of 1,300 words in each of the 58 arguments).

A more balanced Court? Most commentators view the Court as more balanced or less conservative than the previous Term. For example, Justice Sotomayor was in the majority 40% last Term but 65% this Term. Justice Thomas was in the majority 75% last Term but 55% this Term. Put another way, this Term in the divided cases, the liberal justices were in the majority 64% of the time, compared with the conservative justices 73%.¹⁸ Of course, these differences may reflect a different set of cases rather than a change in the direction of the Court. There were 11 (or 12, depending on how 1 case is counted) 6-3 cases, but only 5 were considered ideological. That suggests that, in many cases, the coalitions were somewhat fluid.

“Shadow docket” controversy continues.¹⁹ Shadow docket refers to orders the Court makes that do not follow oral arguments and often do not have written opinions. The orders are all publicly available. This Term a close examination of the approximately 30 shadow docket opinions shows that the overwhelming majority were dissents or explanations about denials of certiorari. The Court ordered only a few stays or injunctions via the shadow docket. One shadow docket stay (that prevented a lower court order from going into effect) is particularly noteworthy. A federal judge had ordered the suspension of the distribution of mifepristone while courts considered claims that the US Food and Drug Administration (FDA) had improperly approved the drug. In a shadow docket order, the Court issued the stay to allow mifepristone to be sold while the case challenging its approval was heard.²⁰ The only opinion was a dissent from Justice Alito. But it also demonstrates the importance of the shadow docket. Without this intervention, in at least part of the country, the distribution of mifepristone would have been interrupted pending the outcome of the FDA cases.

In August, the Court delayed a settlement in the Purdue Pharma liability bankruptcy case.²¹ It also stayed an injunction of a lower court, thereby permitting federal “ghost guns” regulations to go into effect at least temporarily.²²

More ethics rules to come? Another area in which the Court faced criticism was formal ethics rules. The justices make financial disclosures, but these are somewhat ambiguous. There is likely to be increasing pressure for a more complete disclosure of non-financial relationships and more formal ethics rules. ●

The 2022-2023 Term of the Supreme Court illustrates how important the Court has become to health-related matters, including decisions regarding the selection and training of new professionals, the daily practice of medicine, and the future availability of new drugs. The importance of several cases is reinforced by the fact that major medical organizations filed amicus curiae (“friend of the court”) briefs in those cases.

Amicus briefs are filed by individuals or organizations with something significant to say about a case to the court—most often to present a point of view, make an argument, or provide information that the parties to the case may not have communicated. Amicus briefs are burdensome in terms of the time, energy, and cost of preparing and filing. Thus, they are not undertaken lightly. Medical organizations submitted amicus briefs in the first 3 cases we consider.

Admissions, race, and diversity

The case: Students for Fair Admissions v President and Fellows of Harvard College

The American College of Obstetricians and Gynecologists (ACOG) joined an amici curiae brief in Students for Fair Admissions v President and Fellows of Harvard College (and the University of North Carolina [UNC]).¹ This case challenged the use of racial preferences in college admissions. The Association of American Medical Colleges (AAMC) was the lead organization; nearly 40 other health-related organizations joined the brief.

The legal claim. Those filing the suits asserted that racial preferences by public colleges violate the 14th Amendment’s Equal Protection Clause (“no state shall deny to any person … the equal protection of the law”). That is, if a state university gives racial preferences in selective admissions, it denies some other applicant the equal protection of the law. As for private schools (in this case, Harvard), Title VI of the Civil Rights Act of 1964 has the same standards as the Equal Protection Clause. Thus, the Court consolidated the cases and used the same legal standard in considering public and private colleges (with “colleges” including professional and graduate programs as well as undergraduate institutions).

Background. For nearly 50 years, the Supreme Court has allowed limited racial preferences in college admissions. Those preferences could only operate as a plus, however, and not a negative for applicants and be narrowly tailored. The measure was instituted temporarily; in a 2003 case, the Court said, “We expect that 25 years from now, the use of racial preferences will no longer be necessary.”²

Decision. In a 6-3 decision, the Court held (in the UNC case) that racial preferences generally violate the Constitution, and by a 6-2 decision (in the Harvard case) these preferences violate the Civil Rights Act of 1964. (Justice Jackson was recused in the Harvard case because of a conflict.) The opinion covered 237 pages in the US Reports, so any summary is incomplete.

The majority concluded, “The Harvard and UNC admissions programs cannot be reconciled with the guarantees of the Equal Protection Clause. Both programs lack sufficiently focused and measurable objectives warranting the use of race, unavoidably employ race in a negative manner, involve racial stereotyping, and lack meaningful end points. We have never permitted admissions programs to work in that way, and we will not do so today.”³

There were 3 concurring opinions and 2 dissents in the case. The concurrences reviewed the history of the Equal Protection Clause and the Civil Rights Act, the damage racial preferences can do, and the explicit limits the Court said there must be on racial preferences in higher education. The dissents had a different view of the legal history of the 14th Amendment. They said the majority was turning a blind eye to segregation in society and the race-based gap in America.

As a practical matter, this case means that colleges, including professional schools, cannot use racial preferences. The Court said that universities may consider essays and the like in which applicants describe how their own experiences as an individual (including race) have affected their own lives. However, the Court cautioned that “universities may not simply establish through application essays or other means the regime we hold unlawful today.”³

Continue to: The amici brief...

ACOG joined 40 other health-related organizations in filing an amici brief (multiple “friends”) in Students for Fair Admission. The AAMC led the brief, with the others signing as amici.⁴ The brief made 3 essential points: diversity in medical education “markedly improves health outcomes,” and a loss of diversity “threaten[s] patients’ health; medical schools engage in an intense “holistic” review of applicants for admission; and medical schools must consider applicants’ “full background” (including race) to achieve their educational and professional goals.⁴

A powerful part of the brief described the medical school admissions process, particularly the very “holistic” review that is not entirely dependent on admissions scores. The brief effectively weaves the consideration of race into this process, mentioning race (on page 22) only after discussing many other admissions factors.

Child custody decisions related to the Indian Child Welfare Act

The case: Haaland v Brackeen

The American Medical Association (AMA) and the American Academy of Pediatrics filed a brief in Haaland v Brackeen⁵ involving the constitutionality of the 1978 Indian Child Welfare Act (ICWA). The statute followed a terrible history of Indian children being removed from their families inappropriately, as detailed in a concurring opinion by Justice Gorsuch.⁵ The two purposes of the act were to promote raising Native American children in their culture and stem the downward trend in tribal membership.

The legal claim. The Court consolidated several cases. Essentially, a 10-month-old child (A.L.M.) was placed in foster care with the Brackeens in Texas. After more than 1 year, the Brackeens sought adoption; the biological father, mother, and grandparents all supported it. The Navajo and Cherokee Nations objected and informed the Texas court that they had found alternative placement with (nonrelative) tribal members in New Mexico. The “court-appointed guardian and a psychological expert … described the strong emotional bond between A.L.M. and his foster parents.” The court denied the adoption petition based on ICWA’s preference for tribe custody, and the Brackeens filed a lawsuit. The Court noted that the act “requires a state court to place an Indian child with an Indian caretaker, if one is available, even if the child is already living with a non-Indian family and the state court thinks it in the child’s best interest to stay there.” That is, the ICWA may require a placement that the court believes is not in the child’s best interest.⁵

Decision. The constitutional claim in the case was that Congress lacked the authority to impose these substantial rules on states in making child custody decisions. The Supreme Court, in a 7-2 decision, upheld the constitutionality of the ICWA. The Court found the authority primarily in Article 1, Section 8, giving Congress the power to “regulate Commerce with foreign Nations, and among the several States, and with the Indian Tribes.” In addition, the Court suggested that the treaty power and “principles inherent in the Constitution’s structure may empower Congress to act in the field of Indian affairs.”

The amici brief

The joint amici brief of the American Academy of Pediatrics (AAP) and the AMA argued that tribes are “extended families” of Native American children.⁶ It noted the destructive history of removing Native American children from their families and suggested that kinship care improves children’s health. To its credit, the brief also honestly noted the serious mental health and suicide rates in some tribes, which suggest issues that might arise in child custody and adoption cases.

The Court did not, in this case, take up another constitutional issue that the parties raised—whether the strong preference for Native American over non ̶ Native American custody violates the Equal Protection Clause of the 14th Amendment. The Court said the parties to this case did not have standing to raise the issue. Justice Kavanaugh, concurring, said it was a “serious” issue and invited it to be raised in another case.⁵

False Claims Act cases

The case: Costs for SuperValu prescriptions

For physicians and health care organizations, False Claims Act (FCA) cases are an ongoing burden and, some would say, threat. (There are also state FCAs, but here we are discussing the federal act.) The federal government has recovered more than $70 billion since 1986, most from health care entities.⁷The Justice Department identifies “health care fraud” as the largest area of FCA recovery and provides annual details on frauds resulting in liability.⁸

The legal claim. One FCA case this Term involved billings SuperValu made for outpatient prescriptions in Medicare-Medicaid programs. As its “usual and customary” costs, it essentially reported a list price that did not include the substantial discounts it commonly gave.⁹ The charge was that it “knowingly” made a false claim regarding the price of prescriptions. The question was what state of mind, or “scienter,” is required for “knowingly.” Should it be objective (what a reasonable person would know) or subjective (the defendant’s “knowledge and subjective beliefs”)?

Background. Subjective knowledge (what the defendant actually knows) may seem impossible to prove—the defendant could just say, “I did not know I was doing wrong.” Over time the law has developed several ways of demonstrating “knowing.” Justice Thomas, writing for a unanimous Court, held that whistleblowers or the government might prove “knowing” in 3 ways:

1. defendants “actually knew that their reported prices were not their ‘usual and customary’ prices when they reported them”

2. were aware of a substantial risk that their higher, retail prices were not their “usual and customary” prices and intentionally avoided learning whether their reports were accurate

3. were aware of such a substantial and unjustifiable risk but submitted the claims anyway.⁹

Of course, records of the company, information from the whistleblower, and circumstantial evidence may be used to prove any of these; it does not require the company’s admission.

The Court said that if the government or whistleblowers make a showing of any of these 3 things, it is enough.

Decision. The case was returned to the lower court to apply these rules.

The amici brief

The American Hospital Association and America’s Health Insurance Plans filed an amici brief.¹⁰ It reminded the Court that many reimbursement regulations are unclear. Therefore, it is inappropriate to impose FCA liability for guessing incorrectly what the regulations mean. Having to check on every possible ambiguity was unworkable. The Court declined, however, the suggestion that defendants should be able to use any one of many “objectively” reasonable interpretations of regulations.

Continue to: The case: Polansky v Executive Health Resources...

The case: Polansky v Executive Health Resources

Health care providers who dislike the FCA may find solace this Term in this second FCA case.¹¹

The legal claim. Polansky, a physician employed by a medical billing company, became an “intervenor” in a suit claiming the company assisted hospitals in false billing (inpatient claims for outpatient services). The government sought to dismiss the case, but Polansky refused.

Decision. The case eventually reached the Supreme Court, which held that the government may enter an FCA case at any time and move to dismiss the case even over the objection of a whistleblower. The government does not seek to enter a case in order to file dismissal motions often. When it does so, whistleblowers are protected by the fact that the dismissal motion requires a hearing before the federal court.

An important part of this case has escaped much attention. Justices Thomas, Kavanaugh, and Barrett invited litigation to determine if allowing private whistleblowers to represent the government’s interest is consistent with Article II of the Constitution.¹¹ The invitation will likely be accepted. We expect to see cases challenging the place of “intervenors” pursuing claims when the government has declined to take up the case. The private intervenor is a crucial provision of the current FCA, and if such a challenge were successful, it could substantially reduce FCA cases.

Criminal false claims

Another case this Term is cautionary about the consequences of health care misbilling. It resulted in a criminal charge. More importantly, in addition to a basic fraud charge, the government added a charge of aggravated identity theft,¹² which carries a mandatory 2-year prison sentence.

Dubin overbilled Medicaid for psychological testing by saying the testing was done by a licensed psychologist rather than an assistant. The government claimed the “identity theft” was using the patient’s (actual) Medicaid number in submitting the bill.¹² The Court unanimously held the overbilling was not aggravated identity theft as defined in federal law. Dubin could be convicted of fraudulent billing but not aggravated identity theft, thereby avoiding the mandatory prison term.

Patents of “genus” targets

The case: Amgen v Sanofi

This case, which corrected an error of the patent office, received little attention but was likely a turning point in the next generation of pharmaceuticals.¹³

Background. “Genus” patents allow a single pharmaceutical company to patent every antibody that binds to a specific amino acid on a naturally occurring protein. In this case, the patent office had granted a “genus” patent on “all antibodies” that bind to the naturally occurring protein PCSK9 and block it from hindering the body’s mechanism for removing low-density lipoprotein (LDL) cholesterol from the bloodstream,¹³ helping to reduce LDL cholesterol levels. These patents could involve millions of antibodies—and Amgen was claiming a patent on all of them. Amgen and Sanofi marketed their products, each with their own unique amino acid sequence.¹³ Amgen sued Sanofi for violating its patent rights.

Decision. The Court unanimously held that Amgen did not have a valid patent on all antibodies targeting PCSK9, only those that it had explicitly described in its patent application—a ruling based on a 150-year-old technical requirement for receiving a patent. An applicant for a patent must include “a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art…to make and use the same.”¹³ Amgen’s patent provided the description for only a few of the antibodies, but from the description in its application others could not “make and use” all of the antibodies targeting PCSK9.

While the decision was vital for future pharmaceuticals, the patent principle on which it was based has an interesting history. The Court noted that it affected the telegraph (Morse lost part of his patent), electric lights (Edison won his case against other inventors), and the glue for wood veneering (Perkins Glue Company lost).¹³

Continue to: Other notable decisions...

Student loans

The Court struck down the Biden Administration’s student loan forgiveness program, which would have cost approximately $430 billion.¹⁴ The central issue was whether the administration had the authority for such massive loan forgiveness; that is, whether Congress had authorized the broad loan forgiveness. The administration claimed authority from the post ̶ 9/11 HEROES Act, which allows the Secretary of Education to “waive or modify” loan provisions during national emergencies. The temporary hold on loan payments during COVID was based on this provision. However, in a 6-3 decision, the Court held that the act did not allow the secretary to cancel $430 billion in loans. “The Act allows the Secretary to ‘waive or modify’ existing statutory or regulatory provisions applicable to financial assistance programs under the Education Act, not to rewrite that statute from the ground up.”¹⁴

Free speech and the wedding web designer

303 Creative v Elenis involved a creative website designer who did not want to be required to create a website for a gay wedding.¹⁵ The designer had strong beliefs against same-sex marriages, but Colorado sought to force her to do so under the state “public accommodations” law. In a 6-3 decision, the Court held that the designer had a “free speech” right. That is, the state could not compel her to undertake speech expressing things she did not believe. This was because the website design was an expressive, creative activity and therefore was “speech” under the First Amendment.

Wetlands and the Clean Water Act

The essential issue in Sackett v Environmental Protection Agency (EPA) was the definitions of waters of the United States and related wetlands. The broad definition the EPA used meant it had jurisdiction to regulate an extraordinary amount of territory. It had, for example, prevented the Sacketts from building a modest house claiming it was part of the “waters of the United States because they were near a ditch that fed into a creek, which fed into Priest Lake, a navigable, intrastate lake.” The Court held that the EPA exceeded its statutory authority to define “wetlands.”¹⁶

The Court held that under the Clean Water Act, for the EPA to establish jurisdiction over adjacent wetlands, it must demonstrate that¹⁶:

1. “the adjacent body of water constitutes waters of the United States (ie, a relatively permanent body of water connected to traditional interstate navigable waters)…”

2. “…the wetland has a continuous surface connection with that water, making it difficult to determine where the water ends, and the wetland begins.”

Under this definition, the Sacketts could build their house. This was a statutory interpretation case. Therefore, Congress can expand or otherwise change the EPA’s authority under the Clean Water Act and other legislation.

Conclusions: A new justice, “shadow docket,” and ethics rules

SCOTUS’ newest member. When the Marshall called the Court into session on October 3, 2022, it had a new member, Justice Ketanji Brown Jackson. She was sworn in on June 30, 2022, when her predecessor (Justice Breyer) officially retired. She had been a law clerk for Justice Breyer in 1999, as well as a district court judge and court of appeals judge. Those who count such things described her as the “chattiest justice.”¹⁷ She spoke more than any other justice—by one count, a total of 75,632 words (an average of 1,300 words in each of the 58 arguments).

A more balanced Court? Most commentators view the Court as more balanced or less conservative than the previous Term. For example, Justice Sotomayor was in the majority 40% last Term but 65% this Term. Justice Thomas was in the majority 75% last Term but 55% this Term. Put another way, this Term in the divided cases, the liberal justices were in the majority 64% of the time, compared with the conservative justices 73%.¹⁸ Of course, these differences may reflect a different set of cases rather than a change in the direction of the Court. There were 11 (or 12, depending on how 1 case is counted) 6-3 cases, but only 5 were considered ideological. That suggests that, in many cases, the coalitions were somewhat fluid.

“Shadow docket” controversy continues.¹⁹ Shadow docket refers to orders the Court makes that do not follow oral arguments and often do not have written opinions. The orders are all publicly available. This Term a close examination of the approximately 30 shadow docket opinions shows that the overwhelming majority were dissents or explanations about denials of certiorari. The Court ordered only a few stays or injunctions via the shadow docket. One shadow docket stay (that prevented a lower court order from going into effect) is particularly noteworthy. A federal judge had ordered the suspension of the distribution of mifepristone while courts considered claims that the US Food and Drug Administration (FDA) had improperly approved the drug. In a shadow docket order, the Court issued the stay to allow mifepristone to be sold while the case challenging its approval was heard.²⁰ The only opinion was a dissent from Justice Alito. But it also demonstrates the importance of the shadow docket. Without this intervention, in at least part of the country, the distribution of mifepristone would have been interrupted pending the outcome of the FDA cases.

In August, the Court delayed a settlement in the Purdue Pharma liability bankruptcy case.²¹ It also stayed an injunction of a lower court, thereby permitting federal “ghost guns” regulations to go into effect at least temporarily.²²

More ethics rules to come? Another area in which the Court faced criticism was formal ethics rules. The justices make financial disclosures, but these are somewhat ambiguous. There is likely to be increasing pressure for a more complete disclosure of non-financial relationships and more formal ethics rules. ●

The 2022-2023 Term of the Supreme Court illustrates how important the Court has become to health-related matters, including decisions regarding the selection and training of new professionals, the daily practice of medicine, and the future availability of new drugs. The importance of several cases is reinforced by the fact that major medical organizations filed amicus curiae (“friend of the court”) briefs in those cases.

Amicus briefs are filed by individuals or organizations with something significant to say about a case to the court—most often to present a point of view, make an argument, or provide information that the parties to the case may not have communicated. Amicus briefs are burdensome in terms of the time, energy, and cost of preparing and filing. Thus, they are not undertaken lightly. Medical organizations submitted amicus briefs in the first 3 cases we consider.

Admissions, race, and diversity

The case: Students for Fair Admissions v President and Fellows of Harvard College

The American College of Obstetricians and Gynecologists (ACOG) joined an amici curiae brief in Students for Fair Admissions v President and Fellows of Harvard College (and the University of North Carolina [UNC]).¹ This case challenged the use of racial preferences in college admissions. The Association of American Medical Colleges (AAMC) was the lead organization; nearly 40 other health-related organizations joined the brief.

The legal claim. Those filing the suits asserted that racial preferences by public colleges violate the 14th Amendment’s Equal Protection Clause (“no state shall deny to any person … the equal protection of the law”). That is, if a state university gives racial preferences in selective admissions, it denies some other applicant the equal protection of the law. As for private schools (in this case, Harvard), Title VI of the Civil Rights Act of 1964 has the same standards as the Equal Protection Clause. Thus, the Court consolidated the cases and used the same legal standard in considering public and private colleges (with “colleges” including professional and graduate programs as well as undergraduate institutions).

Background. For nearly 50 years, the Supreme Court has allowed limited racial preferences in college admissions. Those preferences could only operate as a plus, however, and not a negative for applicants and be narrowly tailored. The measure was instituted temporarily; in a 2003 case, the Court said, “We expect that 25 years from now, the use of racial preferences will no longer be necessary.”²

Decision. In a 6-3 decision, the Court held (in the UNC case) that racial preferences generally violate the Constitution, and by a 6-2 decision (in the Harvard case) these preferences violate the Civil Rights Act of 1964. (Justice Jackson was recused in the Harvard case because of a conflict.) The opinion covered 237 pages in the US Reports, so any summary is incomplete.

The majority concluded, “The Harvard and UNC admissions programs cannot be reconciled with the guarantees of the Equal Protection Clause. Both programs lack sufficiently focused and measurable objectives warranting the use of race, unavoidably employ race in a negative manner, involve racial stereotyping, and lack meaningful end points. We have never permitted admissions programs to work in that way, and we will not do so today.”³

There were 3 concurring opinions and 2 dissents in the case. The concurrences reviewed the history of the Equal Protection Clause and the Civil Rights Act, the damage racial preferences can do, and the explicit limits the Court said there must be on racial preferences in higher education. The dissents had a different view of the legal history of the 14th Amendment. They said the majority was turning a blind eye to segregation in society and the race-based gap in America.

As a practical matter, this case means that colleges, including professional schools, cannot use racial preferences. The Court said that universities may consider essays and the like in which applicants describe how their own experiences as an individual (including race) have affected their own lives. However, the Court cautioned that “universities may not simply establish through application essays or other means the regime we hold unlawful today.”³

Continue to: The amici brief...

ACOG joined 40 other health-related organizations in filing an amici brief (multiple “friends”) in Students for Fair Admission. The AAMC led the brief, with the others signing as amici.⁴ The brief made 3 essential points: diversity in medical education “markedly improves health outcomes,” and a loss of diversity “threaten[s] patients’ health; medical schools engage in an intense “holistic” review of applicants for admission; and medical schools must consider applicants’ “full background” (including race) to achieve their educational and professional goals.⁴

A powerful part of the brief described the medical school admissions process, particularly the very “holistic” review that is not entirely dependent on admissions scores. The brief effectively weaves the consideration of race into this process, mentioning race (on page 22) only after discussing many other admissions factors.

Child custody decisions related to the Indian Child Welfare Act

The case: Haaland v Brackeen

The American Medical Association (AMA) and the American Academy of Pediatrics filed a brief in Haaland v Brackeen⁵ involving the constitutionality of the 1978 Indian Child Welfare Act (ICWA). The statute followed a terrible history of Indian children being removed from their families inappropriately, as detailed in a concurring opinion by Justice Gorsuch.⁵ The two purposes of the act were to promote raising Native American children in their culture and stem the downward trend in tribal membership.

The legal claim. The Court consolidated several cases. Essentially, a 10-month-old child (A.L.M.) was placed in foster care with the Brackeens in Texas. After more than 1 year, the Brackeens sought adoption; the biological father, mother, and grandparents all supported it. The Navajo and Cherokee Nations objected and informed the Texas court that they had found alternative placement with (nonrelative) tribal members in New Mexico. The “court-appointed guardian and a psychological expert … described the strong emotional bond between A.L.M. and his foster parents.” The court denied the adoption petition based on ICWA’s preference for tribe custody, and the Brackeens filed a lawsuit. The Court noted that the act “requires a state court to place an Indian child with an Indian caretaker, if one is available, even if the child is already living with a non-Indian family and the state court thinks it in the child’s best interest to stay there.” That is, the ICWA may require a placement that the court believes is not in the child’s best interest.⁵

Decision. The constitutional claim in the case was that Congress lacked the authority to impose these substantial rules on states in making child custody decisions. The Supreme Court, in a 7-2 decision, upheld the constitutionality of the ICWA. The Court found the authority primarily in Article 1, Section 8, giving Congress the power to “regulate Commerce with foreign Nations, and among the several States, and with the Indian Tribes.” In addition, the Court suggested that the treaty power and “principles inherent in the Constitution’s structure may empower Congress to act in the field of Indian affairs.”

The amici brief

The joint amici brief of the American Academy of Pediatrics (AAP) and the AMA argued that tribes are “extended families” of Native American children.⁶ It noted the destructive history of removing Native American children from their families and suggested that kinship care improves children’s health. To its credit, the brief also honestly noted the serious mental health and suicide rates in some tribes, which suggest issues that might arise in child custody and adoption cases.

The Court did not, in this case, take up another constitutional issue that the parties raised—whether the strong preference for Native American over non ̶ Native American custody violates the Equal Protection Clause of the 14th Amendment. The Court said the parties to this case did not have standing to raise the issue. Justice Kavanaugh, concurring, said it was a “serious” issue and invited it to be raised in another case.⁵

False Claims Act cases

The case: Costs for SuperValu prescriptions

For physicians and health care organizations, False Claims Act (FCA) cases are an ongoing burden and, some would say, threat. (There are also state FCAs, but here we are discussing the federal act.) The federal government has recovered more than $70 billion since 1986, most from health care entities.⁷The Justice Department identifies “health care fraud” as the largest area of FCA recovery and provides annual details on frauds resulting in liability.⁸

The legal claim. One FCA case this Term involved billings SuperValu made for outpatient prescriptions in Medicare-Medicaid programs. As its “usual and customary” costs, it essentially reported a list price that did not include the substantial discounts it commonly gave.⁹ The charge was that it “knowingly” made a false claim regarding the price of prescriptions. The question was what state of mind, or “scienter,” is required for “knowingly.” Should it be objective (what a reasonable person would know) or subjective (the defendant’s “knowledge and subjective beliefs”)?

Background. Subjective knowledge (what the defendant actually knows) may seem impossible to prove—the defendant could just say, “I did not know I was doing wrong.” Over time the law has developed several ways of demonstrating “knowing.” Justice Thomas, writing for a unanimous Court, held that whistleblowers or the government might prove “knowing” in 3 ways:

1. defendants “actually knew that their reported prices were not their ‘usual and customary’ prices when they reported them”

2. were aware of a substantial risk that their higher, retail prices were not their “usual and customary” prices and intentionally avoided learning whether their reports were accurate

3. were aware of such a substantial and unjustifiable risk but submitted the claims anyway.⁹

Of course, records of the company, information from the whistleblower, and circumstantial evidence may be used to prove any of these; it does not require the company’s admission.

The Court said that if the government or whistleblowers make a showing of any of these 3 things, it is enough.

Decision. The case was returned to the lower court to apply these rules.

The amici brief

The American Hospital Association and America’s Health Insurance Plans filed an amici brief.¹⁰ It reminded the Court that many reimbursement regulations are unclear. Therefore, it is inappropriate to impose FCA liability for guessing incorrectly what the regulations mean. Having to check on every possible ambiguity was unworkable. The Court declined, however, the suggestion that defendants should be able to use any one of many “objectively” reasonable interpretations of regulations.

Continue to: The case: Polansky v Executive Health Resources...

The case: Polansky v Executive Health Resources

Health care providers who dislike the FCA may find solace this Term in this second FCA case.¹¹

The legal claim. Polansky, a physician employed by a medical billing company, became an “intervenor” in a suit claiming the company assisted hospitals in false billing (inpatient claims for outpatient services). The government sought to dismiss the case, but Polansky refused.

Decision. The case eventually reached the Supreme Court, which held that the government may enter an FCA case at any time and move to dismiss the case even over the objection of a whistleblower. The government does not seek to enter a case in order to file dismissal motions often. When it does so, whistleblowers are protected by the fact that the dismissal motion requires a hearing before the federal court.

An important part of this case has escaped much attention. Justices Thomas, Kavanaugh, and Barrett invited litigation to determine if allowing private whistleblowers to represent the government’s interest is consistent with Article II of the Constitution.¹¹ The invitation will likely be accepted. We expect to see cases challenging the place of “intervenors” pursuing claims when the government has declined to take up the case. The private intervenor is a crucial provision of the current FCA, and if such a challenge were successful, it could substantially reduce FCA cases.

Criminal false claims

Another case this Term is cautionary about the consequences of health care misbilling. It resulted in a criminal charge. More importantly, in addition to a basic fraud charge, the government added a charge of aggravated identity theft,¹² which carries a mandatory 2-year prison sentence.

Dubin overbilled Medicaid for psychological testing by saying the testing was done by a licensed psychologist rather than an assistant. The government claimed the “identity theft” was using the patient’s (actual) Medicaid number in submitting the bill.¹² The Court unanimously held the overbilling was not aggravated identity theft as defined in federal law. Dubin could be convicted of fraudulent billing but not aggravated identity theft, thereby avoiding the mandatory prison term.

Patents of “genus” targets

The case: Amgen v Sanofi

This case, which corrected an error of the patent office, received little attention but was likely a turning point in the next generation of pharmaceuticals.¹³

Background. “Genus” patents allow a single pharmaceutical company to patent every antibody that binds to a specific amino acid on a naturally occurring protein. In this case, the patent office had granted a “genus” patent on “all antibodies” that bind to the naturally occurring protein PCSK9 and block it from hindering the body’s mechanism for removing low-density lipoprotein (LDL) cholesterol from the bloodstream,¹³ helping to reduce LDL cholesterol levels. These patents could involve millions of antibodies—and Amgen was claiming a patent on all of them. Amgen and Sanofi marketed their products, each with their own unique amino acid sequence.¹³ Amgen sued Sanofi for violating its patent rights.

Decision. The Court unanimously held that Amgen did not have a valid patent on all antibodies targeting PCSK9, only those that it had explicitly described in its patent application—a ruling based on a 150-year-old technical requirement for receiving a patent. An applicant for a patent must include “a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art…to make and use the same.”¹³ Amgen’s patent provided the description for only a few of the antibodies, but from the description in its application others could not “make and use” all of the antibodies targeting PCSK9.

While the decision was vital for future pharmaceuticals, the patent principle on which it was based has an interesting history. The Court noted that it affected the telegraph (Morse lost part of his patent), electric lights (Edison won his case against other inventors), and the glue for wood veneering (Perkins Glue Company lost).¹³

Continue to: Other notable decisions...

Student loans

The Court struck down the Biden Administration’s student loan forgiveness program, which would have cost approximately $430 billion.¹⁴ The central issue was whether the administration had the authority for such massive loan forgiveness; that is, whether Congress had authorized the broad loan forgiveness. The administration claimed authority from the post ̶ 9/11 HEROES Act, which allows the Secretary of Education to “waive or modify” loan provisions during national emergencies. The temporary hold on loan payments during COVID was based on this provision. However, in a 6-3 decision, the Court held that the act did not allow the secretary to cancel $430 billion in loans. “The Act allows the Secretary to ‘waive or modify’ existing statutory or regulatory provisions applicable to financial assistance programs under the Education Act, not to rewrite that statute from the ground up.”¹⁴

Free speech and the wedding web designer

303 Creative v Elenis involved a creative website designer who did not want to be required to create a website for a gay wedding.¹⁵ The designer had strong beliefs against same-sex marriages, but Colorado sought to force her to do so under the state “public accommodations” law. In a 6-3 decision, the Court held that the designer had a “free speech” right. That is, the state could not compel her to undertake speech expressing things she did not believe. This was because the website design was an expressive, creative activity and therefore was “speech” under the First Amendment.

Wetlands and the Clean Water Act

The essential issue in Sackett v Environmental Protection Agency (EPA) was the definitions of waters of the United States and related wetlands. The broad definition the EPA used meant it had jurisdiction to regulate an extraordinary amount of territory. It had, for example, prevented the Sacketts from building a modest house claiming it was part of the “waters of the United States because they were near a ditch that fed into a creek, which fed into Priest Lake, a navigable, intrastate lake.” The Court held that the EPA exceeded its statutory authority to define “wetlands.”¹⁶

The Court held that under the Clean Water Act, for the EPA to establish jurisdiction over adjacent wetlands, it must demonstrate that¹⁶:

1. “the adjacent body of water constitutes waters of the United States (ie, a relatively permanent body of water connected to traditional interstate navigable waters)…”

2. “…the wetland has a continuous surface connection with that water, making it difficult to determine where the water ends, and the wetland begins.”

Under this definition, the Sacketts could build their house. This was a statutory interpretation case. Therefore, Congress can expand or otherwise change the EPA’s authority under the Clean Water Act and other legislation.

Conclusions: A new justice, “shadow docket,” and ethics rules

SCOTUS’ newest member. When the Marshall called the Court into session on October 3, 2022, it had a new member, Justice Ketanji Brown Jackson. She was sworn in on June 30, 2022, when her predecessor (Justice Breyer) officially retired. She had been a law clerk for Justice Breyer in 1999, as well as a district court judge and court of appeals judge. Those who count such things described her as the “chattiest justice.”¹⁷ She spoke more than any other justice—by one count, a total of 75,632 words (an average of 1,300 words in each of the 58 arguments).

A more balanced Court? Most commentators view the Court as more balanced or less conservative than the previous Term. For example, Justice Sotomayor was in the majority 40% last Term but 65% this Term. Justice Thomas was in the majority 75% last Term but 55% this Term. Put another way, this Term in the divided cases, the liberal justices were in the majority 64% of the time, compared with the conservative justices 73%.¹⁸ Of course, these differences may reflect a different set of cases rather than a change in the direction of the Court. There were 11 (or 12, depending on how 1 case is counted) 6-3 cases, but only 5 were considered ideological. That suggests that, in many cases, the coalitions were somewhat fluid.

“Shadow docket” controversy continues.¹⁹ Shadow docket refers to orders the Court makes that do not follow oral arguments and often do not have written opinions. The orders are all publicly available. This Term a close examination of the approximately 30 shadow docket opinions shows that the overwhelming majority were dissents or explanations about denials of certiorari. The Court ordered only a few stays or injunctions via the shadow docket. One shadow docket stay (that prevented a lower court order from going into effect) is particularly noteworthy. A federal judge had ordered the suspension of the distribution of mifepristone while courts considered claims that the US Food and Drug Administration (FDA) had improperly approved the drug. In a shadow docket order, the Court issued the stay to allow mifepristone to be sold while the case challenging its approval was heard.²⁰ The only opinion was a dissent from Justice Alito. But it also demonstrates the importance of the shadow docket. Without this intervention, in at least part of the country, the distribution of mifepristone would have been interrupted pending the outcome of the FDA cases.

In August, the Court delayed a settlement in the Purdue Pharma liability bankruptcy case.²¹ It also stayed an injunction of a lower court, thereby permitting federal “ghost guns” regulations to go into effect at least temporarily.²²

More ethics rules to come? Another area in which the Court faced criticism was formal ethics rules. The justices make financial disclosures, but these are somewhat ambiguous. There is likely to be increasing pressure for a more complete disclosure of non-financial relationships and more formal ethics rules. ●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Hepatitis B is one of the more common infections encountered in the daily practice of obstetrics. It is responsible for 40% to 45% of all cases of viral hepatitis.^1,2 Hepatitis B may cause serious complications in both the infected mother and neonate.

In this article, I review the virology, epidemiology, and clinical presentation of hepatitis B and then discuss the key diagnostic tests and, subsequently, the clinical management for both the mother and neonate. I focus particular attention on relatively new information about the value of specific antiviral medication to enhance the protective effect of conventional neonatal immunoprophylaxis.

To set the framework for the discussion, consider the following 2 case studies.

CASE 1 Undetectable level of hepatitis B surface antibody in a pregnant woman

A 25-year-old healthy primigravid woman at 10 weeks’ gestation had a series of laboratory studies that included a test for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb). The test for the surface antigen was negative. The test for the surface antibody was below the level of detection. Upon questioning, the patient indicates that she received the 3-dose hepatitis B vaccine when she was age 13 years.

• What treatment, if any, is indicated for this patient?
• What treatment is indicated for her neonate?

CASE 2 Pregnant woman tests positive for hepatitis B surface antigen

A 31-year-old woman (G3P2002) at 12 weeks’ gestation tested positive for HBsAg. She indicates that she never has had symptomatic hepatitis and that she considers herself to be in excellent health.

• What additional laboratory tests are indicated at this time?
• What additional laboratory test should be performed at the end of the second trimester?
• What treatment is indicated for the mother and neonate?

Virology and epidemiology of hepatitis B

Hepatitis B is caused by a double-stranded, enveloped DNA virus. The virus has 10 genotypes and 24 subtypes.³ The organism contains 3 major antigens. Detection of these antigens and their corresponding antibodies is an essential step in the diagnostic workup of patients who may be infected.

The surface antigen (HBsAg) confers infectivity and is the most valuable serologic marker of infection. The e antigen (HBeAg) is not present in every infected patient. It is secreted from infected cells, but it is not incorporated into the viral particle. When present, it denotes a high level of viral replication and exceptionally high infectivity. The core antigen (HBcAg) is a valuable serologic marker for distinguishing between acute and chronic infection.^1-3

Hepatitis B is highly infectious, much more so than HIV or hepatitis C. The virus has an incubation period of 4 weeks to 6 months, and the duration of incubation is inversely related to the size of the viral inoculum. The virus is transmitted in 3 principal ways: sexual contact with contaminated genital tract secretions, contact with infected blood from sharing contaminated drug-injecting paraphernalia or from receiving a blood transfusion (extremely rare today), and transmission from an infected mother to her neonate. Perinatal transmission occurs primarily during the delivery process as opposed to transplacental infection. Transmission also can occur by more casual household contact, such as sharing eating utensils, kissing, and handling an infant.^1,2,4,5

Worldwide, more than 400 million people have chronic hepatitis B infection. In the United States, approximately 1.25 to 1.5 million individuals are infected. Several groups are at particularly high risk for being infected, including^1-3:

• Asians
• Alaska Natives
• sub-Saharan Africans
• sex workers
• intravenous drug users
• individuals with hemophilia
• international travelers
• staff and residents of long-term care facilities
• tattoo recipients.

Continue to: Clinical presentation...

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...

Maternal antiviral therapy

As noted above, neonatal immunoprophylaxis is 85% to 95% effective in preventing perinatal transmission of hepatitis B infection. Failures of prophylaxis are primarily due to antenatal transmission in patients who have exceptionally high viral loads. Several cutoffs have been used to define “high viral load,” including greater than 1 to 2 million copies/mL and a hepatitis B DNA concentration greater than 200,000 IU/mL. There is not a perfect consensus on the appropriate cutoff.

In essence, 2 different approaches have been tried to further reduce the risk of perinatal transmission in these high-risk patients.⁸ The first major initiative was administration of HBIG (100–200 IU) intramuscularly to the patient at 28, 32, and 36 weeks. The outcomes with this approach have been inconsistent, due, at least in part, to varying doses of the agent and various cutoffs for defining “high risk,” and this intervention is no longer recommended.^1,2

The second major approach is administration of specific antiviral drugs to the mother during the third trimester. The first agent widely used in clinical practice was lamivudine. In a systematic review and meta-analysis, Shi and colleagues reported that, in infants whose mothers received lamivudine plus conventional neonatal immunuprophylaxis, the risk of perinatal infection was significantly reduced compared with infants who received only immunoprophylaxis.⁹

Although lamivudine is effective, there is considerable concern about the rapid development of viral resistance to the medication. Accordingly, most attention today is focused on the use of tenofovir to prevent perinatal transmission.

In an important early investigation, Pan and colleagues reported the results of a randomized controlled trial conducted in China in women with a hepatitis B DNA concentration greater than 200,000 IU/mL (viral load > 1,120,000 copies/mL).¹⁰ Patients also were positive for the e antigen. Ninety-two patients were assigned to tenofovir disoproxil fumarate (TDF), 300 mg daily, from 30 to 32 weeks until postpartum week 4 plus conventional neonatal immunoprophylaxis, and 100 patients were assigned to immunoprophylaxis alone. In the intention-to-treat analysis, 18 neonates in the control group were infected compared with 5 in the treatment group (P = .007). In the per-protocol analysis, 7 neonates in the control group were infected compared with 0 in the treatment group (P = .01). No clinically significant adverse maternal or neonatal effects occurred in the treatment group.

Subsequently, Jourdain and colleagues reported a multicenter, double-blind trial conducted in 17 public health hospitals in Thailand.¹¹ TDF (300 mg daily) or placebo was administered from 28 weeks’ gestation until 8 weeks postpartum. Patients in both arms of the study were positive for the e antigen; 87% to 90% of the patients had a serum hepatitis B DNA concentration greater than 200,000 IU/mL.Following birth, infants in both groups received an injection of HBIG and then 4 doses of hepatitis B vaccine (0, 1, 2, 4, and 6 months). Both the HBIG and hepatitis B vaccine were administered very promptly after birth (median time, 1.2–1.3 hours).

At 6 months after delivery, 2% of infants in the placebo group (3 of 147) were HBsAg-positive compared with none of the infants in the treatment arm.¹¹ No serious adverse effects occurred in infants in the TDF group. This difference in outcome was not statistically significant, but the overall rate of infection was so low in both groups that the sample size was definitely too small to exclude a type 2 statistical error. Moreover, the fourth dose of neonatal hepatitis B vaccine may have contributed to the surprisingly low rate of perinatal transmission. Of note, the serum hepatitis B DNA concentration in the TDF group declined from a mean of 7.6 log₁₀ IU/mL to a mean of 4.0 log₁₀ IU/mL at delivery.

In the most recent report, Wang and colleagues reported the results of a prospective cohort study in patients with a hepatitis B virus DNA concentration greater than 200,000 IU/mL.¹² Beginning at either 24 or 32 weeks, patients were assigned to treatment with either oral TDF (300 mg daily) or oral telbivudine (LdT, 600 mg daily). The medications were continued for 4 weeks postpartum. In the intention-to-treat analysis, the rates of perinatal transmission were comparable, 1.5% versus 1.8%. In the per-protocol analysis, no infants in either group were infected. However, the predelivery decline in hepatitis Bvirus DNA concentration was greater in the TDF group. The ALT elevation rate was also lower in the TDF group. Patients in the LdT group had fewer problems with anorexia but more instances of arthralgia compared with those in the TDF group.

Based primarily on these 3 investigations, I recommend that all infected patients with a hepatitis B DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL receive oral TDF, 300 mg daily, from 28 weeks until at least 4 to 8 weeks postpartum. The decision about duration of postpartum treatment should be made in consultation with an infectious disease specialist or hepatologist.

Case studies resolved

CASE 1 No protective level of surface antibody

This patient should promptly receive a single booster dose of the hepatitis B vaccine. The vaccine is an inactivated agent and is safe for administration at any time in pregnancy. Following delivery and prior to discharge from the hospital, the neonate should receive the first dose of the hepatitis B vaccine. A second dose should be administered 1 month later, and a third dose should be administered 6 months after the first dose.

CASE 2 Mother is seropositive for HBsAg

This patient should be tested immediately for HIV infection and hepatitis C and D. The hepatitis B viral genotype should be determined. She also should have a panel of liver function tests. If any of these tests are abnormal, a coagulation profile should be obtained to be certain that the patient is not at risk for a coagulopathy. Near the end of the second trimester, a hepatitis B viral load should be obtained. If the viral DNA concentration is greater than 200,000 IU/mLor a viral load greater than 1,120,000 million copies/mL, the patient should be treated with tenofovir, 300 mg daily, from week 28 until at least 4 weeks after delivery. The neonate should receive an injection of HBIG within 12 hours of birth and the first dose of the hepatitis B vaccine prior to discharge from the hospital. Two additional doses of the vaccine should be administered 1 and 6 months later. ●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Hepatitis B is one of the more common infections encountered in the daily practice of obstetrics. It is responsible for 40% to 45% of all cases of viral hepatitis.^1,2 Hepatitis B may cause serious complications in both the infected mother and neonate.

In this article, I review the virology, epidemiology, and clinical presentation of hepatitis B and then discuss the key diagnostic tests and, subsequently, the clinical management for both the mother and neonate. I focus particular attention on relatively new information about the value of specific antiviral medication to enhance the protective effect of conventional neonatal immunoprophylaxis.

To set the framework for the discussion, consider the following 2 case studies.

CASE 1 Undetectable level of hepatitis B surface antibody in a pregnant woman

A 25-year-old healthy primigravid woman at 10 weeks’ gestation had a series of laboratory studies that included a test for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb). The test for the surface antigen was negative. The test for the surface antibody was below the level of detection. Upon questioning, the patient indicates that she received the 3-dose hepatitis B vaccine when she was age 13 years.

• What treatment, if any, is indicated for this patient?
• What treatment is indicated for her neonate?

CASE 2 Pregnant woman tests positive for hepatitis B surface antigen

A 31-year-old woman (G3P2002) at 12 weeks’ gestation tested positive for HBsAg. She indicates that she never has had symptomatic hepatitis and that she considers herself to be in excellent health.

• What additional laboratory tests are indicated at this time?
• What additional laboratory test should be performed at the end of the second trimester?
• What treatment is indicated for the mother and neonate?

Virology and epidemiology of hepatitis B

Hepatitis B is caused by a double-stranded, enveloped DNA virus. The virus has 10 genotypes and 24 subtypes.³ The organism contains 3 major antigens. Detection of these antigens and their corresponding antibodies is an essential step in the diagnostic workup of patients who may be infected.

The surface antigen (HBsAg) confers infectivity and is the most valuable serologic marker of infection. The e antigen (HBeAg) is not present in every infected patient. It is secreted from infected cells, but it is not incorporated into the viral particle. When present, it denotes a high level of viral replication and exceptionally high infectivity. The core antigen (HBcAg) is a valuable serologic marker for distinguishing between acute and chronic infection.^1-3

Hepatitis B is highly infectious, much more so than HIV or hepatitis C. The virus has an incubation period of 4 weeks to 6 months, and the duration of incubation is inversely related to the size of the viral inoculum. The virus is transmitted in 3 principal ways: sexual contact with contaminated genital tract secretions, contact with infected blood from sharing contaminated drug-injecting paraphernalia or from receiving a blood transfusion (extremely rare today), and transmission from an infected mother to her neonate. Perinatal transmission occurs primarily during the delivery process as opposed to transplacental infection. Transmission also can occur by more casual household contact, such as sharing eating utensils, kissing, and handling an infant.^1,2,4,5

Worldwide, more than 400 million people have chronic hepatitis B infection. In the United States, approximately 1.25 to 1.5 million individuals are infected. Several groups are at particularly high risk for being infected, including^1-3:

• Asians
• Alaska Natives
• sub-Saharan Africans
• sex workers
• intravenous drug users
• individuals with hemophilia
• international travelers
• staff and residents of long-term care facilities
• tattoo recipients.

Continue to: Clinical presentation...

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...

Maternal antiviral therapy

As noted above, neonatal immunoprophylaxis is 85% to 95% effective in preventing perinatal transmission of hepatitis B infection. Failures of prophylaxis are primarily due to antenatal transmission in patients who have exceptionally high viral loads. Several cutoffs have been used to define “high viral load,” including greater than 1 to 2 million copies/mL and a hepatitis B DNA concentration greater than 200,000 IU/mL. There is not a perfect consensus on the appropriate cutoff.

In essence, 2 different approaches have been tried to further reduce the risk of perinatal transmission in these high-risk patients.⁸ The first major initiative was administration of HBIG (100–200 IU) intramuscularly to the patient at 28, 32, and 36 weeks. The outcomes with this approach have been inconsistent, due, at least in part, to varying doses of the agent and various cutoffs for defining “high risk,” and this intervention is no longer recommended.^1,2

The second major approach is administration of specific antiviral drugs to the mother during the third trimester. The first agent widely used in clinical practice was lamivudine. In a systematic review and meta-analysis, Shi and colleagues reported that, in infants whose mothers received lamivudine plus conventional neonatal immunuprophylaxis, the risk of perinatal infection was significantly reduced compared with infants who received only immunoprophylaxis.⁹

Although lamivudine is effective, there is considerable concern about the rapid development of viral resistance to the medication. Accordingly, most attention today is focused on the use of tenofovir to prevent perinatal transmission.

In an important early investigation, Pan and colleagues reported the results of a randomized controlled trial conducted in China in women with a hepatitis B DNA concentration greater than 200,000 IU/mL (viral load > 1,120,000 copies/mL).¹⁰ Patients also were positive for the e antigen. Ninety-two patients were assigned to tenofovir disoproxil fumarate (TDF), 300 mg daily, from 30 to 32 weeks until postpartum week 4 plus conventional neonatal immunoprophylaxis, and 100 patients were assigned to immunoprophylaxis alone. In the intention-to-treat analysis, 18 neonates in the control group were infected compared with 5 in the treatment group (P = .007). In the per-protocol analysis, 7 neonates in the control group were infected compared with 0 in the treatment group (P = .01). No clinically significant adverse maternal or neonatal effects occurred in the treatment group.

Subsequently, Jourdain and colleagues reported a multicenter, double-blind trial conducted in 17 public health hospitals in Thailand.¹¹ TDF (300 mg daily) or placebo was administered from 28 weeks’ gestation until 8 weeks postpartum. Patients in both arms of the study were positive for the e antigen; 87% to 90% of the patients had a serum hepatitis B DNA concentration greater than 200,000 IU/mL.Following birth, infants in both groups received an injection of HBIG and then 4 doses of hepatitis B vaccine (0, 1, 2, 4, and 6 months). Both the HBIG and hepatitis B vaccine were administered very promptly after birth (median time, 1.2–1.3 hours).

At 6 months after delivery, 2% of infants in the placebo group (3 of 147) were HBsAg-positive compared with none of the infants in the treatment arm.¹¹ No serious adverse effects occurred in infants in the TDF group. This difference in outcome was not statistically significant, but the overall rate of infection was so low in both groups that the sample size was definitely too small to exclude a type 2 statistical error. Moreover, the fourth dose of neonatal hepatitis B vaccine may have contributed to the surprisingly low rate of perinatal transmission. Of note, the serum hepatitis B DNA concentration in the TDF group declined from a mean of 7.6 log₁₀ IU/mL to a mean of 4.0 log₁₀ IU/mL at delivery.

In the most recent report, Wang and colleagues reported the results of a prospective cohort study in patients with a hepatitis B virus DNA concentration greater than 200,000 IU/mL.¹² Beginning at either 24 or 32 weeks, patients were assigned to treatment with either oral TDF (300 mg daily) or oral telbivudine (LdT, 600 mg daily). The medications were continued for 4 weeks postpartum. In the intention-to-treat analysis, the rates of perinatal transmission were comparable, 1.5% versus 1.8%. In the per-protocol analysis, no infants in either group were infected. However, the predelivery decline in hepatitis Bvirus DNA concentration was greater in the TDF group. The ALT elevation rate was also lower in the TDF group. Patients in the LdT group had fewer problems with anorexia but more instances of arthralgia compared with those in the TDF group.

Based primarily on these 3 investigations, I recommend that all infected patients with a hepatitis B DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL receive oral TDF, 300 mg daily, from 28 weeks until at least 4 to 8 weeks postpartum. The decision about duration of postpartum treatment should be made in consultation with an infectious disease specialist or hepatologist.

Case studies resolved

CASE 1 No protective level of surface antibody

This patient should promptly receive a single booster dose of the hepatitis B vaccine. The vaccine is an inactivated agent and is safe for administration at any time in pregnancy. Following delivery and prior to discharge from the hospital, the neonate should receive the first dose of the hepatitis B vaccine. A second dose should be administered 1 month later, and a third dose should be administered 6 months after the first dose.

CASE 2 Mother is seropositive for HBsAg

This patient should be tested immediately for HIV infection and hepatitis C and D. The hepatitis B viral genotype should be determined. She also should have a panel of liver function tests. If any of these tests are abnormal, a coagulation profile should be obtained to be certain that the patient is not at risk for a coagulopathy. Near the end of the second trimester, a hepatitis B viral load should be obtained. If the viral DNA concentration is greater than 200,000 IU/mLor a viral load greater than 1,120,000 million copies/mL, the patient should be treated with tenofovir, 300 mg daily, from week 28 until at least 4 weeks after delivery. The neonate should receive an injection of HBIG within 12 hours of birth and the first dose of the hepatitis B vaccine prior to discharge from the hospital. Two additional doses of the vaccine should be administered 1 and 6 months later. ●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Hepatitis B is one of the more common infections encountered in the daily practice of obstetrics. It is responsible for 40% to 45% of all cases of viral hepatitis.^1,2 Hepatitis B may cause serious complications in both the infected mother and neonate.

In this article, I review the virology, epidemiology, and clinical presentation of hepatitis B and then discuss the key diagnostic tests and, subsequently, the clinical management for both the mother and neonate. I focus particular attention on relatively new information about the value of specific antiviral medication to enhance the protective effect of conventional neonatal immunoprophylaxis.

To set the framework for the discussion, consider the following 2 case studies.

CASE 1 Undetectable level of hepatitis B surface antibody in a pregnant woman

A 25-year-old healthy primigravid woman at 10 weeks’ gestation had a series of laboratory studies that included a test for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb). The test for the surface antigen was negative. The test for the surface antibody was below the level of detection. Upon questioning, the patient indicates that she received the 3-dose hepatitis B vaccine when she was age 13 years.

• What treatment, if any, is indicated for this patient?
• What treatment is indicated for her neonate?

CASE 2 Pregnant woman tests positive for hepatitis B surface antigen

A 31-year-old woman (G3P2002) at 12 weeks’ gestation tested positive for HBsAg. She indicates that she never has had symptomatic hepatitis and that she considers herself to be in excellent health.

• What additional laboratory tests are indicated at this time?
• What additional laboratory test should be performed at the end of the second trimester?
• What treatment is indicated for the mother and neonate?

Virology and epidemiology of hepatitis B

Hepatitis B is caused by a double-stranded, enveloped DNA virus. The virus has 10 genotypes and 24 subtypes.³ The organism contains 3 major antigens. Detection of these antigens and their corresponding antibodies is an essential step in the diagnostic workup of patients who may be infected.

The surface antigen (HBsAg) confers infectivity and is the most valuable serologic marker of infection. The e antigen (HBeAg) is not present in every infected patient. It is secreted from infected cells, but it is not incorporated into the viral particle. When present, it denotes a high level of viral replication and exceptionally high infectivity. The core antigen (HBcAg) is a valuable serologic marker for distinguishing between acute and chronic infection.^1-3

Hepatitis B is highly infectious, much more so than HIV or hepatitis C. The virus has an incubation period of 4 weeks to 6 months, and the duration of incubation is inversely related to the size of the viral inoculum. The virus is transmitted in 3 principal ways: sexual contact with contaminated genital tract secretions, contact with infected blood from sharing contaminated drug-injecting paraphernalia or from receiving a blood transfusion (extremely rare today), and transmission from an infected mother to her neonate. Perinatal transmission occurs primarily during the delivery process as opposed to transplacental infection. Transmission also can occur by more casual household contact, such as sharing eating utensils, kissing, and handling an infant.^1,2,4,5

Worldwide, more than 400 million people have chronic hepatitis B infection. In the United States, approximately 1.25 to 1.5 million individuals are infected. Several groups are at particularly high risk for being infected, including^1-3:

• Asians
• Alaska Natives
• sub-Saharan Africans
• sex workers
• intravenous drug users
• individuals with hemophilia
• international travelers
• staff and residents of long-term care facilities
• tattoo recipients.

Continue to: Clinical presentation...

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...

Maternal antiviral therapy

As noted above, neonatal immunoprophylaxis is 85% to 95% effective in preventing perinatal transmission of hepatitis B infection. Failures of prophylaxis are primarily due to antenatal transmission in patients who have exceptionally high viral loads. Several cutoffs have been used to define “high viral load,” including greater than 1 to 2 million copies/mL and a hepatitis B DNA concentration greater than 200,000 IU/mL. There is not a perfect consensus on the appropriate cutoff.

In essence, 2 different approaches have been tried to further reduce the risk of perinatal transmission in these high-risk patients.⁸ The first major initiative was administration of HBIG (100–200 IU) intramuscularly to the patient at 28, 32, and 36 weeks. The outcomes with this approach have been inconsistent, due, at least in part, to varying doses of the agent and various cutoffs for defining “high risk,” and this intervention is no longer recommended.^1,2

The second major approach is administration of specific antiviral drugs to the mother during the third trimester. The first agent widely used in clinical practice was lamivudine. In a systematic review and meta-analysis, Shi and colleagues reported that, in infants whose mothers received lamivudine plus conventional neonatal immunuprophylaxis, the risk of perinatal infection was significantly reduced compared with infants who received only immunoprophylaxis.⁹

Although lamivudine is effective, there is considerable concern about the rapid development of viral resistance to the medication. Accordingly, most attention today is focused on the use of tenofovir to prevent perinatal transmission.

In an important early investigation, Pan and colleagues reported the results of a randomized controlled trial conducted in China in women with a hepatitis B DNA concentration greater than 200,000 IU/mL (viral load > 1,120,000 copies/mL).¹⁰ Patients also were positive for the e antigen. Ninety-two patients were assigned to tenofovir disoproxil fumarate (TDF), 300 mg daily, from 30 to 32 weeks until postpartum week 4 plus conventional neonatal immunoprophylaxis, and 100 patients were assigned to immunoprophylaxis alone. In the intention-to-treat analysis, 18 neonates in the control group were infected compared with 5 in the treatment group (P = .007). In the per-protocol analysis, 7 neonates in the control group were infected compared with 0 in the treatment group (P = .01). No clinically significant adverse maternal or neonatal effects occurred in the treatment group.

Subsequently, Jourdain and colleagues reported a multicenter, double-blind trial conducted in 17 public health hospitals in Thailand.¹¹ TDF (300 mg daily) or placebo was administered from 28 weeks’ gestation until 8 weeks postpartum. Patients in both arms of the study were positive for the e antigen; 87% to 90% of the patients had a serum hepatitis B DNA concentration greater than 200,000 IU/mL.Following birth, infants in both groups received an injection of HBIG and then 4 doses of hepatitis B vaccine (0, 1, 2, 4, and 6 months). Both the HBIG and hepatitis B vaccine were administered very promptly after birth (median time, 1.2–1.3 hours).

At 6 months after delivery, 2% of infants in the placebo group (3 of 147) were HBsAg-positive compared with none of the infants in the treatment arm.¹¹ No serious adverse effects occurred in infants in the TDF group. This difference in outcome was not statistically significant, but the overall rate of infection was so low in both groups that the sample size was definitely too small to exclude a type 2 statistical error. Moreover, the fourth dose of neonatal hepatitis B vaccine may have contributed to the surprisingly low rate of perinatal transmission. Of note, the serum hepatitis B DNA concentration in the TDF group declined from a mean of 7.6 log₁₀ IU/mL to a mean of 4.0 log₁₀ IU/mL at delivery.

In the most recent report, Wang and colleagues reported the results of a prospective cohort study in patients with a hepatitis B virus DNA concentration greater than 200,000 IU/mL.¹² Beginning at either 24 or 32 weeks, patients were assigned to treatment with either oral TDF (300 mg daily) or oral telbivudine (LdT, 600 mg daily). The medications were continued for 4 weeks postpartum. In the intention-to-treat analysis, the rates of perinatal transmission were comparable, 1.5% versus 1.8%. In the per-protocol analysis, no infants in either group were infected. However, the predelivery decline in hepatitis Bvirus DNA concentration was greater in the TDF group. The ALT elevation rate was also lower in the TDF group. Patients in the LdT group had fewer problems with anorexia but more instances of arthralgia compared with those in the TDF group.

Based primarily on these 3 investigations, I recommend that all infected patients with a hepatitis B DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL receive oral TDF, 300 mg daily, from 28 weeks until at least 4 to 8 weeks postpartum. The decision about duration of postpartum treatment should be made in consultation with an infectious disease specialist or hepatologist.

Case studies resolved

CASE 1 No protective level of surface antibody

This patient should promptly receive a single booster dose of the hepatitis B vaccine. The vaccine is an inactivated agent and is safe for administration at any time in pregnancy. Following delivery and prior to discharge from the hospital, the neonate should receive the first dose of the hepatitis B vaccine. A second dose should be administered 1 month later, and a third dose should be administered 6 months after the first dose.

CASE 2 Mother is seropositive for HBsAg

This patient should be tested immediately for HIV infection and hepatitis C and D. The hepatitis B viral genotype should be determined. She also should have a panel of liver function tests. If any of these tests are abnormal, a coagulation profile should be obtained to be certain that the patient is not at risk for a coagulopathy. Near the end of the second trimester, a hepatitis B viral load should be obtained. If the viral DNA concentration is greater than 200,000 IU/mLor a viral load greater than 1,120,000 million copies/mL, the patient should be treated with tenofovir, 300 mg daily, from week 28 until at least 4 weeks after delivery. The neonate should receive an injection of HBIG within 12 hours of birth and the first dose of the hepatitis B vaccine prior to discharge from the hospital. Two additional doses of the vaccine should be administered 1 and 6 months later. ●

Many labels on fish oil supplements make unsubstantiated health claims, and products contain variable daily doses of EPA plus DHA, a cross-sectional study suggests.

Overall, about 74% of more than 2,800 supplements that were examined had labels that made at least one health claim, and only 19% included a U.S. Food and Drug Administration–reviewed qualified health claim (QHC).

©Clayton Hansen/iStockphoto

‘Vague statements’

To evaluate health claims made on fish oil supplement labels in the United States and to examine doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in commonly available formulations, the investigators analyzed labels on supplements obtained from the National Institutes of Health Dietary Supplement Label Database.

The main outcomes were the frequency and types of health claims made on the labels, including use of an FDA-reviewed QHC versus a structure/function claim and the organ system referenced, as well as the total daily doses in combined EPA and DHA supplements from leading manufacturers and retailers.

QHCs are statements regarding a supplement’s or food’s potential to treatment or prevent disease. Such claims undergo evidence review by the FDA and include qualifying language that reflects lack of scientific consensus or uncertainty.

An example: “Consuming EPA and DHA combined may reduce the risk of CHD [coronary heart disease] by lowering blood pressure. However, FDA has concluded that the evidence is inconsistent and inconclusive. One serving of [name of the food or dietary supplement] provides [ ] gram(s) of EPA and DHA.”

By contrast, structure/function claims “describe the role of a nutrient or dietary ingredient intended to affect the structure or function in humans” but do not state that the supplement prevents, treats, or cures any disease. Such a claim “does not require any mitigating language regarding potential scientific uncertainty of the statement.”

Structure/function claims commonly state that the supplement “maintains,” “supports,” or “promotes” the function of certain organs. Examples are “promotes heart health” and “supports heart, mind and mood.”

Among 2,819 fish oil supplements, 2,082 (73.9%) made at least one health claim. Of these, only 399 (19.2%) used a QHC; the rest made only structure/function claims. In addition to heart-health claims, many fish oil supplements also have labels that make claims implying benefit to other organ systems, such as brain/mental health, joint health, and eye health – despite a lack of data from randomized clinical trials that support benefit.

The dose analysis of 255 fish oil supplements across 16 major brands found “substantial variability” in the daily dose of EPA (median interquartile range, 340 [135-647] mg/d), DHA (median IQR, 270 [140-500] mg/d), and total EPA+DHA (median IQR, 600 [300-1,100] mg/d).

Twenty-four (9.4%) of the supplements contained a daily dose of 2 g or more EPA+DHA.

“Significant heterogeneity exists in the daily dose of EPA+DHA in available supplements, leading to potential variability in safety and efficacy between supplements,” the authors conclude. “Increasing regulation of dietary supplement labeling may be needed to prevent consumer misinformation.”

Dr. Navar added, “We now need to understand what consumers are taking away from vague statements like ‘promotes brain health’ or ‘supports joint function’ – and test what language we can use to accurately describe the state of the science around fish oil and heart health.”
 

Enthusiasm vs. evidence

“I agree with these concerns and think that the enthusiasm for these supplements outpaces the evidence from rigorous randomized clinical trials,” JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, said in an interview. “Results of the observational studies have tended to be much more favorable than the randomized clinical trials.

“The labels can be very misleading to the general public,” she noted. “People are confronted with a dizzying array of dietary supplements, many of which include structure/function claims that require minimal, if any, evidence of efficacy. Clinicians should emphasize with patients that a dietary supplement will never be a substitute for a heart-healthy diet and that many supplements are not helpful for people who already follow a healthy diet,” she said.

The VITAL trial, for which Dr. Manson was principal investigator, showed that supplementation with n-3 fatty acids did not lead to a lower incidence of major cardiovascular events or cancer, compared with placebo.

A subgroup analysis showed that 1 g/d conferred a 20% reduction in major events only for participants who ate less than 1.5 servings of fish per week, Dr. Manson said.

Regarding supplement labels, clinicians should recommend that patients look for a U.S. Pharmacopoeia seal or a seal from the National Science Foundation or ConsumerLab, she advised. These seals ensure that the product has been audited for purity and consistency of content and that the dose in the capsule is consistent with what is on the label.

Dr. Manson also would like to see labels explain that most of the products have not been reviewed by the FDA. “Many members of the general public are misled by these labels into thinking that they’re going to receive health benefits. They’re spending a lot of money on supplements that likely provide no benefit and may even be associated with increased risks.”

No funding for the study was reported. Dr. Navar has received grants from BMS, Esperion, Amgen, and Janssen and personal fees from AstraZeneca, Boehringer Ingelheim, Bayer, BMS, Esperion, Janssen, Eli Lilly, Merck, Silence Therapeutics, Novo Nordisk, Novartis, New Amsterdam, and Pfizer outside the submitted work and serves as deputy editor for equity, diversity, and inclusion at JAMA Cardiology.

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

Many labels on fish oil supplements make unsubstantiated health claims, and products contain variable daily doses of EPA plus DHA, a cross-sectional study suggests.

Overall, about 74% of more than 2,800 supplements that were examined had labels that made at least one health claim, and only 19% included a U.S. Food and Drug Administration–reviewed qualified health claim (QHC).

©Clayton Hansen/iStockphoto

‘Vague statements’

To evaluate health claims made on fish oil supplement labels in the United States and to examine doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in commonly available formulations, the investigators analyzed labels on supplements obtained from the National Institutes of Health Dietary Supplement Label Database.

The main outcomes were the frequency and types of health claims made on the labels, including use of an FDA-reviewed QHC versus a structure/function claim and the organ system referenced, as well as the total daily doses in combined EPA and DHA supplements from leading manufacturers and retailers.

QHCs are statements regarding a supplement’s or food’s potential to treatment or prevent disease. Such claims undergo evidence review by the FDA and include qualifying language that reflects lack of scientific consensus or uncertainty.

An example: “Consuming EPA and DHA combined may reduce the risk of CHD [coronary heart disease] by lowering blood pressure. However, FDA has concluded that the evidence is inconsistent and inconclusive. One serving of [name of the food or dietary supplement] provides [ ] gram(s) of EPA and DHA.”

By contrast, structure/function claims “describe the role of a nutrient or dietary ingredient intended to affect the structure or function in humans” but do not state that the supplement prevents, treats, or cures any disease. Such a claim “does not require any mitigating language regarding potential scientific uncertainty of the statement.”

Structure/function claims commonly state that the supplement “maintains,” “supports,” or “promotes” the function of certain organs. Examples are “promotes heart health” and “supports heart, mind and mood.”

Among 2,819 fish oil supplements, 2,082 (73.9%) made at least one health claim. Of these, only 399 (19.2%) used a QHC; the rest made only structure/function claims. In addition to heart-health claims, many fish oil supplements also have labels that make claims implying benefit to other organ systems, such as brain/mental health, joint health, and eye health – despite a lack of data from randomized clinical trials that support benefit.

The dose analysis of 255 fish oil supplements across 16 major brands found “substantial variability” in the daily dose of EPA (median interquartile range, 340 [135-647] mg/d), DHA (median IQR, 270 [140-500] mg/d), and total EPA+DHA (median IQR, 600 [300-1,100] mg/d).

Twenty-four (9.4%) of the supplements contained a daily dose of 2 g or more EPA+DHA.

“Significant heterogeneity exists in the daily dose of EPA+DHA in available supplements, leading to potential variability in safety and efficacy between supplements,” the authors conclude. “Increasing regulation of dietary supplement labeling may be needed to prevent consumer misinformation.”

Dr. Navar added, “We now need to understand what consumers are taking away from vague statements like ‘promotes brain health’ or ‘supports joint function’ – and test what language we can use to accurately describe the state of the science around fish oil and heart health.”
 

Enthusiasm vs. evidence

“I agree with these concerns and think that the enthusiasm for these supplements outpaces the evidence from rigorous randomized clinical trials,” JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, said in an interview. “Results of the observational studies have tended to be much more favorable than the randomized clinical trials.

“The labels can be very misleading to the general public,” she noted. “People are confronted with a dizzying array of dietary supplements, many of which include structure/function claims that require minimal, if any, evidence of efficacy. Clinicians should emphasize with patients that a dietary supplement will never be a substitute for a heart-healthy diet and that many supplements are not helpful for people who already follow a healthy diet,” she said.

The VITAL trial, for which Dr. Manson was principal investigator, showed that supplementation with n-3 fatty acids did not lead to a lower incidence of major cardiovascular events or cancer, compared with placebo.

A subgroup analysis showed that 1 g/d conferred a 20% reduction in major events only for participants who ate less than 1.5 servings of fish per week, Dr. Manson said.

Regarding supplement labels, clinicians should recommend that patients look for a U.S. Pharmacopoeia seal or a seal from the National Science Foundation or ConsumerLab, she advised. These seals ensure that the product has been audited for purity and consistency of content and that the dose in the capsule is consistent with what is on the label.

Dr. Manson also would like to see labels explain that most of the products have not been reviewed by the FDA. “Many members of the general public are misled by these labels into thinking that they’re going to receive health benefits. They’re spending a lot of money on supplements that likely provide no benefit and may even be associated with increased risks.”

No funding for the study was reported. Dr. Navar has received grants from BMS, Esperion, Amgen, and Janssen and personal fees from AstraZeneca, Boehringer Ingelheim, Bayer, BMS, Esperion, Janssen, Eli Lilly, Merck, Silence Therapeutics, Novo Nordisk, Novartis, New Amsterdam, and Pfizer outside the submitted work and serves as deputy editor for equity, diversity, and inclusion at JAMA Cardiology.

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

Many labels on fish oil supplements make unsubstantiated health claims, and products contain variable daily doses of EPA plus DHA, a cross-sectional study suggests.

Overall, about 74% of more than 2,800 supplements that were examined had labels that made at least one health claim, and only 19% included a U.S. Food and Drug Administration–reviewed qualified health claim (QHC).

©Clayton Hansen/iStockphoto

‘Vague statements’

To evaluate health claims made on fish oil supplement labels in the United States and to examine doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in commonly available formulations, the investigators analyzed labels on supplements obtained from the National Institutes of Health Dietary Supplement Label Database.

The main outcomes were the frequency and types of health claims made on the labels, including use of an FDA-reviewed QHC versus a structure/function claim and the organ system referenced, as well as the total daily doses in combined EPA and DHA supplements from leading manufacturers and retailers.

QHCs are statements regarding a supplement’s or food’s potential to treatment or prevent disease. Such claims undergo evidence review by the FDA and include qualifying language that reflects lack of scientific consensus or uncertainty.

An example: “Consuming EPA and DHA combined may reduce the risk of CHD [coronary heart disease] by lowering blood pressure. However, FDA has concluded that the evidence is inconsistent and inconclusive. One serving of [name of the food or dietary supplement] provides [ ] gram(s) of EPA and DHA.”

By contrast, structure/function claims “describe the role of a nutrient or dietary ingredient intended to affect the structure or function in humans” but do not state that the supplement prevents, treats, or cures any disease. Such a claim “does not require any mitigating language regarding potential scientific uncertainty of the statement.”

Structure/function claims commonly state that the supplement “maintains,” “supports,” or “promotes” the function of certain organs. Examples are “promotes heart health” and “supports heart, mind and mood.”

Among 2,819 fish oil supplements, 2,082 (73.9%) made at least one health claim. Of these, only 399 (19.2%) used a QHC; the rest made only structure/function claims. In addition to heart-health claims, many fish oil supplements also have labels that make claims implying benefit to other organ systems, such as brain/mental health, joint health, and eye health – despite a lack of data from randomized clinical trials that support benefit.

The dose analysis of 255 fish oil supplements across 16 major brands found “substantial variability” in the daily dose of EPA (median interquartile range, 340 [135-647] mg/d), DHA (median IQR, 270 [140-500] mg/d), and total EPA+DHA (median IQR, 600 [300-1,100] mg/d).

Twenty-four (9.4%) of the supplements contained a daily dose of 2 g or more EPA+DHA.

“Significant heterogeneity exists in the daily dose of EPA+DHA in available supplements, leading to potential variability in safety and efficacy between supplements,” the authors conclude. “Increasing regulation of dietary supplement labeling may be needed to prevent consumer misinformation.”

Dr. Navar added, “We now need to understand what consumers are taking away from vague statements like ‘promotes brain health’ or ‘supports joint function’ – and test what language we can use to accurately describe the state of the science around fish oil and heart health.”
 

Enthusiasm vs. evidence

“I agree with these concerns and think that the enthusiasm for these supplements outpaces the evidence from rigorous randomized clinical trials,” JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, said in an interview. “Results of the observational studies have tended to be much more favorable than the randomized clinical trials.

“The labels can be very misleading to the general public,” she noted. “People are confronted with a dizzying array of dietary supplements, many of which include structure/function claims that require minimal, if any, evidence of efficacy. Clinicians should emphasize with patients that a dietary supplement will never be a substitute for a heart-healthy diet and that many supplements are not helpful for people who already follow a healthy diet,” she said.

The VITAL trial, for which Dr. Manson was principal investigator, showed that supplementation with n-3 fatty acids did not lead to a lower incidence of major cardiovascular events or cancer, compared with placebo.

A subgroup analysis showed that 1 g/d conferred a 20% reduction in major events only for participants who ate less than 1.5 servings of fish per week, Dr. Manson said.

Regarding supplement labels, clinicians should recommend that patients look for a U.S. Pharmacopoeia seal or a seal from the National Science Foundation or ConsumerLab, she advised. These seals ensure that the product has been audited for purity and consistency of content and that the dose in the capsule is consistent with what is on the label.

Dr. Manson also would like to see labels explain that most of the products have not been reviewed by the FDA. “Many members of the general public are misled by these labels into thinking that they’re going to receive health benefits. They’re spending a lot of money on supplements that likely provide no benefit and may even be associated with increased risks.”

No funding for the study was reported. Dr. Navar has received grants from BMS, Esperion, Amgen, and Janssen and personal fees from AstraZeneca, Boehringer Ingelheim, Bayer, BMS, Esperion, Janssen, Eli Lilly, Merck, Silence Therapeutics, Novo Nordisk, Novartis, New Amsterdam, and Pfizer outside the submitted work and serves as deputy editor for equity, diversity, and inclusion at JAMA Cardiology.

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

Antibiotic resistance is a major public health problem. Few new molecules are in development, but a new antibiotic called clovibactin brings hope.

This drug, isolated from bacteria that haven’t previously been studied, seems to be capable of combating multidrug-resistant “superbugs” thanks to unusual mechanisms of action.

The drug was discovered and has been studied by scientists from Utrecht University in the Netherlands, the University of Bonn in Germany, the German Center for Infection Research, Northeastern University in Boston, and NovoBiotic Pharmaceuticals in Cambridge, Mass.

Their research was published in Cell.

“Since clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and had no time to develop resistance,” Markus Weingarth, MD, PhD, a researcher in Utrecht University’s chemistry department, said in a press release.
 

Microbial “dark matter”

Researchers isolated clovibactin from sandy soil from North Carolina and studied it using the iChip device, which was developed in 2015. This technique allowed them to grow “bacterial dark matter,” so-called unculturable bacteria, which compose a group to which 99% of bacteria belong.

This device also paved the way for the discovery of the antibiotic teixobactin in 2020. Teixobactin is effective against gram-positive bacteria and is one of the first truly new antibiotics in decades. Its mechanism of action is like that of clovibactin.
 

Combats resistant bacteria

In the Cell article, the researchers showed that clovibactin acts via several mechanisms and that it successfully treated mice infected with the superbug Staphylococcus aureus.

Clovibactin exhibited antibacterial activity against a broad range of gram-positive pathogens, including methicillin-resistant S. aureus, daptomycin-resistant and vancomycin-resistant S. aureus strains, and difficult-to-treat vancomycin-resistant Enterococcus faecalis and E faecium (vancomycin-resistant enterococci). Escherichia coli was only marginally affected “compared with an outer membrane deficient E. coli WO153 strain, probably reflecting insufficient penetration of the compound,” the authors wrote.
 

Original mechanism of action

Clovibactin acts not on one but three molecules, all of which are essential to the construction of bacterial walls: C55PP, lipid II, and lipid IIIWTA, which are from different cell wall biosynthetic pathways. Clovibactin binds to the pyrophosphate portion of these precursors.

“Clovibactin wraps around the pyrophosphate like [a] tight glove, like a cage that encloses its target,” said Dr. Weingarth. This is what gives clovibactin its name, which is derived from Greek word klouvi, meaning cage.

The remarkable aspect of clovibactin’s mechanism is that it only binds to the immutable pyrophosphate that is common to cell wall precursors, but it also ignores the variable sugar-peptide part of the targets. The bacteria therefore have a much harder time developing resistance against it. “In fact, we did not observe any resistance to clovibactin in our studies,” Dr. Weingarth confirmed.

Upon binding the target molecules, it self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time and thereby ensure that the target molecules remain sequestered for as long as necessary to kill bacteria.
 

Few side effects

Because of the mechanism of action of the antibiotic, few side effects are predicted. Indeed, clovibactin targets bacteria cells but not human cells.

“Since these fibrils only form on bacterial membranes and not on human membranes, they are presumably also the reason why clovibactin selectively damages bacterial cells but is not toxic to human cells,” said Dr. Weingarth.

Other studies – in particular, studies in humans – are needed before the antibiotic can be considered a potential treatment. In the meantime, regulations regarding the proper use of antibiotics must continue to be applied to limit antibiotic resistance.

In 2019, 4.95 million deaths worldwide were associated with bacterial antimicrobial resistance, including 1.27 million deaths directly attributable to bacterial antimicrobial resistance. If this trend continues without new medicines becoming available to treat bacterial infections, it is estimated that by 2050, 10 million people will die every year from antimicrobial drug resistance.
 

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Antibiotic resistance is a major public health problem. Few new molecules are in development, but a new antibiotic called clovibactin brings hope.

This drug, isolated from bacteria that haven’t previously been studied, seems to be capable of combating multidrug-resistant “superbugs” thanks to unusual mechanisms of action.

The drug was discovered and has been studied by scientists from Utrecht University in the Netherlands, the University of Bonn in Germany, the German Center for Infection Research, Northeastern University in Boston, and NovoBiotic Pharmaceuticals in Cambridge, Mass.

Their research was published in Cell.

“Since clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and had no time to develop resistance,” Markus Weingarth, MD, PhD, a researcher in Utrecht University’s chemistry department, said in a press release.
 

Microbial “dark matter”

Researchers isolated clovibactin from sandy soil from North Carolina and studied it using the iChip device, which was developed in 2015. This technique allowed them to grow “bacterial dark matter,” so-called unculturable bacteria, which compose a group to which 99% of bacteria belong.

This device also paved the way for the discovery of the antibiotic teixobactin in 2020. Teixobactin is effective against gram-positive bacteria and is one of the first truly new antibiotics in decades. Its mechanism of action is like that of clovibactin.
 

Combats resistant bacteria

In the Cell article, the researchers showed that clovibactin acts via several mechanisms and that it successfully treated mice infected with the superbug Staphylococcus aureus.

Clovibactin exhibited antibacterial activity against a broad range of gram-positive pathogens, including methicillin-resistant S. aureus, daptomycin-resistant and vancomycin-resistant S. aureus strains, and difficult-to-treat vancomycin-resistant Enterococcus faecalis and E faecium (vancomycin-resistant enterococci). Escherichia coli was only marginally affected “compared with an outer membrane deficient E. coli WO153 strain, probably reflecting insufficient penetration of the compound,” the authors wrote.
 

Original mechanism of action

Clovibactin acts not on one but three molecules, all of which are essential to the construction of bacterial walls: C55PP, lipid II, and lipid IIIWTA, which are from different cell wall biosynthetic pathways. Clovibactin binds to the pyrophosphate portion of these precursors.

“Clovibactin wraps around the pyrophosphate like [a] tight glove, like a cage that encloses its target,” said Dr. Weingarth. This is what gives clovibactin its name, which is derived from Greek word klouvi, meaning cage.

The remarkable aspect of clovibactin’s mechanism is that it only binds to the immutable pyrophosphate that is common to cell wall precursors, but it also ignores the variable sugar-peptide part of the targets. The bacteria therefore have a much harder time developing resistance against it. “In fact, we did not observe any resistance to clovibactin in our studies,” Dr. Weingarth confirmed.

Upon binding the target molecules, it self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time and thereby ensure that the target molecules remain sequestered for as long as necessary to kill bacteria.
 

Few side effects

Because of the mechanism of action of the antibiotic, few side effects are predicted. Indeed, clovibactin targets bacteria cells but not human cells.

“Since these fibrils only form on bacterial membranes and not on human membranes, they are presumably also the reason why clovibactin selectively damages bacterial cells but is not toxic to human cells,” said Dr. Weingarth.

Other studies – in particular, studies in humans – are needed before the antibiotic can be considered a potential treatment. In the meantime, regulations regarding the proper use of antibiotics must continue to be applied to limit antibiotic resistance.

In 2019, 4.95 million deaths worldwide were associated with bacterial antimicrobial resistance, including 1.27 million deaths directly attributable to bacterial antimicrobial resistance. If this trend continues without new medicines becoming available to treat bacterial infections, it is estimated that by 2050, 10 million people will die every year from antimicrobial drug resistance.
 

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Antibiotic resistance is a major public health problem. Few new molecules are in development, but a new antibiotic called clovibactin brings hope.

This drug, isolated from bacteria that haven’t previously been studied, seems to be capable of combating multidrug-resistant “superbugs” thanks to unusual mechanisms of action.

The drug was discovered and has been studied by scientists from Utrecht University in the Netherlands, the University of Bonn in Germany, the German Center for Infection Research, Northeastern University in Boston, and NovoBiotic Pharmaceuticals in Cambridge, Mass.

Their research was published in Cell.

“Since clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and had no time to develop resistance,” Markus Weingarth, MD, PhD, a researcher in Utrecht University’s chemistry department, said in a press release.
 

Microbial “dark matter”

Researchers isolated clovibactin from sandy soil from North Carolina and studied it using the iChip device, which was developed in 2015. This technique allowed them to grow “bacterial dark matter,” so-called unculturable bacteria, which compose a group to which 99% of bacteria belong.

This device also paved the way for the discovery of the antibiotic teixobactin in 2020. Teixobactin is effective against gram-positive bacteria and is one of the first truly new antibiotics in decades. Its mechanism of action is like that of clovibactin.
 

Combats resistant bacteria

In the Cell article, the researchers showed that clovibactin acts via several mechanisms and that it successfully treated mice infected with the superbug Staphylococcus aureus.

Clovibactin exhibited antibacterial activity against a broad range of gram-positive pathogens, including methicillin-resistant S. aureus, daptomycin-resistant and vancomycin-resistant S. aureus strains, and difficult-to-treat vancomycin-resistant Enterococcus faecalis and E faecium (vancomycin-resistant enterococci). Escherichia coli was only marginally affected “compared with an outer membrane deficient E. coli WO153 strain, probably reflecting insufficient penetration of the compound,” the authors wrote.
 

Original mechanism of action

Clovibactin acts not on one but three molecules, all of which are essential to the construction of bacterial walls: C55PP, lipid II, and lipid IIIWTA, which are from different cell wall biosynthetic pathways. Clovibactin binds to the pyrophosphate portion of these precursors.

“Clovibactin wraps around the pyrophosphate like [a] tight glove, like a cage that encloses its target,” said Dr. Weingarth. This is what gives clovibactin its name, which is derived from Greek word klouvi, meaning cage.

The remarkable aspect of clovibactin’s mechanism is that it only binds to the immutable pyrophosphate that is common to cell wall precursors, but it also ignores the variable sugar-peptide part of the targets. The bacteria therefore have a much harder time developing resistance against it. “In fact, we did not observe any resistance to clovibactin in our studies,” Dr. Weingarth confirmed.

Upon binding the target molecules, it self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time and thereby ensure that the target molecules remain sequestered for as long as necessary to kill bacteria.
 

Few side effects

Because of the mechanism of action of the antibiotic, few side effects are predicted. Indeed, clovibactin targets bacteria cells but not human cells.

“Since these fibrils only form on bacterial membranes and not on human membranes, they are presumably also the reason why clovibactin selectively damages bacterial cells but is not toxic to human cells,” said Dr. Weingarth.

Other studies – in particular, studies in humans – are needed before the antibiotic can be considered a potential treatment. In the meantime, regulations regarding the proper use of antibiotics must continue to be applied to limit antibiotic resistance.

In 2019, 4.95 million deaths worldwide were associated with bacterial antimicrobial resistance, including 1.27 million deaths directly attributable to bacterial antimicrobial resistance. If this trend continues without new medicines becoming available to treat bacterial infections, it is estimated that by 2050, 10 million people will die every year from antimicrobial drug resistance.
 

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Taking a patient’s blood pressure while the patient is lying down may yield more information about their cardiovascular risk than taking the reading while the patient is sitting upright, new preliminary research suggests.

An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.

“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.

Mr. Giao presented the findings at the Hypertension Scientific Sessions.
 

Take seated and supine BP in clinic?

Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.

To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.

As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.

Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).

The results did not differ by antihypertensive medication use (P > .05).

For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.

“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.

“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
 

Busy clinical practice

In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”

She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”

The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.

However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.

“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.

The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.

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

Taking a patient’s blood pressure while the patient is lying down may yield more information about their cardiovascular risk than taking the reading while the patient is sitting upright, new preliminary research suggests.

An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.

“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.

Mr. Giao presented the findings at the Hypertension Scientific Sessions.
 

Take seated and supine BP in clinic?

Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.

To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.

As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.

Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).

The results did not differ by antihypertensive medication use (P > .05).

For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.

“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.

“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
 

Busy clinical practice

In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”

She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”

The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.

However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.

“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.

The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.

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

Taking a patient’s blood pressure while the patient is lying down may yield more information about their cardiovascular risk than taking the reading while the patient is sitting upright, new preliminary research suggests.

An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.

“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.

Mr. Giao presented the findings at the Hypertension Scientific Sessions.
 

Take seated and supine BP in clinic?

Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.

To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.

As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.

Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).

The results did not differ by antihypertensive medication use (P > .05).

For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.

“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.

“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
 

Busy clinical practice

In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”

She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”

The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.

However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.

“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.

The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.

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

Lecanemab (Lequembi, Esai), an amyloid-beta–directed antibody therapy, is approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD). But exactly how the drug clears amyloid-beta wasn’t clear.

Now new research suggests the drug, which was approved by the FDA in January, targets a particular molecular cascade, the plasma contact system, which drives amyloid-beta toxicity.

The investigators tested the effectiveness of various forms of amyloid-beta in activating the plasma contact system and found that amyloid-beta protofibrils, known to be the most toxic form of amyloid-beta, promoted the activation of this molecular cascade and that lecanemab inhibited pathway activation.

“In our study, we looked at lecanemab and found it can block the activation of the contact system, which could be one of the reasons that it works so well for AD,” study coinvestigator Erin Norris, PhD, research associate professor, Rockefeller University, New York, said in an interview.

The study was published online in the Proceedings of the National Academy of Science.
 

Unknown mechanism

“Many years ago, we started looking at the involvement of vascular dysfunction in AD,” Dr. Norris said. “We wanted to see whether or not irregular blood clotting or problems with blood flow was problematic in Alzheimer’s patients.”

The researchers found that fibrin, a major component involved in blood clotting, can extravasate into the brain.

“The blood-brain barrier can break down in Alzheimer’s, so things from the blood can move into the brain and deposit there,” she added. Fibrin then interacts with amyloid-beta, the major pathogenic protein in AD.

Dr. Norris explained that fibrin clots can form in two different ways. One is through the normal process that occurs when there’s an injury and bleeding. The second is through intrinsic clotting, which takes place through the contact system.

“We started looking into this system and found that the plasma of Alzheimer’s patients showed irregular levels of these enzymes and proteins that are part of the intrinsic clotting system compared to those of normal controls,” said Dr. Norris.

“This paper was an extension of years studying this pathway and these mechanisms. It was also inspired by the approval of lecanemab and its release for use in Alzheimer’s patients,” she added.

In previous research, the same researchers found that amyloid-beta has different forms. “It’s normally soluble, and it’s a very tiny molecule,” Dr. Norris said. “But over time, and in different situations, it can start to aggregate, becoming bigger and bigger.”
 

Implications beyond Alzheimer’s

Postmortem tissue analysis has found fibrillar plaques that are “clumped together.” These are insoluble and hard to get rid of, she said. “Protofibrils are the step before amyloid-beta forms fibrils and are considered to be the most toxic form, although the mechanism behind why it’s so toxic is not understood.”

Previous research has already shown that amyloid-beta can activate the contact system. The contact system has two “arms,” the first of which is involved with clotting, and the second with inflammation, Dr. Norris said. In fact, it’s the plasma contact system that links vascular and inflammatory pathways.

The plasma contact system leads to the clotting of fibrin, Dr. Norris continued. It activates factor XII, which leads to blood clotting by binding to coagulation factor XI.

The contact system also causes inflammation – the second “arm.” Bradykinin, a potent inflammatory molecule, is released by binding to high-molecular-weight kininogen (HK). In addition to inflammation, bradykinin can cause edema and blood-brain barrier permeability.

Although it’s been known that amyloid-beta can activate the contact system, the particular form of amyloid-beta implicated in this cascade has not been identified. And so, the researchers incubated amyloid-beta42 with human plasma, testing various types of amyloid-beta – monomers, oligomers, protofibrils, and fibrils – to see which would activate the contact system.

Amyloid-beta protofibrils promoted the activation of the contact system, as evidenced by several reactions, including activation of factor XII, while other forms of amyloid-beta did not. HK also “bound tightly” to amyloid-beta protofibrils, with “weaker” binding to other amyloid-beta species, the authors reported, confirming that amyloid-beta protofibrils bind to HK and factor XII.

Bradykinin levels were increased by amyloid-beta protofibrils, which also induced faster clotting, compared with other forms of amyloid-beta.

The researchers introduced lecanemab into the picture and found it “dramatically inhibited” contact system activation induced by amyloid-beta protofibrils. For example, it blocked the binding of factor XII to amyloid-beta. By contrast, human IgG (which the researchers used as a control) had no effect.

Additionally, lecanemab also prevented accelerated intrinsic coagulation in normal human plasma mediated by amyloid-beta protofibril.

Senior author Sidney Strickland, PhD, the Zachary and Elizabeth M. Fisher professor in Alzheimer’s and neurodegenerative disease, Rockefeller University, said in an interview: “One of the strong motivators for conducting this study was the fact that this drug, which is effective in AD, targets this specific form of amyloid-beta; but no one knows why it›s more toxic. We thought we could see if we could tie it to what we›re working on, and we found it ties in beautifully.”

The findings have implications that go beyond AD, Dr. Strickland said. “The contact system is implicated in lots of different pathologies, including sickle cell anemia, sepsis, inflammatory bowel disease, and so on.” Blocking the contact system might be a helpful approach in these conditions too.
 

Innovative, plausible, but still preliminary

In a comment, Heather M. Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, called the investigation “innovative,” with ideas that are “certainly plausible.” However, “at this time, the work is preliminary and not conclusive.”

The hypothesized mechanisms for why amyloid (lecanemab’s target) is toxic to the brain “does incorporate important AD-related brain changes that have been observed in other studies, including inflammatory/immune changes and vascular-related changes,” said Dr. Snyder, who was not involved with the current study.

However, “additional studies that look both in model systems and in humans are needed to further illuminate these relationships,” Dr. Snyder said.

The study was supported by grants from the National Institutes of Health as well as the Robertson Therapeutic Development Fund, Samuel Newhouse Foundation, John A. Herrmann, and the May and Samuel Rudin Family Foundation. Dr. Norris, Dr. Strickland, and Dr. Snyder declared no relevant financial relationships.

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

Lecanemab (Lequembi, Esai), an amyloid-beta–directed antibody therapy, is approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD). But exactly how the drug clears amyloid-beta wasn’t clear.

Now new research suggests the drug, which was approved by the FDA in January, targets a particular molecular cascade, the plasma contact system, which drives amyloid-beta toxicity.

The investigators tested the effectiveness of various forms of amyloid-beta in activating the plasma contact system and found that amyloid-beta protofibrils, known to be the most toxic form of amyloid-beta, promoted the activation of this molecular cascade and that lecanemab inhibited pathway activation.

“In our study, we looked at lecanemab and found it can block the activation of the contact system, which could be one of the reasons that it works so well for AD,” study coinvestigator Erin Norris, PhD, research associate professor, Rockefeller University, New York, said in an interview.

The study was published online in the Proceedings of the National Academy of Science.
 

Unknown mechanism

“Many years ago, we started looking at the involvement of vascular dysfunction in AD,” Dr. Norris said. “We wanted to see whether or not irregular blood clotting or problems with blood flow was problematic in Alzheimer’s patients.”

The researchers found that fibrin, a major component involved in blood clotting, can extravasate into the brain.

“The blood-brain barrier can break down in Alzheimer’s, so things from the blood can move into the brain and deposit there,” she added. Fibrin then interacts with amyloid-beta, the major pathogenic protein in AD.

Dr. Norris explained that fibrin clots can form in two different ways. One is through the normal process that occurs when there’s an injury and bleeding. The second is through intrinsic clotting, which takes place through the contact system.

“We started looking into this system and found that the plasma of Alzheimer’s patients showed irregular levels of these enzymes and proteins that are part of the intrinsic clotting system compared to those of normal controls,” said Dr. Norris.

“This paper was an extension of years studying this pathway and these mechanisms. It was also inspired by the approval of lecanemab and its release for use in Alzheimer’s patients,” she added.

In previous research, the same researchers found that amyloid-beta has different forms. “It’s normally soluble, and it’s a very tiny molecule,” Dr. Norris said. “But over time, and in different situations, it can start to aggregate, becoming bigger and bigger.”
 

Implications beyond Alzheimer’s

Postmortem tissue analysis has found fibrillar plaques that are “clumped together.” These are insoluble and hard to get rid of, she said. “Protofibrils are the step before amyloid-beta forms fibrils and are considered to be the most toxic form, although the mechanism behind why it’s so toxic is not understood.”

Previous research has already shown that amyloid-beta can activate the contact system. The contact system has two “arms,” the first of which is involved with clotting, and the second with inflammation, Dr. Norris said. In fact, it’s the plasma contact system that links vascular and inflammatory pathways.

The plasma contact system leads to the clotting of fibrin, Dr. Norris continued. It activates factor XII, which leads to blood clotting by binding to coagulation factor XI.

The contact system also causes inflammation – the second “arm.” Bradykinin, a potent inflammatory molecule, is released by binding to high-molecular-weight kininogen (HK). In addition to inflammation, bradykinin can cause edema and blood-brain barrier permeability.

Although it’s been known that amyloid-beta can activate the contact system, the particular form of amyloid-beta implicated in this cascade has not been identified. And so, the researchers incubated amyloid-beta42 with human plasma, testing various types of amyloid-beta – monomers, oligomers, protofibrils, and fibrils – to see which would activate the contact system.

Amyloid-beta protofibrils promoted the activation of the contact system, as evidenced by several reactions, including activation of factor XII, while other forms of amyloid-beta did not. HK also “bound tightly” to amyloid-beta protofibrils, with “weaker” binding to other amyloid-beta species, the authors reported, confirming that amyloid-beta protofibrils bind to HK and factor XII.

Bradykinin levels were increased by amyloid-beta protofibrils, which also induced faster clotting, compared with other forms of amyloid-beta.

The researchers introduced lecanemab into the picture and found it “dramatically inhibited” contact system activation induced by amyloid-beta protofibrils. For example, it blocked the binding of factor XII to amyloid-beta. By contrast, human IgG (which the researchers used as a control) had no effect.

Additionally, lecanemab also prevented accelerated intrinsic coagulation in normal human plasma mediated by amyloid-beta protofibril.

Senior author Sidney Strickland, PhD, the Zachary and Elizabeth M. Fisher professor in Alzheimer’s and neurodegenerative disease, Rockefeller University, said in an interview: “One of the strong motivators for conducting this study was the fact that this drug, which is effective in AD, targets this specific form of amyloid-beta; but no one knows why it›s more toxic. We thought we could see if we could tie it to what we›re working on, and we found it ties in beautifully.”

The findings have implications that go beyond AD, Dr. Strickland said. “The contact system is implicated in lots of different pathologies, including sickle cell anemia, sepsis, inflammatory bowel disease, and so on.” Blocking the contact system might be a helpful approach in these conditions too.
 

Innovative, plausible, but still preliminary

In a comment, Heather M. Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, called the investigation “innovative,” with ideas that are “certainly plausible.” However, “at this time, the work is preliminary and not conclusive.”

The hypothesized mechanisms for why amyloid (lecanemab’s target) is toxic to the brain “does incorporate important AD-related brain changes that have been observed in other studies, including inflammatory/immune changes and vascular-related changes,” said Dr. Snyder, who was not involved with the current study.

However, “additional studies that look both in model systems and in humans are needed to further illuminate these relationships,” Dr. Snyder said.

The study was supported by grants from the National Institutes of Health as well as the Robertson Therapeutic Development Fund, Samuel Newhouse Foundation, John A. Herrmann, and the May and Samuel Rudin Family Foundation. Dr. Norris, Dr. Strickland, and Dr. Snyder declared no relevant financial relationships.

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

Lecanemab (Lequembi, Esai), an amyloid-beta–directed antibody therapy, is approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD). But exactly how the drug clears amyloid-beta wasn’t clear.

Now new research suggests the drug, which was approved by the FDA in January, targets a particular molecular cascade, the plasma contact system, which drives amyloid-beta toxicity.

The investigators tested the effectiveness of various forms of amyloid-beta in activating the plasma contact system and found that amyloid-beta protofibrils, known to be the most toxic form of amyloid-beta, promoted the activation of this molecular cascade and that lecanemab inhibited pathway activation.

“In our study, we looked at lecanemab and found it can block the activation of the contact system, which could be one of the reasons that it works so well for AD,” study coinvestigator Erin Norris, PhD, research associate professor, Rockefeller University, New York, said in an interview.

The study was published online in the Proceedings of the National Academy of Science.
 

Unknown mechanism

“Many years ago, we started looking at the involvement of vascular dysfunction in AD,” Dr. Norris said. “We wanted to see whether or not irregular blood clotting or problems with blood flow was problematic in Alzheimer’s patients.”

The researchers found that fibrin, a major component involved in blood clotting, can extravasate into the brain.

“The blood-brain barrier can break down in Alzheimer’s, so things from the blood can move into the brain and deposit there,” she added. Fibrin then interacts with amyloid-beta, the major pathogenic protein in AD.

Dr. Norris explained that fibrin clots can form in two different ways. One is through the normal process that occurs when there’s an injury and bleeding. The second is through intrinsic clotting, which takes place through the contact system.

“We started looking into this system and found that the plasma of Alzheimer’s patients showed irregular levels of these enzymes and proteins that are part of the intrinsic clotting system compared to those of normal controls,” said Dr. Norris.

“This paper was an extension of years studying this pathway and these mechanisms. It was also inspired by the approval of lecanemab and its release for use in Alzheimer’s patients,” she added.

In previous research, the same researchers found that amyloid-beta has different forms. “It’s normally soluble, and it’s a very tiny molecule,” Dr. Norris said. “But over time, and in different situations, it can start to aggregate, becoming bigger and bigger.”
 

Implications beyond Alzheimer’s

Postmortem tissue analysis has found fibrillar plaques that are “clumped together.” These are insoluble and hard to get rid of, she said. “Protofibrils are the step before amyloid-beta forms fibrils and are considered to be the most toxic form, although the mechanism behind why it’s so toxic is not understood.”

Previous research has already shown that amyloid-beta can activate the contact system. The contact system has two “arms,” the first of which is involved with clotting, and the second with inflammation, Dr. Norris said. In fact, it’s the plasma contact system that links vascular and inflammatory pathways.

The plasma contact system leads to the clotting of fibrin, Dr. Norris continued. It activates factor XII, which leads to blood clotting by binding to coagulation factor XI.

The contact system also causes inflammation – the second “arm.” Bradykinin, a potent inflammatory molecule, is released by binding to high-molecular-weight kininogen (HK). In addition to inflammation, bradykinin can cause edema and blood-brain barrier permeability.

Although it’s been known that amyloid-beta can activate the contact system, the particular form of amyloid-beta implicated in this cascade has not been identified. And so, the researchers incubated amyloid-beta42 with human plasma, testing various types of amyloid-beta – monomers, oligomers, protofibrils, and fibrils – to see which would activate the contact system.

Amyloid-beta protofibrils promoted the activation of the contact system, as evidenced by several reactions, including activation of factor XII, while other forms of amyloid-beta did not. HK also “bound tightly” to amyloid-beta protofibrils, with “weaker” binding to other amyloid-beta species, the authors reported, confirming that amyloid-beta protofibrils bind to HK and factor XII.

Bradykinin levels were increased by amyloid-beta protofibrils, which also induced faster clotting, compared with other forms of amyloid-beta.

The researchers introduced lecanemab into the picture and found it “dramatically inhibited” contact system activation induced by amyloid-beta protofibrils. For example, it blocked the binding of factor XII to amyloid-beta. By contrast, human IgG (which the researchers used as a control) had no effect.

Additionally, lecanemab also prevented accelerated intrinsic coagulation in normal human plasma mediated by amyloid-beta protofibril.

Senior author Sidney Strickland, PhD, the Zachary and Elizabeth M. Fisher professor in Alzheimer’s and neurodegenerative disease, Rockefeller University, said in an interview: “One of the strong motivators for conducting this study was the fact that this drug, which is effective in AD, targets this specific form of amyloid-beta; but no one knows why it›s more toxic. We thought we could see if we could tie it to what we›re working on, and we found it ties in beautifully.”

The findings have implications that go beyond AD, Dr. Strickland said. “The contact system is implicated in lots of different pathologies, including sickle cell anemia, sepsis, inflammatory bowel disease, and so on.” Blocking the contact system might be a helpful approach in these conditions too.
 

Innovative, plausible, but still preliminary

In a comment, Heather M. Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, called the investigation “innovative,” with ideas that are “certainly plausible.” However, “at this time, the work is preliminary and not conclusive.”

The hypothesized mechanisms for why amyloid (lecanemab’s target) is toxic to the brain “does incorporate important AD-related brain changes that have been observed in other studies, including inflammatory/immune changes and vascular-related changes,” said Dr. Snyder, who was not involved with the current study.

However, “additional studies that look both in model systems and in humans are needed to further illuminate these relationships,” Dr. Snyder said.

The study was supported by grants from the National Institutes of Health as well as the Robertson Therapeutic Development Fund, Samuel Newhouse Foundation, John A. Herrmann, and the May and Samuel Rudin Family Foundation. Dr. Norris, Dr. Strickland, and Dr. Snyder declared no relevant financial relationships.

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

The frequency of medication errors among children who take drugs to treat attention-deficit/hyperactivity disorder reported to U.S. poison control centers increased by nearly 300% over a 22-year period, according to results of a study published in the journal Pediatrics.

The dramatic jump is likely attributable to an increase in the prescribing of ADHD medications for children. According to the study authors, in 2019, nearly 10% of children in the United States had been diagnosed with ADHD, and some 3.3 million – or about 5% of all children in the country – had received a prescription for an ADHD medication.

“Because therapeutic errors are preventable, more attention should be given to patient and caregiver education and development of improved child-resistant medication dispensing and tracking systems,” the authors commented.

The investigators analyzed data from the National Poison Data System from 2000 through 2021 for therapeutic errors associated with ADHD medication among patients younger than 20 years.

“As medicine changes, it’s nice to look back at some of these things and see how some of these problems have changed,” said Natalie I. Rine, PharmD, a coauthor of the study and director of the Central Ohio Poison Center at Nationwide Children’s Hospital in Columbus.

The researchers identified 124,383 such errors reported to U.S. poison centers during the study period. The frequency increased by 299%.

Two-thirds (66.6%) of the exposures involved children aged 6-12 years, three-fourths (76.4%) were among males, and half (50.5%) involved amphetamines and related compounds. Most (79.7%) therapeutic errors were linked to exposure to a single substance. Nearly 83% of patients did not receive treatment at a health care facility; however, 2.3% were admitted to the hospital, and 4.2% had a “serious medical outcome,” the researchers found.

The most common scenarios were “inadvertently took or given medication twice” (53.9%), followed by “inadvertently took or given someone else’s medication” (13.4%) and “wrong medication taken or given” (12.9%), according to the researchers. Two percent involved mistakes by a pharmacist or nurse.
 

Easily preventable

Dr. Rine attributed the errors to simple mistakes and said they were likely the product of busy households and distracted caregivers. She added that the errors are easily avoided by storing the medication properly, keeping a sheet with the medication to document what was taken and when, and using a pillbox or one of many apps that can assist in documenting the dispensing of medications.

“I think the biggest thing is that a lot of these errors are preventable, more than anything else,” Dr. Rine said.

The increase in ADHD diagnoses among children and the subsequent prescribing of medications are reasons for the nearly 300% increase in poison control calls. A 2018 study showed that the estimated prevalence of ADHD diagnoses among U.S. children and adolescents increased from 6.1% in 1997-1998 to 10.2% in 2015-2016. The Centers for Disease Control and Prevention states that 6 million children and adolescents aged 3-17 years have been diagnosed with ADHD, and 62% have received ADHD medication.

Colleen Kraft, MD, a pediatrician at Children’s Hospital Los Angeles, said she was not surprised by the reported increase in errors. In addition to the simple uptick in ADHD diagnoses and prescriptions in the past 2 decades, Dr. Kraft said the growing variety of ADHD medication is a cause for more errors.

“Because we have so many more different types of these medications, it’s easy to confuse them, and it’s easy to make an error when you give this to a child,” she said in an interview.

Dr. Kraft also hypothesized that because ADHD can have a genetic component, some parents with undiagnosed and untreated ADHD are responsible for their child’s medication, a scenario ripe for mistakes.
 

Potential dangers

Not all ADHD medicinal overdosing is created equal, Dr. Kraft pointed out. Doubling up on a stimulant such as methylphenidate (Ritalin) or the combination of amphetamine and dextroamphetamine (Adderall) may cause headaches, suppress appetite, and cause an upset stomach, although those symptoms usually clear up in a few hours.

However, she noted, the use of alpha-1 adrenergic blockers is more concerning. Also used to treat high blood pressure, medications such as guanfacine and clonidine cause sedation. A double dose can cause blood pressure to decrease to dangerous levels.

The study’s primary limitation was bias in self-reporting, which may have led to underreporting of incidences, according to the researchers. Not every case in which an error occurs that involves a child’s taking ADHD medication gets reported to poison control, because some will take a wait-and-see approach and may not call if their child is asymptomatic.

“Our data is only as good as what the callers report to us,” Dr. Rine said.

A version of this article appeared on Medscape.com.

The frequency of medication errors among children who take drugs to treat attention-deficit/hyperactivity disorder reported to U.S. poison control centers increased by nearly 300% over a 22-year period, according to results of a study published in the journal Pediatrics.

The dramatic jump is likely attributable to an increase in the prescribing of ADHD medications for children. According to the study authors, in 2019, nearly 10% of children in the United States had been diagnosed with ADHD, and some 3.3 million – or about 5% of all children in the country – had received a prescription for an ADHD medication.

“Because therapeutic errors are preventable, more attention should be given to patient and caregiver education and development of improved child-resistant medication dispensing and tracking systems,” the authors commented.

The investigators analyzed data from the National Poison Data System from 2000 through 2021 for therapeutic errors associated with ADHD medication among patients younger than 20 years.

“As medicine changes, it’s nice to look back at some of these things and see how some of these problems have changed,” said Natalie I. Rine, PharmD, a coauthor of the study and director of the Central Ohio Poison Center at Nationwide Children’s Hospital in Columbus.

The researchers identified 124,383 such errors reported to U.S. poison centers during the study period. The frequency increased by 299%.

Two-thirds (66.6%) of the exposures involved children aged 6-12 years, three-fourths (76.4%) were among males, and half (50.5%) involved amphetamines and related compounds. Most (79.7%) therapeutic errors were linked to exposure to a single substance. Nearly 83% of patients did not receive treatment at a health care facility; however, 2.3% were admitted to the hospital, and 4.2% had a “serious medical outcome,” the researchers found.

The most common scenarios were “inadvertently took or given medication twice” (53.9%), followed by “inadvertently took or given someone else’s medication” (13.4%) and “wrong medication taken or given” (12.9%), according to the researchers. Two percent involved mistakes by a pharmacist or nurse.
 

Easily preventable

Dr. Rine attributed the errors to simple mistakes and said they were likely the product of busy households and distracted caregivers. She added that the errors are easily avoided by storing the medication properly, keeping a sheet with the medication to document what was taken and when, and using a pillbox or one of many apps that can assist in documenting the dispensing of medications.

“I think the biggest thing is that a lot of these errors are preventable, more than anything else,” Dr. Rine said.

The increase in ADHD diagnoses among children and the subsequent prescribing of medications are reasons for the nearly 300% increase in poison control calls. A 2018 study showed that the estimated prevalence of ADHD diagnoses among U.S. children and adolescents increased from 6.1% in 1997-1998 to 10.2% in 2015-2016. The Centers for Disease Control and Prevention states that 6 million children and adolescents aged 3-17 years have been diagnosed with ADHD, and 62% have received ADHD medication.

Colleen Kraft, MD, a pediatrician at Children’s Hospital Los Angeles, said she was not surprised by the reported increase in errors. In addition to the simple uptick in ADHD diagnoses and prescriptions in the past 2 decades, Dr. Kraft said the growing variety of ADHD medication is a cause for more errors.

“Because we have so many more different types of these medications, it’s easy to confuse them, and it’s easy to make an error when you give this to a child,” she said in an interview.

Dr. Kraft also hypothesized that because ADHD can have a genetic component, some parents with undiagnosed and untreated ADHD are responsible for their child’s medication, a scenario ripe for mistakes.
 

Potential dangers

Not all ADHD medicinal overdosing is created equal, Dr. Kraft pointed out. Doubling up on a stimulant such as methylphenidate (Ritalin) or the combination of amphetamine and dextroamphetamine (Adderall) may cause headaches, suppress appetite, and cause an upset stomach, although those symptoms usually clear up in a few hours.

However, she noted, the use of alpha-1 adrenergic blockers is more concerning. Also used to treat high blood pressure, medications such as guanfacine and clonidine cause sedation. A double dose can cause blood pressure to decrease to dangerous levels.

The study’s primary limitation was bias in self-reporting, which may have led to underreporting of incidences, according to the researchers. Not every case in which an error occurs that involves a child’s taking ADHD medication gets reported to poison control, because some will take a wait-and-see approach and may not call if their child is asymptomatic.

“Our data is only as good as what the callers report to us,” Dr. Rine said.

A version of this article appeared on Medscape.com.

The frequency of medication errors among children who take drugs to treat attention-deficit/hyperactivity disorder reported to U.S. poison control centers increased by nearly 300% over a 22-year period, according to results of a study published in the journal Pediatrics.

The dramatic jump is likely attributable to an increase in the prescribing of ADHD medications for children. According to the study authors, in 2019, nearly 10% of children in the United States had been diagnosed with ADHD, and some 3.3 million – or about 5% of all children in the country – had received a prescription for an ADHD medication.

“Because therapeutic errors are preventable, more attention should be given to patient and caregiver education and development of improved child-resistant medication dispensing and tracking systems,” the authors commented.

The investigators analyzed data from the National Poison Data System from 2000 through 2021 for therapeutic errors associated with ADHD medication among patients younger than 20 years.

“As medicine changes, it’s nice to look back at some of these things and see how some of these problems have changed,” said Natalie I. Rine, PharmD, a coauthor of the study and director of the Central Ohio Poison Center at Nationwide Children’s Hospital in Columbus.

The researchers identified 124,383 such errors reported to U.S. poison centers during the study period. The frequency increased by 299%.

Two-thirds (66.6%) of the exposures involved children aged 6-12 years, three-fourths (76.4%) were among males, and half (50.5%) involved amphetamines and related compounds. Most (79.7%) therapeutic errors were linked to exposure to a single substance. Nearly 83% of patients did not receive treatment at a health care facility; however, 2.3% were admitted to the hospital, and 4.2% had a “serious medical outcome,” the researchers found.

The most common scenarios were “inadvertently took or given medication twice” (53.9%), followed by “inadvertently took or given someone else’s medication” (13.4%) and “wrong medication taken or given” (12.9%), according to the researchers. Two percent involved mistakes by a pharmacist or nurse.
 

Easily preventable

Dr. Rine attributed the errors to simple mistakes and said they were likely the product of busy households and distracted caregivers. She added that the errors are easily avoided by storing the medication properly, keeping a sheet with the medication to document what was taken and when, and using a pillbox or one of many apps that can assist in documenting the dispensing of medications.

“I think the biggest thing is that a lot of these errors are preventable, more than anything else,” Dr. Rine said.

The increase in ADHD diagnoses among children and the subsequent prescribing of medications are reasons for the nearly 300% increase in poison control calls. A 2018 study showed that the estimated prevalence of ADHD diagnoses among U.S. children and adolescents increased from 6.1% in 1997-1998 to 10.2% in 2015-2016. The Centers for Disease Control and Prevention states that 6 million children and adolescents aged 3-17 years have been diagnosed with ADHD, and 62% have received ADHD medication.

Colleen Kraft, MD, a pediatrician at Children’s Hospital Los Angeles, said she was not surprised by the reported increase in errors. In addition to the simple uptick in ADHD diagnoses and prescriptions in the past 2 decades, Dr. Kraft said the growing variety of ADHD medication is a cause for more errors.

“Because we have so many more different types of these medications, it’s easy to confuse them, and it’s easy to make an error when you give this to a child,” she said in an interview.

Dr. Kraft also hypothesized that because ADHD can have a genetic component, some parents with undiagnosed and untreated ADHD are responsible for their child’s medication, a scenario ripe for mistakes.
 

Potential dangers

Not all ADHD medicinal overdosing is created equal, Dr. Kraft pointed out. Doubling up on a stimulant such as methylphenidate (Ritalin) or the combination of amphetamine and dextroamphetamine (Adderall) may cause headaches, suppress appetite, and cause an upset stomach, although those symptoms usually clear up in a few hours.

However, she noted, the use of alpha-1 adrenergic blockers is more concerning. Also used to treat high blood pressure, medications such as guanfacine and clonidine cause sedation. A double dose can cause blood pressure to decrease to dangerous levels.

The study’s primary limitation was bias in self-reporting, which may have led to underreporting of incidences, according to the researchers. Not every case in which an error occurs that involves a child’s taking ADHD medication gets reported to poison control, because some will take a wait-and-see approach and may not call if their child is asymptomatic.

“Our data is only as good as what the callers report to us,” Dr. Rine said.

A version of this article appeared on Medscape.com.

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

Long-term follow-up from the CheckMate 227 study has revealed lasting benefit from the combination of the CTLA-4 inhibitor ipilimumab (IPI) and the PD-1 inhibitor nivolumab (NIVO) in non-small cell lung cancer. After 6 years, previous tumor response, tumor burden reduction, and baseline health-related quality of life all correlated with overall survival, according to the latest analysis from the study.

“Patients treated with NIVO-IPI versus chemotherapy continue to derive long term durable efficacy benefit in CheckMate 227, regardless of PD-L1 expression. This represents the longest ever reported follow-up across phase three studies of frontline immunotherapy in patients with metastatic non–small cell lung cancer, and this further highlights the clinical benefit of frontline NIVO-IPI as a treatment in these patients with metastatic non–small cell lung cancer, regardless of the PD-L1 expression,” said Solange Peters, MD, PhD, during a presentation of the latest analysis at the annual World Conference on Lung Cancer. Dr. Peters is a professor of oncology at Lausanne (Switzerland) University Hospital.

The combination of nivolumab and ipilimumab has shown long-term survival benefit in other cancer types, including advanced melanoma, advanced renal cell carcinoma, and unresectable pleural mesothelioma.

The same session featured other studies demonstrating positive outcomes of immunotherapy in NSCLC. Serving as a discussant, Ferdinandos Skoulidis MD, PhD, commented, “I would argue that we are now at an inflection point where we can claim that we are altering the natural history of the disease for a subset of patients.” Dr. Skoulidis is an associate professor of thoracic oncology at the University of Texas MD Anderson Cancer Center.
 

Updated results

CheckMate 227 enrolled patients with metastatic or recurrent NSCLC, excluding those with EGFR/ALK alterations. Patients with PD-L1 expression greater than or equal to 1% (PD-L1 positive, n = 1,189) were randomized to NIVO-IPI, NIVO, or chemotherapy. Patients with PD-L1 expression less than 1% (n = 550, PD-L1 negative) were randomized to NIVO-IPI, NIVO plus chemotherapy, or chemotherapy alone. The 5-year landmark analysis, which was published by the National Center for Biotechnology Information, showed overall survival rate of 24% among PD-L1 greater than or equal to 1% patients (PD-L1 positive) and 19% in PD-L1 less than 1% (PD-L1 negative) patients who received IPI-NIVO therapy, compared with 14% and 7%, respectively, in the chemotherapy only groups.

At WCLC, Dr. Peters presented data extending to 6 years of follow-up, as well as exploratory analyses. At 6 years of follow-up, in PD-L1 positive patients, 22% of the NIVO-IPI group remained alive, versus 13% of the chemotherapy group (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91), while there was no significant improvement in OS for nivolumab alone, compared with chemotherapy. In the PD-L1 negative group, 16% were alive at 6 years in the IPI-NIVO group (HR, 0.65; 95% CI, 0.52-0.81), as were 10% in NIVO plus chemotherapy (HR, 0.79; 95% CI, 0.64-0.98) group, versus 5% in the chemotherapy group. The benefit of NIVO-IPI was significant in both squamous and non-squamous tumors for both PDL1-positive and PD-L1 negative patients.

At 6 years follow-up, 27% of PD-L1 positive patients who responded to NIVO-IPI remained in response, versus 22% in the NIVO group and 4% in the chemotherapy only group. Among PD-L1 negative patients, 25% of combination therapy responders remained in response at 6 years, while there were 10% still in response among the NIVO group, and none in the chemotherapy only group.
 

Exploratory analyses

Dr. Peters presented a slide showing tumor burden reductions occurring in responders. “What has to be concluded from this very interesting graph is that there are more, deeper responses in the NIVO-IPI versus chemotherapy. Very importantly, too, this is strongly correlated with survival. In both treatment arms, a high magnitude of tumor burden reduction is correlated with an improved survival,” said Dr. Peters. Specifically, among PD-L1 positive patients with more than 80% tumor reduction, survival was 59% at 6 years (95% CI, 44-71%). The figure was 68% in the NIVO only arm (95% CI, 47-82%), and 42% in the chemotherapy only arm (95% CI, 15-66%).

Among PD-L1 negative patients, “there are more, deeper responses in NIVO-IPI versus chemotherapy. That is very clear. And probably differently from the positive PD-L1 arm, the tumor burden reduction is correlated with survival but really only strongly observed in the NIVO-IPI arm,” said Dr. Peters. The figure was 20% in the nivolumab arm (95% CI, 3-48%) and 0% in the chemotherapy only arm (95% CI, not available). “So really something is correlating the tumor burden reduction with the outcome and specifically correlating it in the negative PD-L1 with the treatment of NIVO-IPI,” said Dr. Peters.

The researchers also noted longer progression-free survival and overall response rate in the NIVO-IPI group than the chemotherapy group in both PD-L1 positive and PD-L1 negative patients.

With respect to health-related quality of life, the researchers found a correlation between higher scores at baseline on the EQ-5D-3L scale and overall survival in the chemotherapy group (HR, 0.61; 95% CI, 0.51-0.74) and a trend in the NIVO-IPI group (HR, 0.83; 95% CI, 0.69-1.01). “So this baseline history, the quality of life, is correlated with the outcome regardless of the treatment you deliver,” said Dr. Peters.
 

Personalizing immunotherapy in NSCLC

In his comments, Dr. Skoulidis highlighted the length of responses. “Most importantly, approximately 50% of these patients that are alive at six years are also disease free, suggesting that we are indeed making a dent on the natural history of the disease for these patients,” he said.

He also made a case for personalizing immunotherapy and suggested that CheckMate 227 could provide some guidance. “Ipilimumab/nivolumab – the CheckMate 227 regimen – appears to be particularly active in terms of inducing long-term, long-lasting responses and overall survival in patients harboring tumors that are negative for PD-L1,” he said.

Dr. Skoulidis also highlighted the 16% six-year overall survival among PD-L1 negative patients who received NIVO-IPI, calling it “impressive.” Of those who responded, 25% continued to respond at 6 years. “This is particularly notable in the subset of patients with squamous histology and lack of PD-L1 expression, where the six year overall survival rate with NIVO-IPI versus chemo was 18% versus 4%. So perhaps in patients with squamous histology and lack of PD-L1 expression, NIVO-IPI might represent a favorable regimen to improve long term outcomes,” said Dr. Skoulidis.

CheckMate 227 was funded by Bristol Myers Sqiubb. Dr. Peters has financial relationships with a wide range of pharmaceutical companies, including Bristol Myers Squibb. Dr. Skoulidis has financial relationships with Moderna, BioNTech, Amgen, Intellisphere, Navire, BeiGene, Medscape, Calithera Biosciences, Tango Therapeutics, Guardant Health, Novartis, AIMM Therapeutics, Mirati Therapeutics, Boehringer Ingelheim, Merck, and Pfizer.

Long-term follow-up from the CheckMate 227 study has revealed lasting benefit from the combination of the CTLA-4 inhibitor ipilimumab (IPI) and the PD-1 inhibitor nivolumab (NIVO) in non-small cell lung cancer. After 6 years, previous tumor response, tumor burden reduction, and baseline health-related quality of life all correlated with overall survival, according to the latest analysis from the study.

“Patients treated with NIVO-IPI versus chemotherapy continue to derive long term durable efficacy benefit in CheckMate 227, regardless of PD-L1 expression. This represents the longest ever reported follow-up across phase three studies of frontline immunotherapy in patients with metastatic non–small cell lung cancer, and this further highlights the clinical benefit of frontline NIVO-IPI as a treatment in these patients with metastatic non–small cell lung cancer, regardless of the PD-L1 expression,” said Solange Peters, MD, PhD, during a presentation of the latest analysis at the annual World Conference on Lung Cancer. Dr. Peters is a professor of oncology at Lausanne (Switzerland) University Hospital.

The combination of nivolumab and ipilimumab has shown long-term survival benefit in other cancer types, including advanced melanoma, advanced renal cell carcinoma, and unresectable pleural mesothelioma.

The same session featured other studies demonstrating positive outcomes of immunotherapy in NSCLC. Serving as a discussant, Ferdinandos Skoulidis MD, PhD, commented, “I would argue that we are now at an inflection point where we can claim that we are altering the natural history of the disease for a subset of patients.” Dr. Skoulidis is an associate professor of thoracic oncology at the University of Texas MD Anderson Cancer Center.
 

Updated results

CheckMate 227 enrolled patients with metastatic or recurrent NSCLC, excluding those with EGFR/ALK alterations. Patients with PD-L1 expression greater than or equal to 1% (PD-L1 positive, n = 1,189) were randomized to NIVO-IPI, NIVO, or chemotherapy. Patients with PD-L1 expression less than 1% (n = 550, PD-L1 negative) were randomized to NIVO-IPI, NIVO plus chemotherapy, or chemotherapy alone. The 5-year landmark analysis, which was published by the National Center for Biotechnology Information, showed overall survival rate of 24% among PD-L1 greater than or equal to 1% patients (PD-L1 positive) and 19% in PD-L1 less than 1% (PD-L1 negative) patients who received IPI-NIVO therapy, compared with 14% and 7%, respectively, in the chemotherapy only groups.

At WCLC, Dr. Peters presented data extending to 6 years of follow-up, as well as exploratory analyses. At 6 years of follow-up, in PD-L1 positive patients, 22% of the NIVO-IPI group remained alive, versus 13% of the chemotherapy group (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91), while there was no significant improvement in OS for nivolumab alone, compared with chemotherapy. In the PD-L1 negative group, 16% were alive at 6 years in the IPI-NIVO group (HR, 0.65; 95% CI, 0.52-0.81), as were 10% in NIVO plus chemotherapy (HR, 0.79; 95% CI, 0.64-0.98) group, versus 5% in the chemotherapy group. The benefit of NIVO-IPI was significant in both squamous and non-squamous tumors for both PDL1-positive and PD-L1 negative patients.

At 6 years follow-up, 27% of PD-L1 positive patients who responded to NIVO-IPI remained in response, versus 22% in the NIVO group and 4% in the chemotherapy only group. Among PD-L1 negative patients, 25% of combination therapy responders remained in response at 6 years, while there were 10% still in response among the NIVO group, and none in the chemotherapy only group.
 

Exploratory analyses

Dr. Peters presented a slide showing tumor burden reductions occurring in responders. “What has to be concluded from this very interesting graph is that there are more, deeper responses in the NIVO-IPI versus chemotherapy. Very importantly, too, this is strongly correlated with survival. In both treatment arms, a high magnitude of tumor burden reduction is correlated with an improved survival,” said Dr. Peters. Specifically, among PD-L1 positive patients with more than 80% tumor reduction, survival was 59% at 6 years (95% CI, 44-71%). The figure was 68% in the NIVO only arm (95% CI, 47-82%), and 42% in the chemotherapy only arm (95% CI, 15-66%).

Among PD-L1 negative patients, “there are more, deeper responses in NIVO-IPI versus chemotherapy. That is very clear. And probably differently from the positive PD-L1 arm, the tumor burden reduction is correlated with survival but really only strongly observed in the NIVO-IPI arm,” said Dr. Peters. The figure was 20% in the nivolumab arm (95% CI, 3-48%) and 0% in the chemotherapy only arm (95% CI, not available). “So really something is correlating the tumor burden reduction with the outcome and specifically correlating it in the negative PD-L1 with the treatment of NIVO-IPI,” said Dr. Peters.

The researchers also noted longer progression-free survival and overall response rate in the NIVO-IPI group than the chemotherapy group in both PD-L1 positive and PD-L1 negative patients.

With respect to health-related quality of life, the researchers found a correlation between higher scores at baseline on the EQ-5D-3L scale and overall survival in the chemotherapy group (HR, 0.61; 95% CI, 0.51-0.74) and a trend in the NIVO-IPI group (HR, 0.83; 95% CI, 0.69-1.01). “So this baseline history, the quality of life, is correlated with the outcome regardless of the treatment you deliver,” said Dr. Peters.
 

Personalizing immunotherapy in NSCLC

In his comments, Dr. Skoulidis highlighted the length of responses. “Most importantly, approximately 50% of these patients that are alive at six years are also disease free, suggesting that we are indeed making a dent on the natural history of the disease for these patients,” he said.

He also made a case for personalizing immunotherapy and suggested that CheckMate 227 could provide some guidance. “Ipilimumab/nivolumab – the CheckMate 227 regimen – appears to be particularly active in terms of inducing long-term, long-lasting responses and overall survival in patients harboring tumors that are negative for PD-L1,” he said.

Dr. Skoulidis also highlighted the 16% six-year overall survival among PD-L1 negative patients who received NIVO-IPI, calling it “impressive.” Of those who responded, 25% continued to respond at 6 years. “This is particularly notable in the subset of patients with squamous histology and lack of PD-L1 expression, where the six year overall survival rate with NIVO-IPI versus chemo was 18% versus 4%. So perhaps in patients with squamous histology and lack of PD-L1 expression, NIVO-IPI might represent a favorable regimen to improve long term outcomes,” said Dr. Skoulidis.

CheckMate 227 was funded by Bristol Myers Sqiubb. Dr. Peters has financial relationships with a wide range of pharmaceutical companies, including Bristol Myers Squibb. Dr. Skoulidis has financial relationships with Moderna, BioNTech, Amgen, Intellisphere, Navire, BeiGene, Medscape, Calithera Biosciences, Tango Therapeutics, Guardant Health, Novartis, AIMM Therapeutics, Mirati Therapeutics, Boehringer Ingelheim, Merck, and Pfizer.

Long-term follow-up from the CheckMate 227 study has revealed lasting benefit from the combination of the CTLA-4 inhibitor ipilimumab (IPI) and the PD-1 inhibitor nivolumab (NIVO) in non-small cell lung cancer. After 6 years, previous tumor response, tumor burden reduction, and baseline health-related quality of life all correlated with overall survival, according to the latest analysis from the study.

“Patients treated with NIVO-IPI versus chemotherapy continue to derive long term durable efficacy benefit in CheckMate 227, regardless of PD-L1 expression. This represents the longest ever reported follow-up across phase three studies of frontline immunotherapy in patients with metastatic non–small cell lung cancer, and this further highlights the clinical benefit of frontline NIVO-IPI as a treatment in these patients with metastatic non–small cell lung cancer, regardless of the PD-L1 expression,” said Solange Peters, MD, PhD, during a presentation of the latest analysis at the annual World Conference on Lung Cancer. Dr. Peters is a professor of oncology at Lausanne (Switzerland) University Hospital.

The combination of nivolumab and ipilimumab has shown long-term survival benefit in other cancer types, including advanced melanoma, advanced renal cell carcinoma, and unresectable pleural mesothelioma.

The same session featured other studies demonstrating positive outcomes of immunotherapy in NSCLC. Serving as a discussant, Ferdinandos Skoulidis MD, PhD, commented, “I would argue that we are now at an inflection point where we can claim that we are altering the natural history of the disease for a subset of patients.” Dr. Skoulidis is an associate professor of thoracic oncology at the University of Texas MD Anderson Cancer Center.
 

Updated results

CheckMate 227 enrolled patients with metastatic or recurrent NSCLC, excluding those with EGFR/ALK alterations. Patients with PD-L1 expression greater than or equal to 1% (PD-L1 positive, n = 1,189) were randomized to NIVO-IPI, NIVO, or chemotherapy. Patients with PD-L1 expression less than 1% (n = 550, PD-L1 negative) were randomized to NIVO-IPI, NIVO plus chemotherapy, or chemotherapy alone. The 5-year landmark analysis, which was published by the National Center for Biotechnology Information, showed overall survival rate of 24% among PD-L1 greater than or equal to 1% patients (PD-L1 positive) and 19% in PD-L1 less than 1% (PD-L1 negative) patients who received IPI-NIVO therapy, compared with 14% and 7%, respectively, in the chemotherapy only groups.

At WCLC, Dr. Peters presented data extending to 6 years of follow-up, as well as exploratory analyses. At 6 years of follow-up, in PD-L1 positive patients, 22% of the NIVO-IPI group remained alive, versus 13% of the chemotherapy group (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91), while there was no significant improvement in OS for nivolumab alone, compared with chemotherapy. In the PD-L1 negative group, 16% were alive at 6 years in the IPI-NIVO group (HR, 0.65; 95% CI, 0.52-0.81), as were 10% in NIVO plus chemotherapy (HR, 0.79; 95% CI, 0.64-0.98) group, versus 5% in the chemotherapy group. The benefit of NIVO-IPI was significant in both squamous and non-squamous tumors for both PDL1-positive and PD-L1 negative patients.

At 6 years follow-up, 27% of PD-L1 positive patients who responded to NIVO-IPI remained in response, versus 22% in the NIVO group and 4% in the chemotherapy only group. Among PD-L1 negative patients, 25% of combination therapy responders remained in response at 6 years, while there were 10% still in response among the NIVO group, and none in the chemotherapy only group.
 

Exploratory analyses

Dr. Peters presented a slide showing tumor burden reductions occurring in responders. “What has to be concluded from this very interesting graph is that there are more, deeper responses in the NIVO-IPI versus chemotherapy. Very importantly, too, this is strongly correlated with survival. In both treatment arms, a high magnitude of tumor burden reduction is correlated with an improved survival,” said Dr. Peters. Specifically, among PD-L1 positive patients with more than 80% tumor reduction, survival was 59% at 6 years (95% CI, 44-71%). The figure was 68% in the NIVO only arm (95% CI, 47-82%), and 42% in the chemotherapy only arm (95% CI, 15-66%).

Among PD-L1 negative patients, “there are more, deeper responses in NIVO-IPI versus chemotherapy. That is very clear. And probably differently from the positive PD-L1 arm, the tumor burden reduction is correlated with survival but really only strongly observed in the NIVO-IPI arm,” said Dr. Peters. The figure was 20% in the nivolumab arm (95% CI, 3-48%) and 0% in the chemotherapy only arm (95% CI, not available). “So really something is correlating the tumor burden reduction with the outcome and specifically correlating it in the negative PD-L1 with the treatment of NIVO-IPI,” said Dr. Peters.

The researchers also noted longer progression-free survival and overall response rate in the NIVO-IPI group than the chemotherapy group in both PD-L1 positive and PD-L1 negative patients.

With respect to health-related quality of life, the researchers found a correlation between higher scores at baseline on the EQ-5D-3L scale and overall survival in the chemotherapy group (HR, 0.61; 95% CI, 0.51-0.74) and a trend in the NIVO-IPI group (HR, 0.83; 95% CI, 0.69-1.01). “So this baseline history, the quality of life, is correlated with the outcome regardless of the treatment you deliver,” said Dr. Peters.
 

Personalizing immunotherapy in NSCLC

In his comments, Dr. Skoulidis highlighted the length of responses. “Most importantly, approximately 50% of these patients that are alive at six years are also disease free, suggesting that we are indeed making a dent on the natural history of the disease for these patients,” he said.

He also made a case for personalizing immunotherapy and suggested that CheckMate 227 could provide some guidance. “Ipilimumab/nivolumab – the CheckMate 227 regimen – appears to be particularly active in terms of inducing long-term, long-lasting responses and overall survival in patients harboring tumors that are negative for PD-L1,” he said.

Dr. Skoulidis also highlighted the 16% six-year overall survival among PD-L1 negative patients who received NIVO-IPI, calling it “impressive.” Of those who responded, 25% continued to respond at 6 years. “This is particularly notable in the subset of patients with squamous histology and lack of PD-L1 expression, where the six year overall survival rate with NIVO-IPI versus chemo was 18% versus 4%. So perhaps in patients with squamous histology and lack of PD-L1 expression, NIVO-IPI might represent a favorable regimen to improve long term outcomes,” said Dr. Skoulidis.

CheckMate 227 was funded by Bristol Myers Sqiubb. Dr. Peters has financial relationships with a wide range of pharmaceutical companies, including Bristol Myers Squibb. Dr. Skoulidis has financial relationships with Moderna, BioNTech, Amgen, Intellisphere, Navire, BeiGene, Medscape, Calithera Biosciences, Tango Therapeutics, Guardant Health, Novartis, AIMM Therapeutics, Mirati Therapeutics, Boehringer Ingelheim, Merck, and Pfizer.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.