MDedge Infectious Disease

The monkeypox virus is evolving 6-12 times faster than would be expected, according to a new study.

The virus is thought to have a single origin, the genetic data suggests, and is a likely descendant of the strain involved in the 2017-2018 monkeypox outbreak in Nigeria. It’s not clear if these mutations have aided the transmissibility of the virus among people or have any other clinical implications, João Paulo Gomes, PhD, from Portugal’s National Institute of Health, Lisbon, said in an email.

Since the monkeypox outbreak began in May, nearly 7,000 cases of monkeypox have been reported across 52 countries and territories. As of July 5, there were 560 cases in the United States. So far, there have been no deaths.

Orthopoxviruses – the genus to which monkeypox belongs – are large DNA viruses that usually only gain one or two mutations every year. (For comparison, SARS-CoV-2 gains around two mutations every month.) One would expect 5 to 10 mutations in the 2022 monkeypox virus, compared with the 2017 strain, Dr. Gomes said.

In the study, Dr. Gomes and colleagues analyzed 15 monkeypox DNA sequences made available by Portugal and the National Center for Biotechnology Information, Bethesda, Md., between May 20 and May 27, 2022. The analysis revealed that this most recent strain differed by 50 single-nucleotide polymorphisms, compared with previous strains of the virus in 2017-2018.

“This is far beyond what we would expect, specifically for orthopoxvirus,” Andrew Lover, PhD, an epidemiologist at the University of Massachusetts Amherst School of Public Health & Health Sciences, told this news organization. He was not involved with the research. “That suggests [the virus] is trying to figure out the best way to deal with a new host species,” he added.

Rodents are thought to be the natural hosts of the monkeypox virus, he explained, and, in 2022, the infection transferred to humans. “Moving into a new species can ‘turbocharge’ mutations as the virus adapts to a new biological environment,” he explained, though it is not clear if the new mutations Dr. Gomes’s team detected help the 2022 virus spread more easily among people.

Researchers also found that the 2022 virus belonged in clade 3 of the virus, which is part of the less-lethal West-African clade. While the West-African clade has a fatality rate of less than 1%, the Central African clade has a fatality rate of over 10%.

The rapid changes in the viral genome could be driven by a family of proteins thought to play a role in antiviral immunity: apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3). These enzymes can make changes to a viral genome, Dr. Gomes explained, “but sometimes the system is not ‘well regulated,’ and the changes in the genome are not detrimental to the virus.” These APOBEC3-driven mutations have a signature pattern, he said, which was also detected in most of the 50 new mutations Dr. Gomes’s team identified.

However, it is not known if these mutations have clinical implications, Dr. Lover said.

The 2022 monkeypox virus does appear to behave differently than previous strains of the virus, he noted. In the current outbreak, sexual transmission appears to be very common, which is not the case for previous outbreaks, he said. Also, while monkeypox traditionally presents with a rash that can spread to all parts of the body, there have been several instances of patients presenting with just a few “very innocuous lesions,” he added.

Dr. Gomes hopes that specialized lab groups will now be able to tease out whether there is a connection between these identified mutations and changes in the behavior of the virus, including transmissibility.

While none of the findings in this analysis raises any serious concerns, the study “suggests there [are] definitely gaps in our knowledge about monkeypox,” Dr. Lover said. As for the global health response, he said, “We probably should err on the side of caution. ... There are clearly things that we absolutely don’t understand here, in terms of how quickly mutations are popping up.”

Dr. Gomes and Dr. Lover report no relevant financial relationships.

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

The monkeypox virus is evolving 6-12 times faster than would be expected, according to a new study.

The virus is thought to have a single origin, the genetic data suggests, and is a likely descendant of the strain involved in the 2017-2018 monkeypox outbreak in Nigeria. It’s not clear if these mutations have aided the transmissibility of the virus among people or have any other clinical implications, João Paulo Gomes, PhD, from Portugal’s National Institute of Health, Lisbon, said in an email.

Since the monkeypox outbreak began in May, nearly 7,000 cases of monkeypox have been reported across 52 countries and territories. As of July 5, there were 560 cases in the United States. So far, there have been no deaths.

Orthopoxviruses – the genus to which monkeypox belongs – are large DNA viruses that usually only gain one or two mutations every year. (For comparison, SARS-CoV-2 gains around two mutations every month.) One would expect 5 to 10 mutations in the 2022 monkeypox virus, compared with the 2017 strain, Dr. Gomes said.

In the study, Dr. Gomes and colleagues analyzed 15 monkeypox DNA sequences made available by Portugal and the National Center for Biotechnology Information, Bethesda, Md., between May 20 and May 27, 2022. The analysis revealed that this most recent strain differed by 50 single-nucleotide polymorphisms, compared with previous strains of the virus in 2017-2018.

“This is far beyond what we would expect, specifically for orthopoxvirus,” Andrew Lover, PhD, an epidemiologist at the University of Massachusetts Amherst School of Public Health & Health Sciences, told this news organization. He was not involved with the research. “That suggests [the virus] is trying to figure out the best way to deal with a new host species,” he added.

Rodents are thought to be the natural hosts of the monkeypox virus, he explained, and, in 2022, the infection transferred to humans. “Moving into a new species can ‘turbocharge’ mutations as the virus adapts to a new biological environment,” he explained, though it is not clear if the new mutations Dr. Gomes’s team detected help the 2022 virus spread more easily among people.

Researchers also found that the 2022 virus belonged in clade 3 of the virus, which is part of the less-lethal West-African clade. While the West-African clade has a fatality rate of less than 1%, the Central African clade has a fatality rate of over 10%.

The rapid changes in the viral genome could be driven by a family of proteins thought to play a role in antiviral immunity: apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3). These enzymes can make changes to a viral genome, Dr. Gomes explained, “but sometimes the system is not ‘well regulated,’ and the changes in the genome are not detrimental to the virus.” These APOBEC3-driven mutations have a signature pattern, he said, which was also detected in most of the 50 new mutations Dr. Gomes’s team identified.

However, it is not known if these mutations have clinical implications, Dr. Lover said.

The 2022 monkeypox virus does appear to behave differently than previous strains of the virus, he noted. In the current outbreak, sexual transmission appears to be very common, which is not the case for previous outbreaks, he said. Also, while monkeypox traditionally presents with a rash that can spread to all parts of the body, there have been several instances of patients presenting with just a few “very innocuous lesions,” he added.

Dr. Gomes hopes that specialized lab groups will now be able to tease out whether there is a connection between these identified mutations and changes in the behavior of the virus, including transmissibility.

While none of the findings in this analysis raises any serious concerns, the study “suggests there [are] definitely gaps in our knowledge about monkeypox,” Dr. Lover said. As for the global health response, he said, “We probably should err on the side of caution. ... There are clearly things that we absolutely don’t understand here, in terms of how quickly mutations are popping up.”

Dr. Gomes and Dr. Lover report no relevant financial relationships.

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

The monkeypox virus is evolving 6-12 times faster than would be expected, according to a new study.

The virus is thought to have a single origin, the genetic data suggests, and is a likely descendant of the strain involved in the 2017-2018 monkeypox outbreak in Nigeria. It’s not clear if these mutations have aided the transmissibility of the virus among people or have any other clinical implications, João Paulo Gomes, PhD, from Portugal’s National Institute of Health, Lisbon, said in an email.

Since the monkeypox outbreak began in May, nearly 7,000 cases of monkeypox have been reported across 52 countries and territories. As of July 5, there were 560 cases in the United States. So far, there have been no deaths.

Orthopoxviruses – the genus to which monkeypox belongs – are large DNA viruses that usually only gain one or two mutations every year. (For comparison, SARS-CoV-2 gains around two mutations every month.) One would expect 5 to 10 mutations in the 2022 monkeypox virus, compared with the 2017 strain, Dr. Gomes said.

In the study, Dr. Gomes and colleagues analyzed 15 monkeypox DNA sequences made available by Portugal and the National Center for Biotechnology Information, Bethesda, Md., between May 20 and May 27, 2022. The analysis revealed that this most recent strain differed by 50 single-nucleotide polymorphisms, compared with previous strains of the virus in 2017-2018.

“This is far beyond what we would expect, specifically for orthopoxvirus,” Andrew Lover, PhD, an epidemiologist at the University of Massachusetts Amherst School of Public Health & Health Sciences, told this news organization. He was not involved with the research. “That suggests [the virus] is trying to figure out the best way to deal with a new host species,” he added.

Rodents are thought to be the natural hosts of the monkeypox virus, he explained, and, in 2022, the infection transferred to humans. “Moving into a new species can ‘turbocharge’ mutations as the virus adapts to a new biological environment,” he explained, though it is not clear if the new mutations Dr. Gomes’s team detected help the 2022 virus spread more easily among people.

Researchers also found that the 2022 virus belonged in clade 3 of the virus, which is part of the less-lethal West-African clade. While the West-African clade has a fatality rate of less than 1%, the Central African clade has a fatality rate of over 10%.

The rapid changes in the viral genome could be driven by a family of proteins thought to play a role in antiviral immunity: apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3). These enzymes can make changes to a viral genome, Dr. Gomes explained, “but sometimes the system is not ‘well regulated,’ and the changes in the genome are not detrimental to the virus.” These APOBEC3-driven mutations have a signature pattern, he said, which was also detected in most of the 50 new mutations Dr. Gomes’s team identified.

However, it is not known if these mutations have clinical implications, Dr. Lover said.

The 2022 monkeypox virus does appear to behave differently than previous strains of the virus, he noted. In the current outbreak, sexual transmission appears to be very common, which is not the case for previous outbreaks, he said. Also, while monkeypox traditionally presents with a rash that can spread to all parts of the body, there have been several instances of patients presenting with just a few “very innocuous lesions,” he added.

Dr. Gomes hopes that specialized lab groups will now be able to tease out whether there is a connection between these identified mutations and changes in the behavior of the virus, including transmissibility.

While none of the findings in this analysis raises any serious concerns, the study “suggests there [are] definitely gaps in our knowledge about monkeypox,” Dr. Lover said. As for the global health response, he said, “We probably should err on the side of caution. ... There are clearly things that we absolutely don’t understand here, in terms of how quickly mutations are popping up.”

Dr. Gomes and Dr. Lover report no relevant financial relationships.

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

In an April press release, the Strategic Advisory Group of Experts on Immunization (SAGE) of the World Health Organization (WHO) reported the findings of their review concerning the efficacy of various dose schedules for human papillomavirus (HPV). “A single-dose HPV vaccine delivers solid protection against HPV, the virus that causes cervical cancer, that is comparable to 2-dose schedules,” according to SAGE.

This statement comes on the heels of an article published in the November 2021 issue of Lancet Oncology about a study in India. It found that a single dose of the vaccine provides protection against persistent infection from HPV 16 and 18 similar to that provided by two or three doses.

Will this new information lead French authorities to change their recommendations? What do French specialists think? At the 45th Congress of the French Society for Colposcopy and Cervical and Vaginal Diseases (SFCPCV), Geoffroy Canlorbe, MD, PhD, of the department of gynecologic and breast surgery and oncology, Pitié-Salpêtrière Hospital, Paris, shared his thoughts.

With respect to the Indian study, Dr. Canlorbe pointed out that while its findings would need “to be confirmed by other studies,” they were, nonetheless, “excellent news for developing countries where there are challenges when it comes to access to vaccination.”
 

India and France

During the congress press conference, he went on to say that, at this stage, the findings “cannot be extrapolated” to France. This is because the country’s situation is different. HPV vaccination coverage is low; estimates put it at 23.7%, placing the country 28th out of 31 in Europe.

“This poor coverage has nothing to do with health care–related logistical or organizational issues; instead, it has to do with people’s mistrust when it comes to vaccination. Here, people who get the first dose get the subsequent ones,” said Dr. Canlorbe. “The very fact of getting two to three doses allows the person’s body to increase the production of antibodies and get a longer-lasting response to the vaccine.”

In addition, he drew attention to several limitations of the Indian study. Initially, the team had planned to enroll 20,000 participants. In the end, there were around 17,000, and these were allocated to three cohorts: single-dose, two-dose, and three-dose. Furthermore, the primary objective, which had initially been focused on precancerous and cancerous lesions, was revised. The new aim was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years postvaccination. In about 90% of cases, the HPV infection went away spontaneously in 2 years without inducing lesions. Finally, the participants were women in India; therefore, the results cannot necessarily be generalized to the French population.

“This information has to be confirmed. However, as far as I know, there are no new studies going on at the moment. The Indian study, on the other hand, is still in progress,” said Dr. Canlorbe.

“In France, I think that for the time being we should stick to the studies that are currently available, which have demonstrated the efficacy and safety of two or three doses,” he concluded. In support of this approach, he cited a study on the effects of the national HPV vaccination program in England; there, the vaccination coverage is 80%.

This program was associated with a 95% risk reduction for precancerous lesions and an 87% reduction in the number of cancers, confirming the good results already achieved by Sweden and Australia.

In his comments on the WHO’s stance (which differs from that of the French experts), Jean-Luc Mergui, MD, gynecologist in the department of colposcopy and hysteroscopy at Pitié-Salpêtrière, and former president of the SFCPCV, offered an eloquent comparison: “The WHO also recommends 6 months of breastfeeding as a method of contraception, but this isn’t what’s recommended in France, for the risk of getting pregnant nevertheless remains.”
 

Indian study highlights

Partha Basu, MD, PhD, of the International Agency for Research on Cancer (IARC) in Lyon, France, and colleagues compared vaccine efficacy of a single dose of Gardasil (HPV 9-valent vaccine, recombinant) to that of two and three doses in protecting against persistent HPV 16 and HPV 18 infection at 10 years postvaccination.

According to the protocol, the plan was to recruit 20,000 unmarried girls, aged 10-18 years, from across India. Recruitment was initiated in September 2009. However, in response to seven unexplained deaths reported in another ongoing HPV vaccination demonstration program in the country, the Indian government issued a notification in April 2010 to stop further recruitment and HPV vaccination in all clinical trials. At this point, Dr. Basu and his team had recruited 17,729 eligible girls.

After suspension of recruitment and vaccination, their randomized trial was converted to a longitudinal, prospective, cohort study by default.

Vaccinated participants were followed up over a median duration of 9 years. In all, 4,348 participants had three doses, 4,980 had two doses (at 0 and 6 months), and 4,949 had a single dose. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Participants were invited to an annual cervical cancer screening once they reached age 25 years and were married.

A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and HPV 18, the genotypes responsible for nearly 70% of cervical cancers, compared with that provided by two or three doses. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95.4% (95% confidence interval [CI], 85.0-99.9) in the single-dose default cohort (2,135 women assessed), 93.1% (95% CI, 77.3-99.8) in the two-dose cohort (1,452 women assessed), and 93.3% (95% CI, 77.5-99.7) in three-dose recipients (1,460 women assessed).

Dr. Canlorbe reported no relevant financial relationships regarding the content of this article.

This article was translated from the Medscape French edition. An English version appeared on Medscape.com.

In an April press release, the Strategic Advisory Group of Experts on Immunization (SAGE) of the World Health Organization (WHO) reported the findings of their review concerning the efficacy of various dose schedules for human papillomavirus (HPV). “A single-dose HPV vaccine delivers solid protection against HPV, the virus that causes cervical cancer, that is comparable to 2-dose schedules,” according to SAGE.

This statement comes on the heels of an article published in the November 2021 issue of Lancet Oncology about a study in India. It found that a single dose of the vaccine provides protection against persistent infection from HPV 16 and 18 similar to that provided by two or three doses.

Will this new information lead French authorities to change their recommendations? What do French specialists think? At the 45th Congress of the French Society for Colposcopy and Cervical and Vaginal Diseases (SFCPCV), Geoffroy Canlorbe, MD, PhD, of the department of gynecologic and breast surgery and oncology, Pitié-Salpêtrière Hospital, Paris, shared his thoughts.

With respect to the Indian study, Dr. Canlorbe pointed out that while its findings would need “to be confirmed by other studies,” they were, nonetheless, “excellent news for developing countries where there are challenges when it comes to access to vaccination.”
 

India and France

During the congress press conference, he went on to say that, at this stage, the findings “cannot be extrapolated” to France. This is because the country’s situation is different. HPV vaccination coverage is low; estimates put it at 23.7%, placing the country 28th out of 31 in Europe.

“This poor coverage has nothing to do with health care–related logistical or organizational issues; instead, it has to do with people’s mistrust when it comes to vaccination. Here, people who get the first dose get the subsequent ones,” said Dr. Canlorbe. “The very fact of getting two to three doses allows the person’s body to increase the production of antibodies and get a longer-lasting response to the vaccine.”

In addition, he drew attention to several limitations of the Indian study. Initially, the team had planned to enroll 20,000 participants. In the end, there were around 17,000, and these were allocated to three cohorts: single-dose, two-dose, and three-dose. Furthermore, the primary objective, which had initially been focused on precancerous and cancerous lesions, was revised. The new aim was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years postvaccination. In about 90% of cases, the HPV infection went away spontaneously in 2 years without inducing lesions. Finally, the participants were women in India; therefore, the results cannot necessarily be generalized to the French population.

“This information has to be confirmed. However, as far as I know, there are no new studies going on at the moment. The Indian study, on the other hand, is still in progress,” said Dr. Canlorbe.

“In France, I think that for the time being we should stick to the studies that are currently available, which have demonstrated the efficacy and safety of two or three doses,” he concluded. In support of this approach, he cited a study on the effects of the national HPV vaccination program in England; there, the vaccination coverage is 80%.

This program was associated with a 95% risk reduction for precancerous lesions and an 87% reduction in the number of cancers, confirming the good results already achieved by Sweden and Australia.

In his comments on the WHO’s stance (which differs from that of the French experts), Jean-Luc Mergui, MD, gynecologist in the department of colposcopy and hysteroscopy at Pitié-Salpêtrière, and former president of the SFCPCV, offered an eloquent comparison: “The WHO also recommends 6 months of breastfeeding as a method of contraception, but this isn’t what’s recommended in France, for the risk of getting pregnant nevertheless remains.”
 

Indian study highlights

Partha Basu, MD, PhD, of the International Agency for Research on Cancer (IARC) in Lyon, France, and colleagues compared vaccine efficacy of a single dose of Gardasil (HPV 9-valent vaccine, recombinant) to that of two and three doses in protecting against persistent HPV 16 and HPV 18 infection at 10 years postvaccination.

According to the protocol, the plan was to recruit 20,000 unmarried girls, aged 10-18 years, from across India. Recruitment was initiated in September 2009. However, in response to seven unexplained deaths reported in another ongoing HPV vaccination demonstration program in the country, the Indian government issued a notification in April 2010 to stop further recruitment and HPV vaccination in all clinical trials. At this point, Dr. Basu and his team had recruited 17,729 eligible girls.

After suspension of recruitment and vaccination, their randomized trial was converted to a longitudinal, prospective, cohort study by default.

Vaccinated participants were followed up over a median duration of 9 years. In all, 4,348 participants had three doses, 4,980 had two doses (at 0 and 6 months), and 4,949 had a single dose. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Participants were invited to an annual cervical cancer screening once they reached age 25 years and were married.

A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and HPV 18, the genotypes responsible for nearly 70% of cervical cancers, compared with that provided by two or three doses. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95.4% (95% confidence interval [CI], 85.0-99.9) in the single-dose default cohort (2,135 women assessed), 93.1% (95% CI, 77.3-99.8) in the two-dose cohort (1,452 women assessed), and 93.3% (95% CI, 77.5-99.7) in three-dose recipients (1,460 women assessed).

Dr. Canlorbe reported no relevant financial relationships regarding the content of this article.

This article was translated from the Medscape French edition. An English version appeared on Medscape.com.

In an April press release, the Strategic Advisory Group of Experts on Immunization (SAGE) of the World Health Organization (WHO) reported the findings of their review concerning the efficacy of various dose schedules for human papillomavirus (HPV). “A single-dose HPV vaccine delivers solid protection against HPV, the virus that causes cervical cancer, that is comparable to 2-dose schedules,” according to SAGE.

This statement comes on the heels of an article published in the November 2021 issue of Lancet Oncology about a study in India. It found that a single dose of the vaccine provides protection against persistent infection from HPV 16 and 18 similar to that provided by two or three doses.

Will this new information lead French authorities to change their recommendations? What do French specialists think? At the 45th Congress of the French Society for Colposcopy and Cervical and Vaginal Diseases (SFCPCV), Geoffroy Canlorbe, MD, PhD, of the department of gynecologic and breast surgery and oncology, Pitié-Salpêtrière Hospital, Paris, shared his thoughts.

With respect to the Indian study, Dr. Canlorbe pointed out that while its findings would need “to be confirmed by other studies,” they were, nonetheless, “excellent news for developing countries where there are challenges when it comes to access to vaccination.”
 

India and France

During the congress press conference, he went on to say that, at this stage, the findings “cannot be extrapolated” to France. This is because the country’s situation is different. HPV vaccination coverage is low; estimates put it at 23.7%, placing the country 28th out of 31 in Europe.

“This poor coverage has nothing to do with health care–related logistical or organizational issues; instead, it has to do with people’s mistrust when it comes to vaccination. Here, people who get the first dose get the subsequent ones,” said Dr. Canlorbe. “The very fact of getting two to three doses allows the person’s body to increase the production of antibodies and get a longer-lasting response to the vaccine.”

In addition, he drew attention to several limitations of the Indian study. Initially, the team had planned to enroll 20,000 participants. In the end, there were around 17,000, and these were allocated to three cohorts: single-dose, two-dose, and three-dose. Furthermore, the primary objective, which had initially been focused on precancerous and cancerous lesions, was revised. The new aim was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years postvaccination. In about 90% of cases, the HPV infection went away spontaneously in 2 years without inducing lesions. Finally, the participants were women in India; therefore, the results cannot necessarily be generalized to the French population.

“This information has to be confirmed. However, as far as I know, there are no new studies going on at the moment. The Indian study, on the other hand, is still in progress,” said Dr. Canlorbe.

“In France, I think that for the time being we should stick to the studies that are currently available, which have demonstrated the efficacy and safety of two or three doses,” he concluded. In support of this approach, he cited a study on the effects of the national HPV vaccination program in England; there, the vaccination coverage is 80%.

This program was associated with a 95% risk reduction for precancerous lesions and an 87% reduction in the number of cancers, confirming the good results already achieved by Sweden and Australia.

In his comments on the WHO’s stance (which differs from that of the French experts), Jean-Luc Mergui, MD, gynecologist in the department of colposcopy and hysteroscopy at Pitié-Salpêtrière, and former president of the SFCPCV, offered an eloquent comparison: “The WHO also recommends 6 months of breastfeeding as a method of contraception, but this isn’t what’s recommended in France, for the risk of getting pregnant nevertheless remains.”
 

Indian study highlights

Partha Basu, MD, PhD, of the International Agency for Research on Cancer (IARC) in Lyon, France, and colleagues compared vaccine efficacy of a single dose of Gardasil (HPV 9-valent vaccine, recombinant) to that of two and three doses in protecting against persistent HPV 16 and HPV 18 infection at 10 years postvaccination.

According to the protocol, the plan was to recruit 20,000 unmarried girls, aged 10-18 years, from across India. Recruitment was initiated in September 2009. However, in response to seven unexplained deaths reported in another ongoing HPV vaccination demonstration program in the country, the Indian government issued a notification in April 2010 to stop further recruitment and HPV vaccination in all clinical trials. At this point, Dr. Basu and his team had recruited 17,729 eligible girls.

After suspension of recruitment and vaccination, their randomized trial was converted to a longitudinal, prospective, cohort study by default.

Vaccinated participants were followed up over a median duration of 9 years. In all, 4,348 participants had three doses, 4,980 had two doses (at 0 and 6 months), and 4,949 had a single dose. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Participants were invited to an annual cervical cancer screening once they reached age 25 years and were married.

A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and HPV 18, the genotypes responsible for nearly 70% of cervical cancers, compared with that provided by two or three doses. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95.4% (95% confidence interval [CI], 85.0-99.9) in the single-dose default cohort (2,135 women assessed), 93.1% (95% CI, 77.3-99.8) in the two-dose cohort (1,452 women assessed), and 93.3% (95% CI, 77.5-99.7) in three-dose recipients (1,460 women assessed).

Dr. Canlorbe reported no relevant financial relationships regarding the content of this article.

This article was translated from the Medscape French edition. An English version appeared on Medscape.com.

When Amy Moser had a simple urinary tract infection in her late 20s, her doctor prescribed Cipro, a powerful antibiotic used to treat anthrax and some of the most fearsome bacterial infections.

Nearly 2 weeks after she finished her treatment, her left kneecap dislocated while she was trying on a swimsuit at a retail store. Shortly afterward, she had painful ligament ruptures in her wrists, then her shoulder dislocated, followed by three Achilles tendon tears.

“That’s when I fell apart,” says Ms. Moser, a Phoenix health blogger and book author. “From that moment on, for almost the next 2.5 years consistently, I had new tendon tears every few weeks.”

Ms. Moser’s doctors had no answer for what was causing her injuries, all of which required surgical fixes. A married mother of three, she was otherwise healthy and fit. So, after her third Achilles tear, she turned to the FDA’s website for answers. There, she found many warnings about side effects of Cipro, Levaquin, and other so-called fluoroquinolones, including risks for tendon and ligament injuries.

“When all the ruptures started to happen, my doctor kept asking me if I’d ever taken Levaquin, and every time I was like, ‘No.’ So I did what all doctors don’t want you to do: I Googled ‘Levaquin,’ ” she recalls.

Her search led to FDA warnings and articles about the possibility of tendon and ligament ruptures with fluroquinolones.

“That was the first time I’d ever even heard that word ‘fluroquinolones,’ and I found Cipro on that list ... and I realized that I’d just been prescribed that before everything started,” she says.

That was 12 years ago. Since then, the FDA has issued more warnings about fluoroquinolone risks. In that time, Ms. Moser, now 40, has had more than 30 surgeries to correct tendon ruptures and injuries, including a double-knee replacement this year.

“I am in chronic pain all the time,” she says. “I am chronically injured. I have a lot of tears that I’ve not fixed because they’re very complicated, and I don’t know if the rest of my body can handle the strain of recovering from those surgeries.”

Ms. Moser’s is hardly an isolated case. Since the 1980s, more than 60,000 patients have reported hundreds of thousands of serious events linked to fluoroquinolones to the FDA, including 6,575 reports of deaths.

The most common side effects were tendon rupture, as well as neurological and psychiatric symptoms. But experts estimate only 1%-10% of such events are reported to the FDA. That suggests that fluoroquinolones might have harmed hundreds of thousands of people in the United States alone, says Charles Bennett, MD, a hematologist at the University of South Carolina’s College of Pharmacy, Columbia.

Yet despite the many patient reports and FDA warnings on dangerous side effects, many doctors continue to wrongly prescribe fluoroquinolones for simple urinary tract infections, sinus infections, and respiratory issues better treated with less risky antibiotics.

“There probably is overprescription by primary care doctors for urinary tract infections and respiratory infections, when there could be alternatives that are safer to use,” says Amesh Adalja, MD, an infectious disease specialist and senior scholar with the Johns Hopkins Center for Health Security.

“I would say that’s probably the case in the outpatient setting, not necessarily in the hospital setting or among infectious disease doctors ... but I think it’s important to say there are still some judicious uses of fluoroquinolones,” he says. “However, there probably is a lot of injudicious use of fluoroquinolones along with many other antibiotics in the primary care setting.”
 

FDA warnings on fluoroquinolones

Fluoroquinolones are a class of broad-spectrum antibiotics used for decades to treat certain bacterial infections.

FDA-approved fluoroquinolones include ciprofloxacin (Cipro), ciprofloxacin extended-release tablets, delafloxacin (Baxdela), gemifloxacin (Factive) levofloxacin (Levaquin), moxifloxacin (Avelox), and ofloxacin (Floxin). More than 60 generic versions of these brand-name medicines are also on the market, making them among the most prescribed antibiotics in the U.S.

Over the past 2 decades, a wide range of physical and mental health side effects have been tied to fluoroquinolones. As a result of these “adverse event reports” and research published in medical literature, the FDA has required an escalating series of warnings and safety labeling changes for doctors who prescribe these drugs.

• In 2008, the FDA first added a “black box” warning to fluoroquinolones, citing an increased risk of tendinitis and tendon rupture in patients prescribed these meds.
• In 2011, the agency required the warning label to include risks of worsening symptoms for those with myasthenia gravis, a chronic autoimmune disease that causes muscle weakness, vision problems, and speech problems.
• In 2013, regulators required updated labels noting the potential for irreversible peripheral neuropathy (serious nerve damage).
• In 2016, the FDA issued its strongest warning against the use of such antibiotics for simple bacterial infections – such as uncomplicated urinary tract infections (UTIs), acute sinusitis, and acute bronchitis – saying the “association of fluoroquinolones with disabling and potentially permanent side effects involving tendons, muscles, joints, nerves and the central nervous system ... outweighs the benefits for patients.”
• And in 2018, regulators required safety labeling changes to include warnings about the risks of aortic aneurysm – a life-threatening enlargement of the main vessel that delivers blood to the body – as well as mental health side effects and serious blood sugar disturbances.

But FDA regulators have stopped short of barring fluoroquinolone use in the treatment of bacterial infections, citing the benefits for certain conditions.

“For some patients, the benefits of fluoroquinolones may continue to outweigh the risks for treatment of serious bacterial infections, such as pneumonia or intra-abdominal infections,” said former FDA Commissioner Scott Gottlieb, MD, “but there are other serious, known risks associated with these strong antibiotics that must be carefully weighed when considering their use.”

In December 2021, a study published in the journal JAMA Network Open found the FDA’s warnings may have helped lower prescribing of the drugs in Medicare patients. But not all doctors have been responsive to those warnings, researchers found.

“An overall decline in change over time and an immediate change in fluoroquinolone prescribing was observed after the 2016 FDA warning,” the authors concluded. “Certain physicians, such as primary care physicians, were more responsive to FDA warnings than others. ... Findings of this study suggest that identifying the association of physician and organizational characteristics with fluoroquinolone prescribing practices could help in developing mechanisms for improving de-adoption.”

Some critics say the FDA should do more to spotlight the dangers of fluoroquinolones and require doctors and patients to sign checklist consent forms to show they are aware of the potential side effects of these drugs.

Rachel Brummert, a patient advocate who sits on an FDA consumer advisory board, believes the FDA needs to improve its communication to doctors on fluoroquinolone risks and get tougher with those who continue to inappropriately prescribe the drugs.

“I think there needs to be a system in place, where if something comes down from the FDA about a drug, the physician has to sign off on it, the patient has to sign off on it and mark that they understand that there are these ‘black box’ warnings,” says Ms. Brummert, 52, a representative on the FDA’s Medical Devices Advisory Committee.

As an example, she points to Australia’s medical laws requiring doctors and patients to sign a checklist before any fluoroquinolone prescription is approved.

“When a physician prescribes a fluoroquinolone antibiotic, there’s a checklist – does the patient have an infection, is it a simple infection, do they have allergies?” she notes. “And you can’t even get the prescription out – it won’t even print out, it won’t go into the system – unless you check all of the boxes. But we don’t do that here. We don’t have that type of system right now.”

Ms. Brummert says such a system might have prevented the harm from taking Levaquin her doctor prescribed for a suspected sinus infection in 2006.

Soon after she began taking the antibiotic, she ruptured her Achilles tendon, requiring surgery. By 2009, she’d had three ruptures, each needing surgical fixes. To date, she’s had more than 30 surgeries to correct tendon ruptures. She’s also had seizures, blood pressure issues, depression, chronic pain, and memory problems she attributes to taking Levaquin.

As it turns out, her doctor misdiagnosed her condition – a misstep that would have been averted with a system like Australia’s, which requires doctors to verify the presence of a bacterial infection through a simple test before prescribing a fluoroquinolone.

“When I got the Levaquin, it was for a suspected sinus infection that it turned out I didn’t even have in the first place,” she notes. “So, I took the Levaquin basically for nothing. But what I would have asked my doctor had I known is: ‘Why should I take something so strong for so simple an infection?’

“It seems common sense to me now that you don’t prescribe something that can kill anthrax for a simple sinus infection. It’s like an atom bomb killing a mosquito. I agree that there are uses for these drugs, but they are being overprescribed. And so, here I am 16 years later – I’m still rupturing, I’m still having surgery, and I’m still in pain – all for something I didn’t even need medicine for in the first place.”
 

Should guidelines be stronger?

So, why are so many doctors continuing to prescribe fluoroquinolones for simple infections? Dr. Adalja and other experts say several things are at work.

For one thing, Dr. Adalja notes, fluoroquinolones are broad-spectrum antibiotics that are effective against dangerous germs, including “gram-negative” bacterial infections, and are “100% bioavailable.” That means they are as effective when given in pill form as they are if put directly into a vein. So they can be used in an outpatient setting or to allow a patient to be discharged from a hospital sooner because they don’t need an IV to receive treatment.

“There are still some uses for these drugs because they are so bioavailable, and I think that drives some of the use, and those are legitimate uses, knowing that there are risks when you do it,” he says. “But no drug is without risks, and you have to weigh risks and benefits – that’s what medicine is about: deciding what the best drug is for a patient.”

But Dr. Adalja says the overprescription of fluoroquinolones is part of the larger trend of antibiotic overuse. That is driving up antibiotic resistance, which in turn is another thing leading doctors to turn to Cipro and other fluoroquinolones after other drugs have proven ineffective.

“You can’t separate this from the fact that 80% of antibiotic prescriptions in the outpatient setting are probably illegitimate or not warranted,” he notes. “And because fluoroquinolones are highly effective drugs against certain pathogens, they are the go-to [drug] for many people who are prescribing antibiotics.”

That’s why patients should be wary whenever a doctor prescribes a fluoroquinolone, or any drug to treat a suspected infection, he says.

“Any time a patient is getting prescribed an antibiotic by a physician, they should ask: ‘Do I really need this antibiotic?’ That should be the first question they ask,” he advises. “And if they’re getting a fluoroquinolone, they may want to ask: ‘Is this the best antibiotic for me?’ ”
 

What you can do

Ms. Brummert and Ms. Moser say they are sharing their stories to raise awareness of the dangers of fluoroquinolones.

Ms. Moser has published a book on her experiences, “The Magnificent Story of a Lame Author,” and provides a wealth of consumer resources on her blog: Mountains and Mustard Seeds.

“As much as I hate what has happened to me, it has put me in a place where I am glad that I can inform other patients,” she says.

Ms. Brummert supplements her advocacy work as an FDA adviser with useful materials she provides on her website: Drugwatch.com.

“Pain into purpose – that’s what I call it,” she says. “I can’t change what happened to me, but I can warn others.”

The upshot for patients?

• the FDA’s Drug Safety Communication on Fluoroquinolones online to learn more about the risks and benefits of these powerful antibiotics.
• If you believe you’ve been harmed by fluoroquinolones, MedWatch website to report your experiences.

Ms. Brummert also advises patients to ask 12 critical questions of any doctor who wants to prescribe a fluoroquinolone, including the following listed on her website:

• For what condition is this medication prescribed, and is there another drug specific to my condition?
• What are the risks associated with this medication, and do the benefits outweigh them?
• Will this medication interact with my other drugs and/or other health conditions?
• What are the “boxed” warnings for this medication, and where can I report adverse events?

“I would also do my own research,” she says. “I wouldn’t just take a prescription from a physician and just say, ‘OK, doctor knows best.’ ”

Ms. Moser agrees that you have to be your own patient advocate and not simply take a doctor’s advice on any medical issue without having a deeper conversation.

“I’ve had arguments with doctors who legitimately did not believe me when I told them what happened to me,” she says. “And I actually told them, ‘Go get your Physicians’ Desk Reference [for prescription drugs]’ and they opened the book in front of me and read the warnings. Obviously, they had not been keeping up with the added warnings. So, I do think that doctors do need to be better informed.”

“So, yes, it’s the FDA’s responsibility, but it is also the doctors’ responsibility to make sure that they’re watching out for the side effects and they’re reporting them when their patients come up with them and making those connections.”

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

When Amy Moser had a simple urinary tract infection in her late 20s, her doctor prescribed Cipro, a powerful antibiotic used to treat anthrax and some of the most fearsome bacterial infections.

Nearly 2 weeks after she finished her treatment, her left kneecap dislocated while she was trying on a swimsuit at a retail store. Shortly afterward, she had painful ligament ruptures in her wrists, then her shoulder dislocated, followed by three Achilles tendon tears.

“That’s when I fell apart,” says Ms. Moser, a Phoenix health blogger and book author. “From that moment on, for almost the next 2.5 years consistently, I had new tendon tears every few weeks.”

Ms. Moser’s doctors had no answer for what was causing her injuries, all of which required surgical fixes. A married mother of three, she was otherwise healthy and fit. So, after her third Achilles tear, she turned to the FDA’s website for answers. There, she found many warnings about side effects of Cipro, Levaquin, and other so-called fluoroquinolones, including risks for tendon and ligament injuries.

“When all the ruptures started to happen, my doctor kept asking me if I’d ever taken Levaquin, and every time I was like, ‘No.’ So I did what all doctors don’t want you to do: I Googled ‘Levaquin,’ ” she recalls.

Her search led to FDA warnings and articles about the possibility of tendon and ligament ruptures with fluroquinolones.

“That was the first time I’d ever even heard that word ‘fluroquinolones,’ and I found Cipro on that list ... and I realized that I’d just been prescribed that before everything started,” she says.

That was 12 years ago. Since then, the FDA has issued more warnings about fluoroquinolone risks. In that time, Ms. Moser, now 40, has had more than 30 surgeries to correct tendon ruptures and injuries, including a double-knee replacement this year.

“I am in chronic pain all the time,” she says. “I am chronically injured. I have a lot of tears that I’ve not fixed because they’re very complicated, and I don’t know if the rest of my body can handle the strain of recovering from those surgeries.”

Ms. Moser’s is hardly an isolated case. Since the 1980s, more than 60,000 patients have reported hundreds of thousands of serious events linked to fluoroquinolones to the FDA, including 6,575 reports of deaths.

The most common side effects were tendon rupture, as well as neurological and psychiatric symptoms. But experts estimate only 1%-10% of such events are reported to the FDA. That suggests that fluoroquinolones might have harmed hundreds of thousands of people in the United States alone, says Charles Bennett, MD, a hematologist at the University of South Carolina’s College of Pharmacy, Columbia.

Yet despite the many patient reports and FDA warnings on dangerous side effects, many doctors continue to wrongly prescribe fluoroquinolones for simple urinary tract infections, sinus infections, and respiratory issues better treated with less risky antibiotics.

“There probably is overprescription by primary care doctors for urinary tract infections and respiratory infections, when there could be alternatives that are safer to use,” says Amesh Adalja, MD, an infectious disease specialist and senior scholar with the Johns Hopkins Center for Health Security.

“I would say that’s probably the case in the outpatient setting, not necessarily in the hospital setting or among infectious disease doctors ... but I think it’s important to say there are still some judicious uses of fluoroquinolones,” he says. “However, there probably is a lot of injudicious use of fluoroquinolones along with many other antibiotics in the primary care setting.”
 

FDA warnings on fluoroquinolones

Fluoroquinolones are a class of broad-spectrum antibiotics used for decades to treat certain bacterial infections.

FDA-approved fluoroquinolones include ciprofloxacin (Cipro), ciprofloxacin extended-release tablets, delafloxacin (Baxdela), gemifloxacin (Factive) levofloxacin (Levaquin), moxifloxacin (Avelox), and ofloxacin (Floxin). More than 60 generic versions of these brand-name medicines are also on the market, making them among the most prescribed antibiotics in the U.S.

Over the past 2 decades, a wide range of physical and mental health side effects have been tied to fluoroquinolones. As a result of these “adverse event reports” and research published in medical literature, the FDA has required an escalating series of warnings and safety labeling changes for doctors who prescribe these drugs.

• In 2008, the FDA first added a “black box” warning to fluoroquinolones, citing an increased risk of tendinitis and tendon rupture in patients prescribed these meds.
• In 2011, the agency required the warning label to include risks of worsening symptoms for those with myasthenia gravis, a chronic autoimmune disease that causes muscle weakness, vision problems, and speech problems.
• In 2013, regulators required updated labels noting the potential for irreversible peripheral neuropathy (serious nerve damage).
• In 2016, the FDA issued its strongest warning against the use of such antibiotics for simple bacterial infections – such as uncomplicated urinary tract infections (UTIs), acute sinusitis, and acute bronchitis – saying the “association of fluoroquinolones with disabling and potentially permanent side effects involving tendons, muscles, joints, nerves and the central nervous system ... outweighs the benefits for patients.”
• And in 2018, regulators required safety labeling changes to include warnings about the risks of aortic aneurysm – a life-threatening enlargement of the main vessel that delivers blood to the body – as well as mental health side effects and serious blood sugar disturbances.

But FDA regulators have stopped short of barring fluoroquinolone use in the treatment of bacterial infections, citing the benefits for certain conditions.

“For some patients, the benefits of fluoroquinolones may continue to outweigh the risks for treatment of serious bacterial infections, such as pneumonia or intra-abdominal infections,” said former FDA Commissioner Scott Gottlieb, MD, “but there are other serious, known risks associated with these strong antibiotics that must be carefully weighed when considering their use.”

In December 2021, a study published in the journal JAMA Network Open found the FDA’s warnings may have helped lower prescribing of the drugs in Medicare patients. But not all doctors have been responsive to those warnings, researchers found.

“An overall decline in change over time and an immediate change in fluoroquinolone prescribing was observed after the 2016 FDA warning,” the authors concluded. “Certain physicians, such as primary care physicians, were more responsive to FDA warnings than others. ... Findings of this study suggest that identifying the association of physician and organizational characteristics with fluoroquinolone prescribing practices could help in developing mechanisms for improving de-adoption.”

Some critics say the FDA should do more to spotlight the dangers of fluoroquinolones and require doctors and patients to sign checklist consent forms to show they are aware of the potential side effects of these drugs.

Rachel Brummert, a patient advocate who sits on an FDA consumer advisory board, believes the FDA needs to improve its communication to doctors on fluoroquinolone risks and get tougher with those who continue to inappropriately prescribe the drugs.

“I think there needs to be a system in place, where if something comes down from the FDA about a drug, the physician has to sign off on it, the patient has to sign off on it and mark that they understand that there are these ‘black box’ warnings,” says Ms. Brummert, 52, a representative on the FDA’s Medical Devices Advisory Committee.

As an example, she points to Australia’s medical laws requiring doctors and patients to sign a checklist before any fluoroquinolone prescription is approved.

“When a physician prescribes a fluoroquinolone antibiotic, there’s a checklist – does the patient have an infection, is it a simple infection, do they have allergies?” she notes. “And you can’t even get the prescription out – it won’t even print out, it won’t go into the system – unless you check all of the boxes. But we don’t do that here. We don’t have that type of system right now.”

Ms. Brummert says such a system might have prevented the harm from taking Levaquin her doctor prescribed for a suspected sinus infection in 2006.

Soon after she began taking the antibiotic, she ruptured her Achilles tendon, requiring surgery. By 2009, she’d had three ruptures, each needing surgical fixes. To date, she’s had more than 30 surgeries to correct tendon ruptures. She’s also had seizures, blood pressure issues, depression, chronic pain, and memory problems she attributes to taking Levaquin.

As it turns out, her doctor misdiagnosed her condition – a misstep that would have been averted with a system like Australia’s, which requires doctors to verify the presence of a bacterial infection through a simple test before prescribing a fluoroquinolone.

“When I got the Levaquin, it was for a suspected sinus infection that it turned out I didn’t even have in the first place,” she notes. “So, I took the Levaquin basically for nothing. But what I would have asked my doctor had I known is: ‘Why should I take something so strong for so simple an infection?’

“It seems common sense to me now that you don’t prescribe something that can kill anthrax for a simple sinus infection. It’s like an atom bomb killing a mosquito. I agree that there are uses for these drugs, but they are being overprescribed. And so, here I am 16 years later – I’m still rupturing, I’m still having surgery, and I’m still in pain – all for something I didn’t even need medicine for in the first place.”
 

Should guidelines be stronger?

So, why are so many doctors continuing to prescribe fluoroquinolones for simple infections? Dr. Adalja and other experts say several things are at work.

For one thing, Dr. Adalja notes, fluoroquinolones are broad-spectrum antibiotics that are effective against dangerous germs, including “gram-negative” bacterial infections, and are “100% bioavailable.” That means they are as effective when given in pill form as they are if put directly into a vein. So they can be used in an outpatient setting or to allow a patient to be discharged from a hospital sooner because they don’t need an IV to receive treatment.

“There are still some uses for these drugs because they are so bioavailable, and I think that drives some of the use, and those are legitimate uses, knowing that there are risks when you do it,” he says. “But no drug is without risks, and you have to weigh risks and benefits – that’s what medicine is about: deciding what the best drug is for a patient.”

But Dr. Adalja says the overprescription of fluoroquinolones is part of the larger trend of antibiotic overuse. That is driving up antibiotic resistance, which in turn is another thing leading doctors to turn to Cipro and other fluoroquinolones after other drugs have proven ineffective.

“You can’t separate this from the fact that 80% of antibiotic prescriptions in the outpatient setting are probably illegitimate or not warranted,” he notes. “And because fluoroquinolones are highly effective drugs against certain pathogens, they are the go-to [drug] for many people who are prescribing antibiotics.”

That’s why patients should be wary whenever a doctor prescribes a fluoroquinolone, or any drug to treat a suspected infection, he says.

“Any time a patient is getting prescribed an antibiotic by a physician, they should ask: ‘Do I really need this antibiotic?’ That should be the first question they ask,” he advises. “And if they’re getting a fluoroquinolone, they may want to ask: ‘Is this the best antibiotic for me?’ ”
 

What you can do

Ms. Brummert and Ms. Moser say they are sharing their stories to raise awareness of the dangers of fluoroquinolones.

Ms. Moser has published a book on her experiences, “The Magnificent Story of a Lame Author,” and provides a wealth of consumer resources on her blog: Mountains and Mustard Seeds.

“As much as I hate what has happened to me, it has put me in a place where I am glad that I can inform other patients,” she says.

Ms. Brummert supplements her advocacy work as an FDA adviser with useful materials she provides on her website: Drugwatch.com.

“Pain into purpose – that’s what I call it,” she says. “I can’t change what happened to me, but I can warn others.”

The upshot for patients?

• the FDA’s Drug Safety Communication on Fluoroquinolones online to learn more about the risks and benefits of these powerful antibiotics.
• If you believe you’ve been harmed by fluoroquinolones, MedWatch website to report your experiences.

Ms. Brummert also advises patients to ask 12 critical questions of any doctor who wants to prescribe a fluoroquinolone, including the following listed on her website:

• For what condition is this medication prescribed, and is there another drug specific to my condition?
• What are the risks associated with this medication, and do the benefits outweigh them?
• Will this medication interact with my other drugs and/or other health conditions?
• What are the “boxed” warnings for this medication, and where can I report adverse events?

“I would also do my own research,” she says. “I wouldn’t just take a prescription from a physician and just say, ‘OK, doctor knows best.’ ”

Ms. Moser agrees that you have to be your own patient advocate and not simply take a doctor’s advice on any medical issue without having a deeper conversation.

“I’ve had arguments with doctors who legitimately did not believe me when I told them what happened to me,” she says. “And I actually told them, ‘Go get your Physicians’ Desk Reference [for prescription drugs]’ and they opened the book in front of me and read the warnings. Obviously, they had not been keeping up with the added warnings. So, I do think that doctors do need to be better informed.”

“So, yes, it’s the FDA’s responsibility, but it is also the doctors’ responsibility to make sure that they’re watching out for the side effects and they’re reporting them when their patients come up with them and making those connections.”

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

When Amy Moser had a simple urinary tract infection in her late 20s, her doctor prescribed Cipro, a powerful antibiotic used to treat anthrax and some of the most fearsome bacterial infections.

Nearly 2 weeks after she finished her treatment, her left kneecap dislocated while she was trying on a swimsuit at a retail store. Shortly afterward, she had painful ligament ruptures in her wrists, then her shoulder dislocated, followed by three Achilles tendon tears.

“That’s when I fell apart,” says Ms. Moser, a Phoenix health blogger and book author. “From that moment on, for almost the next 2.5 years consistently, I had new tendon tears every few weeks.”

Ms. Moser’s doctors had no answer for what was causing her injuries, all of which required surgical fixes. A married mother of three, she was otherwise healthy and fit. So, after her third Achilles tear, she turned to the FDA’s website for answers. There, she found many warnings about side effects of Cipro, Levaquin, and other so-called fluoroquinolones, including risks for tendon and ligament injuries.

“When all the ruptures started to happen, my doctor kept asking me if I’d ever taken Levaquin, and every time I was like, ‘No.’ So I did what all doctors don’t want you to do: I Googled ‘Levaquin,’ ” she recalls.

Her search led to FDA warnings and articles about the possibility of tendon and ligament ruptures with fluroquinolones.

“That was the first time I’d ever even heard that word ‘fluroquinolones,’ and I found Cipro on that list ... and I realized that I’d just been prescribed that before everything started,” she says.

That was 12 years ago. Since then, the FDA has issued more warnings about fluoroquinolone risks. In that time, Ms. Moser, now 40, has had more than 30 surgeries to correct tendon ruptures and injuries, including a double-knee replacement this year.

“I am in chronic pain all the time,” she says. “I am chronically injured. I have a lot of tears that I’ve not fixed because they’re very complicated, and I don’t know if the rest of my body can handle the strain of recovering from those surgeries.”

Ms. Moser’s is hardly an isolated case. Since the 1980s, more than 60,000 patients have reported hundreds of thousands of serious events linked to fluoroquinolones to the FDA, including 6,575 reports of deaths.

The most common side effects were tendon rupture, as well as neurological and psychiatric symptoms. But experts estimate only 1%-10% of such events are reported to the FDA. That suggests that fluoroquinolones might have harmed hundreds of thousands of people in the United States alone, says Charles Bennett, MD, a hematologist at the University of South Carolina’s College of Pharmacy, Columbia.

Yet despite the many patient reports and FDA warnings on dangerous side effects, many doctors continue to wrongly prescribe fluoroquinolones for simple urinary tract infections, sinus infections, and respiratory issues better treated with less risky antibiotics.

“There probably is overprescription by primary care doctors for urinary tract infections and respiratory infections, when there could be alternatives that are safer to use,” says Amesh Adalja, MD, an infectious disease specialist and senior scholar with the Johns Hopkins Center for Health Security.

“I would say that’s probably the case in the outpatient setting, not necessarily in the hospital setting or among infectious disease doctors ... but I think it’s important to say there are still some judicious uses of fluoroquinolones,” he says. “However, there probably is a lot of injudicious use of fluoroquinolones along with many other antibiotics in the primary care setting.”
 

FDA warnings on fluoroquinolones

Fluoroquinolones are a class of broad-spectrum antibiotics used for decades to treat certain bacterial infections.

FDA-approved fluoroquinolones include ciprofloxacin (Cipro), ciprofloxacin extended-release tablets, delafloxacin (Baxdela), gemifloxacin (Factive) levofloxacin (Levaquin), moxifloxacin (Avelox), and ofloxacin (Floxin). More than 60 generic versions of these brand-name medicines are also on the market, making them among the most prescribed antibiotics in the U.S.

Over the past 2 decades, a wide range of physical and mental health side effects have been tied to fluoroquinolones. As a result of these “adverse event reports” and research published in medical literature, the FDA has required an escalating series of warnings and safety labeling changes for doctors who prescribe these drugs.

• In 2008, the FDA first added a “black box” warning to fluoroquinolones, citing an increased risk of tendinitis and tendon rupture in patients prescribed these meds.
• In 2011, the agency required the warning label to include risks of worsening symptoms for those with myasthenia gravis, a chronic autoimmune disease that causes muscle weakness, vision problems, and speech problems.
• In 2013, regulators required updated labels noting the potential for irreversible peripheral neuropathy (serious nerve damage).
• In 2016, the FDA issued its strongest warning against the use of such antibiotics for simple bacterial infections – such as uncomplicated urinary tract infections (UTIs), acute sinusitis, and acute bronchitis – saying the “association of fluoroquinolones with disabling and potentially permanent side effects involving tendons, muscles, joints, nerves and the central nervous system ... outweighs the benefits for patients.”
• And in 2018, regulators required safety labeling changes to include warnings about the risks of aortic aneurysm – a life-threatening enlargement of the main vessel that delivers blood to the body – as well as mental health side effects and serious blood sugar disturbances.

But FDA regulators have stopped short of barring fluoroquinolone use in the treatment of bacterial infections, citing the benefits for certain conditions.

“For some patients, the benefits of fluoroquinolones may continue to outweigh the risks for treatment of serious bacterial infections, such as pneumonia or intra-abdominal infections,” said former FDA Commissioner Scott Gottlieb, MD, “but there are other serious, known risks associated with these strong antibiotics that must be carefully weighed when considering their use.”

In December 2021, a study published in the journal JAMA Network Open found the FDA’s warnings may have helped lower prescribing of the drugs in Medicare patients. But not all doctors have been responsive to those warnings, researchers found.

“An overall decline in change over time and an immediate change in fluoroquinolone prescribing was observed after the 2016 FDA warning,” the authors concluded. “Certain physicians, such as primary care physicians, were more responsive to FDA warnings than others. ... Findings of this study suggest that identifying the association of physician and organizational characteristics with fluoroquinolone prescribing practices could help in developing mechanisms for improving de-adoption.”

Some critics say the FDA should do more to spotlight the dangers of fluoroquinolones and require doctors and patients to sign checklist consent forms to show they are aware of the potential side effects of these drugs.

Rachel Brummert, a patient advocate who sits on an FDA consumer advisory board, believes the FDA needs to improve its communication to doctors on fluoroquinolone risks and get tougher with those who continue to inappropriately prescribe the drugs.

“I think there needs to be a system in place, where if something comes down from the FDA about a drug, the physician has to sign off on it, the patient has to sign off on it and mark that they understand that there are these ‘black box’ warnings,” says Ms. Brummert, 52, a representative on the FDA’s Medical Devices Advisory Committee.

As an example, she points to Australia’s medical laws requiring doctors and patients to sign a checklist before any fluoroquinolone prescription is approved.

“When a physician prescribes a fluoroquinolone antibiotic, there’s a checklist – does the patient have an infection, is it a simple infection, do they have allergies?” she notes. “And you can’t even get the prescription out – it won’t even print out, it won’t go into the system – unless you check all of the boxes. But we don’t do that here. We don’t have that type of system right now.”

Ms. Brummert says such a system might have prevented the harm from taking Levaquin her doctor prescribed for a suspected sinus infection in 2006.

Soon after she began taking the antibiotic, she ruptured her Achilles tendon, requiring surgery. By 2009, she’d had three ruptures, each needing surgical fixes. To date, she’s had more than 30 surgeries to correct tendon ruptures. She’s also had seizures, blood pressure issues, depression, chronic pain, and memory problems she attributes to taking Levaquin.

As it turns out, her doctor misdiagnosed her condition – a misstep that would have been averted with a system like Australia’s, which requires doctors to verify the presence of a bacterial infection through a simple test before prescribing a fluoroquinolone.

“When I got the Levaquin, it was for a suspected sinus infection that it turned out I didn’t even have in the first place,” she notes. “So, I took the Levaquin basically for nothing. But what I would have asked my doctor had I known is: ‘Why should I take something so strong for so simple an infection?’

“It seems common sense to me now that you don’t prescribe something that can kill anthrax for a simple sinus infection. It’s like an atom bomb killing a mosquito. I agree that there are uses for these drugs, but they are being overprescribed. And so, here I am 16 years later – I’m still rupturing, I’m still having surgery, and I’m still in pain – all for something I didn’t even need medicine for in the first place.”
 

Should guidelines be stronger?

So, why are so many doctors continuing to prescribe fluoroquinolones for simple infections? Dr. Adalja and other experts say several things are at work.

For one thing, Dr. Adalja notes, fluoroquinolones are broad-spectrum antibiotics that are effective against dangerous germs, including “gram-negative” bacterial infections, and are “100% bioavailable.” That means they are as effective when given in pill form as they are if put directly into a vein. So they can be used in an outpatient setting or to allow a patient to be discharged from a hospital sooner because they don’t need an IV to receive treatment.

“There are still some uses for these drugs because they are so bioavailable, and I think that drives some of the use, and those are legitimate uses, knowing that there are risks when you do it,” he says. “But no drug is without risks, and you have to weigh risks and benefits – that’s what medicine is about: deciding what the best drug is for a patient.”

But Dr. Adalja says the overprescription of fluoroquinolones is part of the larger trend of antibiotic overuse. That is driving up antibiotic resistance, which in turn is another thing leading doctors to turn to Cipro and other fluoroquinolones after other drugs have proven ineffective.

“You can’t separate this from the fact that 80% of antibiotic prescriptions in the outpatient setting are probably illegitimate or not warranted,” he notes. “And because fluoroquinolones are highly effective drugs against certain pathogens, they are the go-to [drug] for many people who are prescribing antibiotics.”

That’s why patients should be wary whenever a doctor prescribes a fluoroquinolone, or any drug to treat a suspected infection, he says.

“Any time a patient is getting prescribed an antibiotic by a physician, they should ask: ‘Do I really need this antibiotic?’ That should be the first question they ask,” he advises. “And if they’re getting a fluoroquinolone, they may want to ask: ‘Is this the best antibiotic for me?’ ”
 

What you can do

Ms. Brummert and Ms. Moser say they are sharing their stories to raise awareness of the dangers of fluoroquinolones.

Ms. Moser has published a book on her experiences, “The Magnificent Story of a Lame Author,” and provides a wealth of consumer resources on her blog: Mountains and Mustard Seeds.

“As much as I hate what has happened to me, it has put me in a place where I am glad that I can inform other patients,” she says.

Ms. Brummert supplements her advocacy work as an FDA adviser with useful materials she provides on her website: Drugwatch.com.

“Pain into purpose – that’s what I call it,” she says. “I can’t change what happened to me, but I can warn others.”

The upshot for patients?

• the FDA’s Drug Safety Communication on Fluoroquinolones online to learn more about the risks and benefits of these powerful antibiotics.
• If you believe you’ve been harmed by fluoroquinolones, MedWatch website to report your experiences.

Ms. Brummert also advises patients to ask 12 critical questions of any doctor who wants to prescribe a fluoroquinolone, including the following listed on her website:

• For what condition is this medication prescribed, and is there another drug specific to my condition?
• What are the risks associated with this medication, and do the benefits outweigh them?
• Will this medication interact with my other drugs and/or other health conditions?
• What are the “boxed” warnings for this medication, and where can I report adverse events?

“I would also do my own research,” she says. “I wouldn’t just take a prescription from a physician and just say, ‘OK, doctor knows best.’ ”

Ms. Moser agrees that you have to be your own patient advocate and not simply take a doctor’s advice on any medical issue without having a deeper conversation.

“I’ve had arguments with doctors who legitimately did not believe me when I told them what happened to me,” she says. “And I actually told them, ‘Go get your Physicians’ Desk Reference [for prescription drugs]’ and they opened the book in front of me and read the warnings. Obviously, they had not been keeping up with the added warnings. So, I do think that doctors do need to be better informed.”

“So, yes, it’s the FDA’s responsibility, but it is also the doctors’ responsibility to make sure that they’re watching out for the side effects and they’re reporting them when their patients come up with them and making those connections.”

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

How satisfied are physicians that they are fairly compensated for their dedication, skills, and time? That’s a subject that seems to steer many physicians to heated emotions and to a variety of issues with today’s medical field – not all of which directly affect their pay.

Medscape’s Physician Compensation Report 2022: “Incomes Gain, Pay Gaps Remain” generally shows encouraging trends. Physician income rose from a year earlier, when it stagnated as COVID-19 restrictions led patients to stay home and medical practices to cut hours or close. And for the first time in Medscape’s 11 years of reporting on physician compensation, average income rose for every medical specialty surveyed.

Heartening findings, right? Yet the tone of comments to the report was anything but peppy. Many commenters were highly distressed or even angry about their compensation. One physician even complained his plumber earns more than he does.

A family physician lamented that he has “made less in the past 3 years, with more hassles and work” and he “can’t wait to retire next year.” Meanwhile, he complained, the U.S. health system is “the costliest, yet wasteful, with worse outcomes; reactive, not preventative; and has the costliest drugs and social issues.”
 

Do NPs and PAs encroach on your income?

The conversation about fair compensation launched some commenters into a discussion about competition from nurse practitioners (NPs) and physician assistants (PAs). Some physicians expressed wariness at best, and anger at worst, about NPs and PAs evolving beyond traditional doctor support roles into certain direct patient support.

One-fourth of respondents in the compensation report said their income was negatively affected by competition from NPs, PAs, and other nonphysician providers. For example, with states like Arkansas expanding independent practice for certified registered nurse anesthetists (CRNAs), one commenter complained, “we are no longer needed.”

Added another physician, “primary care, especially internal medicine, is just going away for doctors. We wasted, by all accounts, 4 full years of our working lives because NPs are ‘just as good.’ ”

Greater independence for NPs and PAs strengthens the hands of health insurers and “will end up hastening the demise of primary care as we have known it,” another reader predicted. Other physicians’ takes: “For the institution, it’s much cheaper to hire NPs than to hire doctors” and “overall, physician negotiating power will decrease in the future.”
 

Medicare reimbursement rates grate

Although 7 in 10 respondents in the compensation report said they would continue to accept new Medicare or Medicaid patients, comments reveal resentment about the practical need to work with Medicare and its resentment rates.

“An open question to Medicare: Are you doing the dumbest thing possible by paying low wages and giving huge administrative burdens for internal medicine on purpose?” one physician wrote. “Or are you really that short-sighted?”

Another reader cited an analysis from the American College of Surgeons of Medicare’s 1998 surgical CPT codes. If Medicare had left those codes alone beyond annual inflation adjustments, the study found, reimbursement rates by 2019 would be half of what they became.

Another way of looking at the code reimbursement increases is a 50% pay cut over 20 years for doctors and medical practices, that reader insisted. “The rising cost of employee wages, particularly of the last two-and-a-half years of COVID-19, combined with the effective pay cuts over the last 20 years, equals time to quit!”

Another commenter concurred. “In the 1990s, most full-time docs were making almost double what you see [in the report], and everything cost almost half of what it does now. So, MD purchasing power is between half and one-quarter of what it was in the early 1990s.”
 

Are self-pay models better?

Do physicians have a better chance at consistently fair income under a self-pay practice that avoids dealing with insurance companies?

One commenter hypothesized that psychiatrists once trailed internists in income but today earn more because many “quit working for insurance and went to a cash business 15 years ago.” Many family physicians did something similar by switching to a direct primary care model, he said.

This physician said he has done the same “with great results” for patients as well: shorter office visits, faster booking of appointments, no deductibles owed. Best of all, “I love practicing medicine again, and my patients love the great health care they receive.”

Another commenter agreed. “Two words: cash practice.” But another objected, “I guess only the very rich can afford to cover your business costs.”

Regardless of the payment model, another physician argued for private practice over employed positions. “Save on the bureaucratic expenses. Go back to private practice and get rid of electronic records.”

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

How satisfied are physicians that they are fairly compensated for their dedication, skills, and time? That’s a subject that seems to steer many physicians to heated emotions and to a variety of issues with today’s medical field – not all of which directly affect their pay.

Medscape’s Physician Compensation Report 2022: “Incomes Gain, Pay Gaps Remain” generally shows encouraging trends. Physician income rose from a year earlier, when it stagnated as COVID-19 restrictions led patients to stay home and medical practices to cut hours or close. And for the first time in Medscape’s 11 years of reporting on physician compensation, average income rose for every medical specialty surveyed.

Heartening findings, right? Yet the tone of comments to the report was anything but peppy. Many commenters were highly distressed or even angry about their compensation. One physician even complained his plumber earns more than he does.

A family physician lamented that he has “made less in the past 3 years, with more hassles and work” and he “can’t wait to retire next year.” Meanwhile, he complained, the U.S. health system is “the costliest, yet wasteful, with worse outcomes; reactive, not preventative; and has the costliest drugs and social issues.”
 

Do NPs and PAs encroach on your income?

The conversation about fair compensation launched some commenters into a discussion about competition from nurse practitioners (NPs) and physician assistants (PAs). Some physicians expressed wariness at best, and anger at worst, about NPs and PAs evolving beyond traditional doctor support roles into certain direct patient support.

One-fourth of respondents in the compensation report said their income was negatively affected by competition from NPs, PAs, and other nonphysician providers. For example, with states like Arkansas expanding independent practice for certified registered nurse anesthetists (CRNAs), one commenter complained, “we are no longer needed.”

Added another physician, “primary care, especially internal medicine, is just going away for doctors. We wasted, by all accounts, 4 full years of our working lives because NPs are ‘just as good.’ ”

Greater independence for NPs and PAs strengthens the hands of health insurers and “will end up hastening the demise of primary care as we have known it,” another reader predicted. Other physicians’ takes: “For the institution, it’s much cheaper to hire NPs than to hire doctors” and “overall, physician negotiating power will decrease in the future.”
 

Medicare reimbursement rates grate

Although 7 in 10 respondents in the compensation report said they would continue to accept new Medicare or Medicaid patients, comments reveal resentment about the practical need to work with Medicare and its resentment rates.

“An open question to Medicare: Are you doing the dumbest thing possible by paying low wages and giving huge administrative burdens for internal medicine on purpose?” one physician wrote. “Or are you really that short-sighted?”

Another reader cited an analysis from the American College of Surgeons of Medicare’s 1998 surgical CPT codes. If Medicare had left those codes alone beyond annual inflation adjustments, the study found, reimbursement rates by 2019 would be half of what they became.

Another way of looking at the code reimbursement increases is a 50% pay cut over 20 years for doctors and medical practices, that reader insisted. “The rising cost of employee wages, particularly of the last two-and-a-half years of COVID-19, combined with the effective pay cuts over the last 20 years, equals time to quit!”

Another commenter concurred. “In the 1990s, most full-time docs were making almost double what you see [in the report], and everything cost almost half of what it does now. So, MD purchasing power is between half and one-quarter of what it was in the early 1990s.”
 

Are self-pay models better?

Do physicians have a better chance at consistently fair income under a self-pay practice that avoids dealing with insurance companies?

One commenter hypothesized that psychiatrists once trailed internists in income but today earn more because many “quit working for insurance and went to a cash business 15 years ago.” Many family physicians did something similar by switching to a direct primary care model, he said.

This physician said he has done the same “with great results” for patients as well: shorter office visits, faster booking of appointments, no deductibles owed. Best of all, “I love practicing medicine again, and my patients love the great health care they receive.”

Another commenter agreed. “Two words: cash practice.” But another objected, “I guess only the very rich can afford to cover your business costs.”

Regardless of the payment model, another physician argued for private practice over employed positions. “Save on the bureaucratic expenses. Go back to private practice and get rid of electronic records.”

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

How satisfied are physicians that they are fairly compensated for their dedication, skills, and time? That’s a subject that seems to steer many physicians to heated emotions and to a variety of issues with today’s medical field – not all of which directly affect their pay.

Medscape’s Physician Compensation Report 2022: “Incomes Gain, Pay Gaps Remain” generally shows encouraging trends. Physician income rose from a year earlier, when it stagnated as COVID-19 restrictions led patients to stay home and medical practices to cut hours or close. And for the first time in Medscape’s 11 years of reporting on physician compensation, average income rose for every medical specialty surveyed.

Heartening findings, right? Yet the tone of comments to the report was anything but peppy. Many commenters were highly distressed or even angry about their compensation. One physician even complained his plumber earns more than he does.

A family physician lamented that he has “made less in the past 3 years, with more hassles and work” and he “can’t wait to retire next year.” Meanwhile, he complained, the U.S. health system is “the costliest, yet wasteful, with worse outcomes; reactive, not preventative; and has the costliest drugs and social issues.”
 

Do NPs and PAs encroach on your income?

The conversation about fair compensation launched some commenters into a discussion about competition from nurse practitioners (NPs) and physician assistants (PAs). Some physicians expressed wariness at best, and anger at worst, about NPs and PAs evolving beyond traditional doctor support roles into certain direct patient support.

One-fourth of respondents in the compensation report said their income was negatively affected by competition from NPs, PAs, and other nonphysician providers. For example, with states like Arkansas expanding independent practice for certified registered nurse anesthetists (CRNAs), one commenter complained, “we are no longer needed.”

Added another physician, “primary care, especially internal medicine, is just going away for doctors. We wasted, by all accounts, 4 full years of our working lives because NPs are ‘just as good.’ ”

Greater independence for NPs and PAs strengthens the hands of health insurers and “will end up hastening the demise of primary care as we have known it,” another reader predicted. Other physicians’ takes: “For the institution, it’s much cheaper to hire NPs than to hire doctors” and “overall, physician negotiating power will decrease in the future.”
 

Medicare reimbursement rates grate

Although 7 in 10 respondents in the compensation report said they would continue to accept new Medicare or Medicaid patients, comments reveal resentment about the practical need to work with Medicare and its resentment rates.

“An open question to Medicare: Are you doing the dumbest thing possible by paying low wages and giving huge administrative burdens for internal medicine on purpose?” one physician wrote. “Or are you really that short-sighted?”

Another reader cited an analysis from the American College of Surgeons of Medicare’s 1998 surgical CPT codes. If Medicare had left those codes alone beyond annual inflation adjustments, the study found, reimbursement rates by 2019 would be half of what they became.

Another way of looking at the code reimbursement increases is a 50% pay cut over 20 years for doctors and medical practices, that reader insisted. “The rising cost of employee wages, particularly of the last two-and-a-half years of COVID-19, combined with the effective pay cuts over the last 20 years, equals time to quit!”

Another commenter concurred. “In the 1990s, most full-time docs were making almost double what you see [in the report], and everything cost almost half of what it does now. So, MD purchasing power is between half and one-quarter of what it was in the early 1990s.”
 

Are self-pay models better?

Do physicians have a better chance at consistently fair income under a self-pay practice that avoids dealing with insurance companies?

One commenter hypothesized that psychiatrists once trailed internists in income but today earn more because many “quit working for insurance and went to a cash business 15 years ago.” Many family physicians did something similar by switching to a direct primary care model, he said.

This physician said he has done the same “with great results” for patients as well: shorter office visits, faster booking of appointments, no deductibles owed. Best of all, “I love practicing medicine again, and my patients love the great health care they receive.”

Another commenter agreed. “Two words: cash practice.” But another objected, “I guess only the very rich can afford to cover your business costs.”

Regardless of the payment model, another physician argued for private practice over employed positions. “Save on the bureaucratic expenses. Go back to private practice and get rid of electronic records.”

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

LONDON – Achieving a functional cure for hepatitis B virus (HBV) is not going to be easily achieved with the drugs that are currently in development, according to a presentation at the annual International Liver Congress sponsored by the European Association for the Study of the Liver.

“Intriguing results have been presented at ILC 2022 that must be carefully interpreted,” said Jean-Michel Pawlotsky, MD, PhD, of Henri Mondor Hospital in Créteil, France, during the viral hepatitis highlights session on the closing day of the meeting.

“New HBV drug development looks more complicated than initially expected and its goals and strategies need to be redefined and refocused,” he added

Steve Forrest & Andrew McConnell/EASL

“This is really something that came from the discussions we had during the sessions but also in the corridors,” Dr. Pawlotsky added. “We know it’s going to be difficult; we have to reset, restart – not from zero, but from not much – and revise our strategy,” he suggested.

There are many new drugs under investigation for HBV, Dr. Pawlotsky said, noting that the number of studies being presented at the meeting was reminiscent of the flurry of activity before a functional cure for hepatitis C had been found. “It’s good to see that this is happening again for HBV,” he said.

Indeed, there are many new direct-acting antiviral agents, immunomodulatory, or other approaches being tested, and some of the more advanced studies are “teaching us a few things and probably raising more questions than getting answers,” Dr. Pawlotsky said.
 

The B-CLEAR study

One these studies is the phase 2b B-CLEAR study presented during the late-breaker session. This study involved bepirovirsen, an antisense oligonucleotide, and tested its efficacy and safety in patients with chronic hepatitis B virus infection who were either on or off stable nucleos(t)ide analogue (NA/NUC) therapy.

A similar proportion (28% and 29%, respectively) of patients achieved an hepatitis B surface antigen (HBsAg) level below the lower limit of quantification at the end of 24 weeks treatment. However, the effect on HBsAg varied according to the treatment arm, with changes to the dosing or switching to placebo indicating that the effect might wane when the treatment is stopped or if the dose is reduced.

“Interestingly, ALT elevations were observed in association with most HBsAg declines,” Dr. Pawlotsky pointed out. “I think we still have to determine whether this is good flare/bad flare, good sign/bad sign, of what is going to happen afterward.”
 

The REEF studies

Another approach highlighted was the combination of the silencing or small interfering RNA (siRNA) JNJ-3989 with the capsid assembly modulator (CAM) JNJ-6379 in the phase 2 REEF-1 and REEF-2 studies.

REEF-1, conducted in patients who were either hepatitis B e antigen (HBeAg) positive or negative who were not treated with NA/NUC or were NA/NUC suppressed, showed a dose-dependent, but variable effect among individual patients as might be expected at the end of 48 weeks’ treatment. This was sustained at week 72, which was 24 weeks’ follow-up after stopping treatment.

However, pointed out Dr. Pawlotsky “I think the most important part of this is that if you add a CAM on top of the siRNA, you do not improve the effect on HBsAg levels.”

Then there is the REEF-2 study, testing the same combination but in only patients who were NA suppressed or HBeAg negative alongside standard NA/NUC therapy. As well as being the first novel combination treatment trial to report, this was essentially a stopping trial, Kosh Agarwal, BMedSci (Hons), MBBS, MD, one of the study’s investigators explained separately at a media briefing.

Patients (n = 130) were treated for 48 weeks, then all treatment – including NA/NUC – was discontinued, with 48 weeks of follow-up after discontinuation, said Dr. Agarwal, who is a consultant hepatologist based at the Institute of Liver Studies at King’s College Hospital, London. He presented data from the first 24 week period after treatment had ended.

At the end of treatment, the combination had resulted in a mean reduction in HBsAg of 1.89 log₁₀ IU/mL versus a reduction of 0.06 for the NA/NUC-only group, which acted as the control group in this trial. But “no patient in this study lost their surface antigen, i.e., were cured of their hepatitis B in the active arm or in the control arm,” Dr. Agarwal said.

“We didn’t achieve a cure, but a significant proportion were in a ‘controlled’ viral stage,” said Dr. Agarwal. Indeed, during his presentation of the findings, he showed that HBsAg inhibition was maintained in the majority (72%) of patients after stopping the combination.

While the trial’s primary endpoint wasn’t met, “it’s a really important study,” said Dr. Agarwal. “This [study] was fulfilled and delivered in the COVID era, so a lot of patients were looked after very carefully by sites in Europe,” he observed.

Further follow-up from the trial is expected, and Dr. Agarwal said that the subsequent discussion will “take us back to the drawing board to think about whether we need better antiviral treatments or whether we need to think about different combinations, and whether actually stopping treatment with every treatment is the right strategy to take.”

Both Dr. Agarwal and Dr. Pawlotsky flagged up the case of one patient in the trial who had been in the control arm and had experienced severe HBV reactivation that required a liver transplant.

“This patient is a warning signal,” Dr. Pawlotsky suggested in his talk. “When we think about NUC stopping, we have to think about the potential benefit in terms of HbsAg loss but also the potential risks.”

While Dr. Agarwal had noted that it highlights that “careful design of retreatment criteria is important in studies assessing the NA/NUC-stopping concept”.
 

Monoclonal antibody shows promise

Other combinations could involve an siRNA and an immunomodulatory agent and, during the poster sessions at the meeting, Dr. Agarwal also presented data from an ongoing phase 1 study with a novel, neutralizing monoclonal antibody called VIR-3434.

This monoclonal antibody is novel because it is thought to have several modes of action, first by binding to HBV and affecting its entry into liver cells, then by presenting the virus to T cells and stimulating a ‘vaccinal’ or immune effect, and then by helping the with the clearance of HBsAg and delivery of the virus to dendritic cells.

In the study, single doses of VIR-3434 were found to be well tolerated and to produce rapid reductions in HBsAg, with the highest dose used (300 mg) producing the greatest and most durable effect up to week 8.

VIR-3434 is also being tested in combination with other drugs in the phase 2 MARCH trial. One of these combinations is VIR-3434 together with an investigational siRNA dubbed VIR-2218. Preclinical work presented at ILC 2022 suggests that this combination appears to be capable of reducing HBsAg to a greater extent than using either agent alone.
 

Rethinking the strategy to get to a cure

Of course, VIR-3434 is one of several immunomodulatory compounds in development. There are therapeutic vaccines, drugs targeting the innate immune response, other monoclonal antibodies, T-cell receptors, checkpoint inhibitors and PD-L1 inhibitors. Then there are other compounds such as entry inhibitors, apoptosis inducers, and farnesoid X receptor agonists.

“I finish this meeting with more questions than answers,” Dr. Pawlotsky said. “What is the right target to enhance specific anti-HBV immunity? Does in vivo induction of immune responses translate into any beneficial effect on HBV infection? Will therapeutic vaccines every work in a viral infection?”

Moreover, he asked, “how can we avoid the side effect of enhancing multiple and complex nonspecific immune responses? Are treatment-induced flares good flares or bad flares? All of these are questions that are really unanswered and that we’ll have to get answers to in the near future.”

The B-CLEAR study was sponsored by GlaxoSmithKline. The REEF-2 study was sponsored by Janssen Research & Development. The VIR-3434 studies were funded by Vir Biotechnology. Dr. Pawlotsky has received grant and research support, acted as a consultant, adviser, or speaker, and participated in advisory boards for multiple pharmaceutical and biotechnology companies. This news organization was unable to verify Dr. Agarwal’s ties to Vir Biotechnology, but he presented one of the posters on VIR-3434 at the meeting and has been involved in the phase 1 study that was reported.


 

LONDON – Achieving a functional cure for hepatitis B virus (HBV) is not going to be easily achieved with the drugs that are currently in development, according to a presentation at the annual International Liver Congress sponsored by the European Association for the Study of the Liver.

“Intriguing results have been presented at ILC 2022 that must be carefully interpreted,” said Jean-Michel Pawlotsky, MD, PhD, of Henri Mondor Hospital in Créteil, France, during the viral hepatitis highlights session on the closing day of the meeting.

“New HBV drug development looks more complicated than initially expected and its goals and strategies need to be redefined and refocused,” he added

Steve Forrest & Andrew McConnell/EASL

“This is really something that came from the discussions we had during the sessions but also in the corridors,” Dr. Pawlotsky added. “We know it’s going to be difficult; we have to reset, restart – not from zero, but from not much – and revise our strategy,” he suggested.

There are many new drugs under investigation for HBV, Dr. Pawlotsky said, noting that the number of studies being presented at the meeting was reminiscent of the flurry of activity before a functional cure for hepatitis C had been found. “It’s good to see that this is happening again for HBV,” he said.

Indeed, there are many new direct-acting antiviral agents, immunomodulatory, or other approaches being tested, and some of the more advanced studies are “teaching us a few things and probably raising more questions than getting answers,” Dr. Pawlotsky said.
 

The B-CLEAR study

One these studies is the phase 2b B-CLEAR study presented during the late-breaker session. This study involved bepirovirsen, an antisense oligonucleotide, and tested its efficacy and safety in patients with chronic hepatitis B virus infection who were either on or off stable nucleos(t)ide analogue (NA/NUC) therapy.

A similar proportion (28% and 29%, respectively) of patients achieved an hepatitis B surface antigen (HBsAg) level below the lower limit of quantification at the end of 24 weeks treatment. However, the effect on HBsAg varied according to the treatment arm, with changes to the dosing or switching to placebo indicating that the effect might wane when the treatment is stopped or if the dose is reduced.

“Interestingly, ALT elevations were observed in association with most HBsAg declines,” Dr. Pawlotsky pointed out. “I think we still have to determine whether this is good flare/bad flare, good sign/bad sign, of what is going to happen afterward.”
 

The REEF studies

Another approach highlighted was the combination of the silencing or small interfering RNA (siRNA) JNJ-3989 with the capsid assembly modulator (CAM) JNJ-6379 in the phase 2 REEF-1 and REEF-2 studies.

REEF-1, conducted in patients who were either hepatitis B e antigen (HBeAg) positive or negative who were not treated with NA/NUC or were NA/NUC suppressed, showed a dose-dependent, but variable effect among individual patients as might be expected at the end of 48 weeks’ treatment. This was sustained at week 72, which was 24 weeks’ follow-up after stopping treatment.

However, pointed out Dr. Pawlotsky “I think the most important part of this is that if you add a CAM on top of the siRNA, you do not improve the effect on HBsAg levels.”

Then there is the REEF-2 study, testing the same combination but in only patients who were NA suppressed or HBeAg negative alongside standard NA/NUC therapy. As well as being the first novel combination treatment trial to report, this was essentially a stopping trial, Kosh Agarwal, BMedSci (Hons), MBBS, MD, one of the study’s investigators explained separately at a media briefing.

Patients (n = 130) were treated for 48 weeks, then all treatment – including NA/NUC – was discontinued, with 48 weeks of follow-up after discontinuation, said Dr. Agarwal, who is a consultant hepatologist based at the Institute of Liver Studies at King’s College Hospital, London. He presented data from the first 24 week period after treatment had ended.

At the end of treatment, the combination had resulted in a mean reduction in HBsAg of 1.89 log₁₀ IU/mL versus a reduction of 0.06 for the NA/NUC-only group, which acted as the control group in this trial. But “no patient in this study lost their surface antigen, i.e., were cured of their hepatitis B in the active arm or in the control arm,” Dr. Agarwal said.

“We didn’t achieve a cure, but a significant proportion were in a ‘controlled’ viral stage,” said Dr. Agarwal. Indeed, during his presentation of the findings, he showed that HBsAg inhibition was maintained in the majority (72%) of patients after stopping the combination.

While the trial’s primary endpoint wasn’t met, “it’s a really important study,” said Dr. Agarwal. “This [study] was fulfilled and delivered in the COVID era, so a lot of patients were looked after very carefully by sites in Europe,” he observed.

Further follow-up from the trial is expected, and Dr. Agarwal said that the subsequent discussion will “take us back to the drawing board to think about whether we need better antiviral treatments or whether we need to think about different combinations, and whether actually stopping treatment with every treatment is the right strategy to take.”

Both Dr. Agarwal and Dr. Pawlotsky flagged up the case of one patient in the trial who had been in the control arm and had experienced severe HBV reactivation that required a liver transplant.

“This patient is a warning signal,” Dr. Pawlotsky suggested in his talk. “When we think about NUC stopping, we have to think about the potential benefit in terms of HbsAg loss but also the potential risks.”

While Dr. Agarwal had noted that it highlights that “careful design of retreatment criteria is important in studies assessing the NA/NUC-stopping concept”.
 

Monoclonal antibody shows promise

Other combinations could involve an siRNA and an immunomodulatory agent and, during the poster sessions at the meeting, Dr. Agarwal also presented data from an ongoing phase 1 study with a novel, neutralizing monoclonal antibody called VIR-3434.

This monoclonal antibody is novel because it is thought to have several modes of action, first by binding to HBV and affecting its entry into liver cells, then by presenting the virus to T cells and stimulating a ‘vaccinal’ or immune effect, and then by helping the with the clearance of HBsAg and delivery of the virus to dendritic cells.

In the study, single doses of VIR-3434 were found to be well tolerated and to produce rapid reductions in HBsAg, with the highest dose used (300 mg) producing the greatest and most durable effect up to week 8.

VIR-3434 is also being tested in combination with other drugs in the phase 2 MARCH trial. One of these combinations is VIR-3434 together with an investigational siRNA dubbed VIR-2218. Preclinical work presented at ILC 2022 suggests that this combination appears to be capable of reducing HBsAg to a greater extent than using either agent alone.
 

Rethinking the strategy to get to a cure

Of course, VIR-3434 is one of several immunomodulatory compounds in development. There are therapeutic vaccines, drugs targeting the innate immune response, other monoclonal antibodies, T-cell receptors, checkpoint inhibitors and PD-L1 inhibitors. Then there are other compounds such as entry inhibitors, apoptosis inducers, and farnesoid X receptor agonists.

“I finish this meeting with more questions than answers,” Dr. Pawlotsky said. “What is the right target to enhance specific anti-HBV immunity? Does in vivo induction of immune responses translate into any beneficial effect on HBV infection? Will therapeutic vaccines every work in a viral infection?”

Moreover, he asked, “how can we avoid the side effect of enhancing multiple and complex nonspecific immune responses? Are treatment-induced flares good flares or bad flares? All of these are questions that are really unanswered and that we’ll have to get answers to in the near future.”

The B-CLEAR study was sponsored by GlaxoSmithKline. The REEF-2 study was sponsored by Janssen Research & Development. The VIR-3434 studies were funded by Vir Biotechnology. Dr. Pawlotsky has received grant and research support, acted as a consultant, adviser, or speaker, and participated in advisory boards for multiple pharmaceutical and biotechnology companies. This news organization was unable to verify Dr. Agarwal’s ties to Vir Biotechnology, but he presented one of the posters on VIR-3434 at the meeting and has been involved in the phase 1 study that was reported.


 

LONDON – Achieving a functional cure for hepatitis B virus (HBV) is not going to be easily achieved with the drugs that are currently in development, according to a presentation at the annual International Liver Congress sponsored by the European Association for the Study of the Liver.

“Intriguing results have been presented at ILC 2022 that must be carefully interpreted,” said Jean-Michel Pawlotsky, MD, PhD, of Henri Mondor Hospital in Créteil, France, during the viral hepatitis highlights session on the closing day of the meeting.

“New HBV drug development looks more complicated than initially expected and its goals and strategies need to be redefined and refocused,” he added

Steve Forrest & Andrew McConnell/EASL

“This is really something that came from the discussions we had during the sessions but also in the corridors,” Dr. Pawlotsky added. “We know it’s going to be difficult; we have to reset, restart – not from zero, but from not much – and revise our strategy,” he suggested.

There are many new drugs under investigation for HBV, Dr. Pawlotsky said, noting that the number of studies being presented at the meeting was reminiscent of the flurry of activity before a functional cure for hepatitis C had been found. “It’s good to see that this is happening again for HBV,” he said.

Indeed, there are many new direct-acting antiviral agents, immunomodulatory, or other approaches being tested, and some of the more advanced studies are “teaching us a few things and probably raising more questions than getting answers,” Dr. Pawlotsky said.
 

The B-CLEAR study

One these studies is the phase 2b B-CLEAR study presented during the late-breaker session. This study involved bepirovirsen, an antisense oligonucleotide, and tested its efficacy and safety in patients with chronic hepatitis B virus infection who were either on or off stable nucleos(t)ide analogue (NA/NUC) therapy.

A similar proportion (28% and 29%, respectively) of patients achieved an hepatitis B surface antigen (HBsAg) level below the lower limit of quantification at the end of 24 weeks treatment. However, the effect on HBsAg varied according to the treatment arm, with changes to the dosing or switching to placebo indicating that the effect might wane when the treatment is stopped or if the dose is reduced.

“Interestingly, ALT elevations were observed in association with most HBsAg declines,” Dr. Pawlotsky pointed out. “I think we still have to determine whether this is good flare/bad flare, good sign/bad sign, of what is going to happen afterward.”
 

The REEF studies

Another approach highlighted was the combination of the silencing or small interfering RNA (siRNA) JNJ-3989 with the capsid assembly modulator (CAM) JNJ-6379 in the phase 2 REEF-1 and REEF-2 studies.

REEF-1, conducted in patients who were either hepatitis B e antigen (HBeAg) positive or negative who were not treated with NA/NUC or were NA/NUC suppressed, showed a dose-dependent, but variable effect among individual patients as might be expected at the end of 48 weeks’ treatment. This was sustained at week 72, which was 24 weeks’ follow-up after stopping treatment.

However, pointed out Dr. Pawlotsky “I think the most important part of this is that if you add a CAM on top of the siRNA, you do not improve the effect on HBsAg levels.”

Then there is the REEF-2 study, testing the same combination but in only patients who were NA suppressed or HBeAg negative alongside standard NA/NUC therapy. As well as being the first novel combination treatment trial to report, this was essentially a stopping trial, Kosh Agarwal, BMedSci (Hons), MBBS, MD, one of the study’s investigators explained separately at a media briefing.

Patients (n = 130) were treated for 48 weeks, then all treatment – including NA/NUC – was discontinued, with 48 weeks of follow-up after discontinuation, said Dr. Agarwal, who is a consultant hepatologist based at the Institute of Liver Studies at King’s College Hospital, London. He presented data from the first 24 week period after treatment had ended.

At the end of treatment, the combination had resulted in a mean reduction in HBsAg of 1.89 log₁₀ IU/mL versus a reduction of 0.06 for the NA/NUC-only group, which acted as the control group in this trial. But “no patient in this study lost their surface antigen, i.e., were cured of their hepatitis B in the active arm or in the control arm,” Dr. Agarwal said.

“We didn’t achieve a cure, but a significant proportion were in a ‘controlled’ viral stage,” said Dr. Agarwal. Indeed, during his presentation of the findings, he showed that HBsAg inhibition was maintained in the majority (72%) of patients after stopping the combination.

While the trial’s primary endpoint wasn’t met, “it’s a really important study,” said Dr. Agarwal. “This [study] was fulfilled and delivered in the COVID era, so a lot of patients were looked after very carefully by sites in Europe,” he observed.

Further follow-up from the trial is expected, and Dr. Agarwal said that the subsequent discussion will “take us back to the drawing board to think about whether we need better antiviral treatments or whether we need to think about different combinations, and whether actually stopping treatment with every treatment is the right strategy to take.”

Both Dr. Agarwal and Dr. Pawlotsky flagged up the case of one patient in the trial who had been in the control arm and had experienced severe HBV reactivation that required a liver transplant.

“This patient is a warning signal,” Dr. Pawlotsky suggested in his talk. “When we think about NUC stopping, we have to think about the potential benefit in terms of HbsAg loss but also the potential risks.”

While Dr. Agarwal had noted that it highlights that “careful design of retreatment criteria is important in studies assessing the NA/NUC-stopping concept”.
 

Monoclonal antibody shows promise

Other combinations could involve an siRNA and an immunomodulatory agent and, during the poster sessions at the meeting, Dr. Agarwal also presented data from an ongoing phase 1 study with a novel, neutralizing monoclonal antibody called VIR-3434.

This monoclonal antibody is novel because it is thought to have several modes of action, first by binding to HBV and affecting its entry into liver cells, then by presenting the virus to T cells and stimulating a ‘vaccinal’ or immune effect, and then by helping the with the clearance of HBsAg and delivery of the virus to dendritic cells.

In the study, single doses of VIR-3434 were found to be well tolerated and to produce rapid reductions in HBsAg, with the highest dose used (300 mg) producing the greatest and most durable effect up to week 8.

VIR-3434 is also being tested in combination with other drugs in the phase 2 MARCH trial. One of these combinations is VIR-3434 together with an investigational siRNA dubbed VIR-2218. Preclinical work presented at ILC 2022 suggests that this combination appears to be capable of reducing HBsAg to a greater extent than using either agent alone.
 

Rethinking the strategy to get to a cure

Of course, VIR-3434 is one of several immunomodulatory compounds in development. There are therapeutic vaccines, drugs targeting the innate immune response, other monoclonal antibodies, T-cell receptors, checkpoint inhibitors and PD-L1 inhibitors. Then there are other compounds such as entry inhibitors, apoptosis inducers, and farnesoid X receptor agonists.

“I finish this meeting with more questions than answers,” Dr. Pawlotsky said. “What is the right target to enhance specific anti-HBV immunity? Does in vivo induction of immune responses translate into any beneficial effect on HBV infection? Will therapeutic vaccines every work in a viral infection?”

Moreover, he asked, “how can we avoid the side effect of enhancing multiple and complex nonspecific immune responses? Are treatment-induced flares good flares or bad flares? All of these are questions that are really unanswered and that we’ll have to get answers to in the near future.”

The B-CLEAR study was sponsored by GlaxoSmithKline. The REEF-2 study was sponsored by Janssen Research & Development. The VIR-3434 studies were funded by Vir Biotechnology. Dr. Pawlotsky has received grant and research support, acted as a consultant, adviser, or speaker, and participated in advisory boards for multiple pharmaceutical and biotechnology companies. This news organization was unable to verify Dr. Agarwal’s ties to Vir Biotechnology, but he presented one of the posters on VIR-3434 at the meeting and has been involved in the phase 1 study that was reported.


 

Consumers, employers, and just about everyone else interested in health care prices will soon get an unprecedented look at what insurers pay for care, perhaps helping answer a question that has long dogged those who buy insurance: Are we getting the best deal we can?

As of July 1, health insurers and self-insured employers must post on websites just about every price they’ve negotiated with providers for health care services, item by item. About the only thing excluded are the prices paid for prescription drugs, except those administered in hospitals or doctors’ offices.

The federally required data release could affect future prices or even how employers contract for health care. Many will see for the first time how well their insurers are doing, compared with others.

The new rules are far broader than those that went into effect in 2021 requiring hospitals to post their negotiated rates for the public to see. Now insurers must post the amounts paid for “every physician in network, every hospital, every surgery center, every nursing facility,” said Jeffrey Leibach, a partner at the consulting firm Guidehouse.

“When you start doing the math, you’re talking trillions of records,” he said. The fines the federal government could impose for noncompliance are also heftier than the penalties that hospitals face.

Federal officials learned from the hospital experience and gave insurers more direction on what was expected, said Mr. Leibach. Insurers or self-insured employers could be fined as much as $100 a day for each violation, for each affected enrollee if they fail to provide the data.

“Get your calculator out: All of a sudden you are in the millions pretty fast,” Mr. Leibach said.

Determined consumers, especially those with high-deductible health plans, may try to dig in right away and use the data to try comparing what they will have to pay at different hospitals, clinics, or doctor offices for specific services.

But each database’s enormous size may mean that most people “will find it very hard to use the data in a nuanced way,” said Katherine Baicker, dean of the University of Chicago Harris School of Public Policy.

At least at first.

Entrepreneurs are expected to quickly translate the information into more user-friendly formats so it can be incorporated into new or existing services that estimate costs for patients. And starting Jan. 1, the rules require insurers to provide online tools that will help people get up-front cost estimates for about 500 so-called “shoppable” services, meaning medical care they can schedule ahead of time.

Once those things happen, “you’ll at least have the options in front of you,” said Chris Severn, CEO of Turquoise Health, an online company that has posted price information made available under the rules for hospitals, although many hospitals have yet to comply.

With the addition of the insurers’ data, sites like his will be able to drill down further into cost variation from one place to another or among insurers.

“If you’re going to get an x-ray, you will be able to see that you can do it for $250 at this hospital, $75 at the imaging center down the road, or your specialist can do it in office for $25,” he said.

Everyone will know everyone else’s business: for example, how much insurers Aetna and Humana pay the same surgery center for a knee replacement.

The requirements stem from the Affordable Care Act and a 2019 executive order by then-President Donald Trump.

“These plans are supposed to be acting on behalf of employers in negotiating good rates, and the little insight we have on that shows it has not happened,” said Elizabeth Mitchell, president and CEO of the Purchaser Business Group on Health, an affiliation of employers who offer job-based health benefits to workers. “I do believe the dynamics are going to change.”

Other observers are more circumspect.

“Maybe at best this will reduce the wide variance of prices out there,” said Zack Cooper, director of health policy at the Yale University Institution for Social and Policy Studies, New Haven, Conn. “But it won’t be unleashing a consumer revolution.”

Still, the biggest value of the July data release may well be to shed light on how successful insurers have been at negotiating prices. It comes on the heels of research that has shown tremendous variation in what is paid for health care. A recent study by Rand, for example, shows that employers that offer job-based insurance plans paid, on average, 224% more than Medicare for the same services.

Tens of thousands of employers who buy insurance coverage for their workers will get this more-complete pricing picture – and may not like what they see.

“What we’re learning from the hospital data is that insurers are really bad at negotiating,” said Gerard Anderson, a professor in the department of health policy at the Johns Hopkins Bloomberg, Baltimore, citing research that found that negotiated rates for hospital care can be higher than what the facilities accept from patients who are not using insurance and are paying cash.

That could add to the frustration that Ms. Mitchell and others say employers have with the current health insurance system. More might try to contract with providers directly, only using insurance companies for claims processing.

Other employers may bring their insurers back to the bargaining table.

“For the first time, an employer will be able to go to an insurance company and say: ‘You have not negotiated a good-enough deal, and we know that because we can see the same provider has negotiated a better deal with another company,’ ” said James Gelfand, president of the ERISA Industry Committee, a trade group of self-insured employers.

If that happens, he added, “patients will be able to save money.”

That’s not necessarily a given, however.

Because this kind of public release of pricing data hasn’t been tried widely in health care before, how it will affect future spending remains uncertain. If insurers are pushed back to the bargaining table or providers see where they stand relative to their peers, prices could drop. However, some providers could raise their prices if they see they are charging less than their peers.

“Downward pressure may not be a given,” said Kelley Schultz, vice president of commercial policy for AHIP, the industry’s trade lobby.

Ms. Baicker said that, even after the data is out, rates will continue to be heavily influenced by local conditions, such as the size of an insurer or employer – providers often give bigger discounts, for example, to the insurers or self-insured employers that can send them the most patients. The number of hospitals in a region also matters – if an area has only one, for instance, that usually means the facility can demand higher rates.

Another unknown: Will insurers meet the deadline and provide usable data?

Ms. Schultz, at AHIP, said the industry is well on the way, partly because the original deadline was extended by 6 months. She expects insurers to do better than the hospital industry. “We saw a lot of hospitals that just decided not to post files or make them difficult to find,” she said.

So far, more than 300 noncompliant hospitals received warning letters from the government. But they could face fines of $300 a day fines for failing to comply, which is less than what insurers potentially face, although the federal government has recently upped the ante to up to $5,500 a day for the largest facilities.

Even after the pricing data is public, “I don’t think things will change overnight,” said Mr. Leibach. “Patients are still going to make care decisions based on their doctors and referrals, a lot of reasons other than price.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Consumers, employers, and just about everyone else interested in health care prices will soon get an unprecedented look at what insurers pay for care, perhaps helping answer a question that has long dogged those who buy insurance: Are we getting the best deal we can?

As of July 1, health insurers and self-insured employers must post on websites just about every price they’ve negotiated with providers for health care services, item by item. About the only thing excluded are the prices paid for prescription drugs, except those administered in hospitals or doctors’ offices.

The federally required data release could affect future prices or even how employers contract for health care. Many will see for the first time how well their insurers are doing, compared with others.

The new rules are far broader than those that went into effect in 2021 requiring hospitals to post their negotiated rates for the public to see. Now insurers must post the amounts paid for “every physician in network, every hospital, every surgery center, every nursing facility,” said Jeffrey Leibach, a partner at the consulting firm Guidehouse.

“When you start doing the math, you’re talking trillions of records,” he said. The fines the federal government could impose for noncompliance are also heftier than the penalties that hospitals face.

Federal officials learned from the hospital experience and gave insurers more direction on what was expected, said Mr. Leibach. Insurers or self-insured employers could be fined as much as $100 a day for each violation, for each affected enrollee if they fail to provide the data.

“Get your calculator out: All of a sudden you are in the millions pretty fast,” Mr. Leibach said.

Determined consumers, especially those with high-deductible health plans, may try to dig in right away and use the data to try comparing what they will have to pay at different hospitals, clinics, or doctor offices for specific services.

But each database’s enormous size may mean that most people “will find it very hard to use the data in a nuanced way,” said Katherine Baicker, dean of the University of Chicago Harris School of Public Policy.

At least at first.

Entrepreneurs are expected to quickly translate the information into more user-friendly formats so it can be incorporated into new or existing services that estimate costs for patients. And starting Jan. 1, the rules require insurers to provide online tools that will help people get up-front cost estimates for about 500 so-called “shoppable” services, meaning medical care they can schedule ahead of time.

Once those things happen, “you’ll at least have the options in front of you,” said Chris Severn, CEO of Turquoise Health, an online company that has posted price information made available under the rules for hospitals, although many hospitals have yet to comply.

With the addition of the insurers’ data, sites like his will be able to drill down further into cost variation from one place to another or among insurers.

“If you’re going to get an x-ray, you will be able to see that you can do it for $250 at this hospital, $75 at the imaging center down the road, or your specialist can do it in office for $25,” he said.

Everyone will know everyone else’s business: for example, how much insurers Aetna and Humana pay the same surgery center for a knee replacement.

The requirements stem from the Affordable Care Act and a 2019 executive order by then-President Donald Trump.

“These plans are supposed to be acting on behalf of employers in negotiating good rates, and the little insight we have on that shows it has not happened,” said Elizabeth Mitchell, president and CEO of the Purchaser Business Group on Health, an affiliation of employers who offer job-based health benefits to workers. “I do believe the dynamics are going to change.”

Other observers are more circumspect.

“Maybe at best this will reduce the wide variance of prices out there,” said Zack Cooper, director of health policy at the Yale University Institution for Social and Policy Studies, New Haven, Conn. “But it won’t be unleashing a consumer revolution.”

Still, the biggest value of the July data release may well be to shed light on how successful insurers have been at negotiating prices. It comes on the heels of research that has shown tremendous variation in what is paid for health care. A recent study by Rand, for example, shows that employers that offer job-based insurance plans paid, on average, 224% more than Medicare for the same services.

Tens of thousands of employers who buy insurance coverage for their workers will get this more-complete pricing picture – and may not like what they see.

“What we’re learning from the hospital data is that insurers are really bad at negotiating,” said Gerard Anderson, a professor in the department of health policy at the Johns Hopkins Bloomberg, Baltimore, citing research that found that negotiated rates for hospital care can be higher than what the facilities accept from patients who are not using insurance and are paying cash.

That could add to the frustration that Ms. Mitchell and others say employers have with the current health insurance system. More might try to contract with providers directly, only using insurance companies for claims processing.

Other employers may bring their insurers back to the bargaining table.

“For the first time, an employer will be able to go to an insurance company and say: ‘You have not negotiated a good-enough deal, and we know that because we can see the same provider has negotiated a better deal with another company,’ ” said James Gelfand, president of the ERISA Industry Committee, a trade group of self-insured employers.

If that happens, he added, “patients will be able to save money.”

That’s not necessarily a given, however.

Because this kind of public release of pricing data hasn’t been tried widely in health care before, how it will affect future spending remains uncertain. If insurers are pushed back to the bargaining table or providers see where they stand relative to their peers, prices could drop. However, some providers could raise their prices if they see they are charging less than their peers.

“Downward pressure may not be a given,” said Kelley Schultz, vice president of commercial policy for AHIP, the industry’s trade lobby.

Ms. Baicker said that, even after the data is out, rates will continue to be heavily influenced by local conditions, such as the size of an insurer or employer – providers often give bigger discounts, for example, to the insurers or self-insured employers that can send them the most patients. The number of hospitals in a region also matters – if an area has only one, for instance, that usually means the facility can demand higher rates.

Another unknown: Will insurers meet the deadline and provide usable data?

Ms. Schultz, at AHIP, said the industry is well on the way, partly because the original deadline was extended by 6 months. She expects insurers to do better than the hospital industry. “We saw a lot of hospitals that just decided not to post files or make them difficult to find,” she said.

So far, more than 300 noncompliant hospitals received warning letters from the government. But they could face fines of $300 a day fines for failing to comply, which is less than what insurers potentially face, although the federal government has recently upped the ante to up to $5,500 a day for the largest facilities.

Even after the pricing data is public, “I don’t think things will change overnight,” said Mr. Leibach. “Patients are still going to make care decisions based on their doctors and referrals, a lot of reasons other than price.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Consumers, employers, and just about everyone else interested in health care prices will soon get an unprecedented look at what insurers pay for care, perhaps helping answer a question that has long dogged those who buy insurance: Are we getting the best deal we can?

As of July 1, health insurers and self-insured employers must post on websites just about every price they’ve negotiated with providers for health care services, item by item. About the only thing excluded are the prices paid for prescription drugs, except those administered in hospitals or doctors’ offices.

The federally required data release could affect future prices or even how employers contract for health care. Many will see for the first time how well their insurers are doing, compared with others.

The new rules are far broader than those that went into effect in 2021 requiring hospitals to post their negotiated rates for the public to see. Now insurers must post the amounts paid for “every physician in network, every hospital, every surgery center, every nursing facility,” said Jeffrey Leibach, a partner at the consulting firm Guidehouse.

“When you start doing the math, you’re talking trillions of records,” he said. The fines the federal government could impose for noncompliance are also heftier than the penalties that hospitals face.

Federal officials learned from the hospital experience and gave insurers more direction on what was expected, said Mr. Leibach. Insurers or self-insured employers could be fined as much as $100 a day for each violation, for each affected enrollee if they fail to provide the data.

“Get your calculator out: All of a sudden you are in the millions pretty fast,” Mr. Leibach said.

Determined consumers, especially those with high-deductible health plans, may try to dig in right away and use the data to try comparing what they will have to pay at different hospitals, clinics, or doctor offices for specific services.

But each database’s enormous size may mean that most people “will find it very hard to use the data in a nuanced way,” said Katherine Baicker, dean of the University of Chicago Harris School of Public Policy.

At least at first.

Entrepreneurs are expected to quickly translate the information into more user-friendly formats so it can be incorporated into new or existing services that estimate costs for patients. And starting Jan. 1, the rules require insurers to provide online tools that will help people get up-front cost estimates for about 500 so-called “shoppable” services, meaning medical care they can schedule ahead of time.

Once those things happen, “you’ll at least have the options in front of you,” said Chris Severn, CEO of Turquoise Health, an online company that has posted price information made available under the rules for hospitals, although many hospitals have yet to comply.

With the addition of the insurers’ data, sites like his will be able to drill down further into cost variation from one place to another or among insurers.

“If you’re going to get an x-ray, you will be able to see that you can do it for $250 at this hospital, $75 at the imaging center down the road, or your specialist can do it in office for $25,” he said.

Everyone will know everyone else’s business: for example, how much insurers Aetna and Humana pay the same surgery center for a knee replacement.

The requirements stem from the Affordable Care Act and a 2019 executive order by then-President Donald Trump.

“These plans are supposed to be acting on behalf of employers in negotiating good rates, and the little insight we have on that shows it has not happened,” said Elizabeth Mitchell, president and CEO of the Purchaser Business Group on Health, an affiliation of employers who offer job-based health benefits to workers. “I do believe the dynamics are going to change.”

Other observers are more circumspect.

“Maybe at best this will reduce the wide variance of prices out there,” said Zack Cooper, director of health policy at the Yale University Institution for Social and Policy Studies, New Haven, Conn. “But it won’t be unleashing a consumer revolution.”

Still, the biggest value of the July data release may well be to shed light on how successful insurers have been at negotiating prices. It comes on the heels of research that has shown tremendous variation in what is paid for health care. A recent study by Rand, for example, shows that employers that offer job-based insurance plans paid, on average, 224% more than Medicare for the same services.

Tens of thousands of employers who buy insurance coverage for their workers will get this more-complete pricing picture – and may not like what they see.

“What we’re learning from the hospital data is that insurers are really bad at negotiating,” said Gerard Anderson, a professor in the department of health policy at the Johns Hopkins Bloomberg, Baltimore, citing research that found that negotiated rates for hospital care can be higher than what the facilities accept from patients who are not using insurance and are paying cash.

That could add to the frustration that Ms. Mitchell and others say employers have with the current health insurance system. More might try to contract with providers directly, only using insurance companies for claims processing.

Other employers may bring their insurers back to the bargaining table.

“For the first time, an employer will be able to go to an insurance company and say: ‘You have not negotiated a good-enough deal, and we know that because we can see the same provider has negotiated a better deal with another company,’ ” said James Gelfand, president of the ERISA Industry Committee, a trade group of self-insured employers.

If that happens, he added, “patients will be able to save money.”

That’s not necessarily a given, however.

Because this kind of public release of pricing data hasn’t been tried widely in health care before, how it will affect future spending remains uncertain. If insurers are pushed back to the bargaining table or providers see where they stand relative to their peers, prices could drop. However, some providers could raise their prices if they see they are charging less than their peers.

“Downward pressure may not be a given,” said Kelley Schultz, vice president of commercial policy for AHIP, the industry’s trade lobby.

Ms. Baicker said that, even after the data is out, rates will continue to be heavily influenced by local conditions, such as the size of an insurer or employer – providers often give bigger discounts, for example, to the insurers or self-insured employers that can send them the most patients. The number of hospitals in a region also matters – if an area has only one, for instance, that usually means the facility can demand higher rates.

Another unknown: Will insurers meet the deadline and provide usable data?

Ms. Schultz, at AHIP, said the industry is well on the way, partly because the original deadline was extended by 6 months. She expects insurers to do better than the hospital industry. “We saw a lot of hospitals that just decided not to post files or make them difficult to find,” she said.

So far, more than 300 noncompliant hospitals received warning letters from the government. But they could face fines of $300 a day fines for failing to comply, which is less than what insurers potentially face, although the federal government has recently upped the ante to up to $5,500 a day for the largest facilities.

Even after the pricing data is public, “I don’t think things will change overnight,” said Mr. Leibach. “Patients are still going to make care decisions based on their doctors and referrals, a lot of reasons other than price.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

The fourth vaccination against COVID-19 is the subject of intense discussion. Immunity against new Omicron variants (currently BA.4 and BA.5) is getting weaker and weaker. Is another vaccination with the available vaccines worth it?

For Leif Erik Sander, MD, director of infectious diseases and pneumology at Charité University Medicine, Berlin, the latest data send a clear message. “The COVID-19 vaccination is still effective against Omicron. After three doses of the vaccine, it continues to prevent severe diseases, respiratory failures, and death,” he reported at the 62nd Congress of the German Pneumology and Respiratory Medicine Society in Leipzig.

The most recent data from the United Kingdom show that the vaccine’s effectiveness against Omicron decreases after just a few months, which speaks in favor of a fourth vaccination. “Omicron is a development that we did not anticipate occurring so early on,” said Dr. Sander.

In terms of phylogenetics, Omicron is far removed from the previous variants of concern. More than 30 mutations to the spike protein (the antigen that is vaccinated against) foster the loss of immunity.
 

Boosters broaden immunity

“The booster makes all the difference here,” emphasized Dr. Sander. Experiments at Charité Berlin show that after double vaccination, the vaccination sera from healthy young people no longer neutralizes Omicron. But a third vaccination confers a very good neutralizing titer, even against Omicron.

“The third vaccination broadens the humoral immune response against the spike protein so that conserved epitopes that are unchanged, even in Omicron, are addressed, with the result that you have neutralization capacity again,” the infectious diseases specialist explained.
 

Continued protection

However, data from the United Kingdom on vaccine effectiveness show where the limit lies. Initially, after three doses, vaccine effectiveness against symptomatic disease after Omicron infection is very good. This effectiveness decreases significantly over the course of the next few months. “Lots of people experience an Omicron infection despite the booster,” said Mr. Sander.

Nonetheless, the high incidence of Omicron infections in the recent past has not overwhelmed the health care system. “This is because the vaccine’s effectiveness against severe diseases that require hospitalization and against respiratory failure is still good in the at-risk population over the age of 65, once they have had their three vaccinations,” said Dr. Sander. The data also show that there is good protection of over 90%, even against mortality.
 

Waning observed

It could be said that currently, vaccination even continues to work against Omicron, says Dr. Sander. It prevents severe disease, respiratory failure, and death. Nonetheless, after just 3 months, a slight waning of immune protection can be observed in all three endpoints.

Therefore, the question arises as to whether a fourth vaccination is worthwhile. In Israel, “Delta was successfully eradicated with the third vaccination,” and now they are trying this again for Omicron with a fourth vaccination, reported Dr. Sander.
 

Fourth vaccination protective

The first investigations show that protection against severe disease can be increased once more. “For the over-60s, protection is almost quadrupled through the fourth vaccination,” says Dr. Sander. “However, this is still plagued with a lot of uncertainty; it is still not known how stable it is.”

There is hope on the basis of results of an as yet non–peer-reviewed study from Sweden, which is currently available only as a preprint. That study shows that a fourth vaccination in a high-risk population of care-home residents and people older than 80 years can halve overall mortality. “If this can be confirmed and replicated, it must be recommended quite extensively for this high-risk group,” said Dr. Sander. The Standing Committee on Vaccination in Germany is currently recommending that high-risk groups be vaccinated against COVID-19 for the fourth time. To date, though, this has only been implemented halfheartedly.
 

Propensity for mutation

Omicron keeps developing. Following BA.1 and the more infectious subvariant BA.2, BA.4 and BA.5 are spreading in Germany. “To date, there is no evidence that vaccine protection against severe diseases has changed as a result of BA.2 emerging,” said Dr. Sander.

However, the loss of immunity against BA.4 and BA.5 is more strongly pronounced. “If you were infected with BA.1, you are not immune to BA.5,” says Dr. Sander. Lessened immunity from BA.4 and BA.5 is even more pronounced. “Anyone who was infected with BA.1 is not immune to BA.5,” says Dr. Sander. The two clades not only have spike protein mutations shared by BA.2 but also additional spike protein mutations. According to the expert, it could well be that these strains will prevail because they are best able to avoid the immunity of the population.
 

Adapted vaccines feasible?

“Vaccines adapted to BA.1 were developed very early on and were also part of clinical research,” said Dr. Sander. The initial data indicate that additional antibody responses are being mobilized that may neutralize the new variants.

It was deduced from trials on monkeys that the available vaccines were so good that only small improvements were to be expected, said Dr. Sander.
 

Moderna’s adapted vaccine

The U.S. pharmaceutical company Moderna recently submitted the first results regarding its bivalent Omicron vaccine mRNA-1273.214, which is adapted to Omicron BA.1. Data from BioNTech are expected soon.

Moderna tested a booster that contains both the spike mRNA from the original vaccine and a new mRNA adapted to the Omicron variant BA.1. The experimental vaccine mRNA-1273.214 exhibited an eightfold increase in geometric mean neutralization titer against Omicron in study participants who were seronegative at the start, compared with the already-approved vaccine.

In its latest notice, Moderna did not publish any data on how effective the updated vaccine is against the virus variants BA.4 or BA.5. Data on clinical endpoints, such as hospitalization or mortality, are also not available.
 

Conservative epitopes

Should it be assumed that the development of vaccines will always lag the emergence of new subvariants? In this respect, Dr. Sander appears optimistic. “The immunological mechanism is clear, that various B cells and antibodies will be formed that are directed against conservative epitopes that have various variants. This is good news, since we do not want to protect against BA.1 now, just for BA.8 to emerge when the vaccine goes to market. We want to protect ourselves as broadly as possible, and it seems like it may be possible to do so with this vaccine.”

Double vaccination?

Dr. Sander anticipates that a fourth vaccination against COVID-19 will occur with the next wave of the coronavirus in September or October. He remarked that coupling it with the influenza vaccination should be considered.

The coronavirus pandemic has led to shifts in other seasonal waves of pathogens. In the summer, pediatric departments were unexpectedly inundated with children suffering from RSV infections. And while the flu season over the past 2 years has been almost absent, the influenza wave may occur significantly earlier than usual this year.

“In Australia, the influenza wave arrived much earlier this year than usual, which may of course also be fruitful for us,” said Dr. Sander. “Perhaps we will also get influenza as early as in September or October. I would then plead for vaccine centers to be allowed to vaccinate against both influenza and COVID-19 at the same time. Maybe then we will also have a reasonable influenza vaccination rate,” he added.

This article was translated from the Medscape German edition.

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

The fourth vaccination against COVID-19 is the subject of intense discussion. Immunity against new Omicron variants (currently BA.4 and BA.5) is getting weaker and weaker. Is another vaccination with the available vaccines worth it?

For Leif Erik Sander, MD, director of infectious diseases and pneumology at Charité University Medicine, Berlin, the latest data send a clear message. “The COVID-19 vaccination is still effective against Omicron. After three doses of the vaccine, it continues to prevent severe diseases, respiratory failures, and death,” he reported at the 62nd Congress of the German Pneumology and Respiratory Medicine Society in Leipzig.

The most recent data from the United Kingdom show that the vaccine’s effectiveness against Omicron decreases after just a few months, which speaks in favor of a fourth vaccination. “Omicron is a development that we did not anticipate occurring so early on,” said Dr. Sander.

In terms of phylogenetics, Omicron is far removed from the previous variants of concern. More than 30 mutations to the spike protein (the antigen that is vaccinated against) foster the loss of immunity.
 

Boosters broaden immunity

“The booster makes all the difference here,” emphasized Dr. Sander. Experiments at Charité Berlin show that after double vaccination, the vaccination sera from healthy young people no longer neutralizes Omicron. But a third vaccination confers a very good neutralizing titer, even against Omicron.

“The third vaccination broadens the humoral immune response against the spike protein so that conserved epitopes that are unchanged, even in Omicron, are addressed, with the result that you have neutralization capacity again,” the infectious diseases specialist explained.
 

Continued protection

However, data from the United Kingdom on vaccine effectiveness show where the limit lies. Initially, after three doses, vaccine effectiveness against symptomatic disease after Omicron infection is very good. This effectiveness decreases significantly over the course of the next few months. “Lots of people experience an Omicron infection despite the booster,” said Mr. Sander.

Nonetheless, the high incidence of Omicron infections in the recent past has not overwhelmed the health care system. “This is because the vaccine’s effectiveness against severe diseases that require hospitalization and against respiratory failure is still good in the at-risk population over the age of 65, once they have had their three vaccinations,” said Dr. Sander. The data also show that there is good protection of over 90%, even against mortality.
 

Waning observed

It could be said that currently, vaccination even continues to work against Omicron, says Dr. Sander. It prevents severe disease, respiratory failure, and death. Nonetheless, after just 3 months, a slight waning of immune protection can be observed in all three endpoints.

Therefore, the question arises as to whether a fourth vaccination is worthwhile. In Israel, “Delta was successfully eradicated with the third vaccination,” and now they are trying this again for Omicron with a fourth vaccination, reported Dr. Sander.
 

Fourth vaccination protective

The first investigations show that protection against severe disease can be increased once more. “For the over-60s, protection is almost quadrupled through the fourth vaccination,” says Dr. Sander. “However, this is still plagued with a lot of uncertainty; it is still not known how stable it is.”

There is hope on the basis of results of an as yet non–peer-reviewed study from Sweden, which is currently available only as a preprint. That study shows that a fourth vaccination in a high-risk population of care-home residents and people older than 80 years can halve overall mortality. “If this can be confirmed and replicated, it must be recommended quite extensively for this high-risk group,” said Dr. Sander. The Standing Committee on Vaccination in Germany is currently recommending that high-risk groups be vaccinated against COVID-19 for the fourth time. To date, though, this has only been implemented halfheartedly.
 

Propensity for mutation

Omicron keeps developing. Following BA.1 and the more infectious subvariant BA.2, BA.4 and BA.5 are spreading in Germany. “To date, there is no evidence that vaccine protection against severe diseases has changed as a result of BA.2 emerging,” said Dr. Sander.

However, the loss of immunity against BA.4 and BA.5 is more strongly pronounced. “If you were infected with BA.1, you are not immune to BA.5,” says Dr. Sander. Lessened immunity from BA.4 and BA.5 is even more pronounced. “Anyone who was infected with BA.1 is not immune to BA.5,” says Dr. Sander. The two clades not only have spike protein mutations shared by BA.2 but also additional spike protein mutations. According to the expert, it could well be that these strains will prevail because they are best able to avoid the immunity of the population.
 

Adapted vaccines feasible?

“Vaccines adapted to BA.1 were developed very early on and were also part of clinical research,” said Dr. Sander. The initial data indicate that additional antibody responses are being mobilized that may neutralize the new variants.

It was deduced from trials on monkeys that the available vaccines were so good that only small improvements were to be expected, said Dr. Sander.
 

Moderna’s adapted vaccine

The U.S. pharmaceutical company Moderna recently submitted the first results regarding its bivalent Omicron vaccine mRNA-1273.214, which is adapted to Omicron BA.1. Data from BioNTech are expected soon.

Moderna tested a booster that contains both the spike mRNA from the original vaccine and a new mRNA adapted to the Omicron variant BA.1. The experimental vaccine mRNA-1273.214 exhibited an eightfold increase in geometric mean neutralization titer against Omicron in study participants who were seronegative at the start, compared with the already-approved vaccine.

In its latest notice, Moderna did not publish any data on how effective the updated vaccine is against the virus variants BA.4 or BA.5. Data on clinical endpoints, such as hospitalization or mortality, are also not available.
 

Conservative epitopes

Should it be assumed that the development of vaccines will always lag the emergence of new subvariants? In this respect, Dr. Sander appears optimistic. “The immunological mechanism is clear, that various B cells and antibodies will be formed that are directed against conservative epitopes that have various variants. This is good news, since we do not want to protect against BA.1 now, just for BA.8 to emerge when the vaccine goes to market. We want to protect ourselves as broadly as possible, and it seems like it may be possible to do so with this vaccine.”

Double vaccination?

Dr. Sander anticipates that a fourth vaccination against COVID-19 will occur with the next wave of the coronavirus in September or October. He remarked that coupling it with the influenza vaccination should be considered.

The coronavirus pandemic has led to shifts in other seasonal waves of pathogens. In the summer, pediatric departments were unexpectedly inundated with children suffering from RSV infections. And while the flu season over the past 2 years has been almost absent, the influenza wave may occur significantly earlier than usual this year.

“In Australia, the influenza wave arrived much earlier this year than usual, which may of course also be fruitful for us,” said Dr. Sander. “Perhaps we will also get influenza as early as in September or October. I would then plead for vaccine centers to be allowed to vaccinate against both influenza and COVID-19 at the same time. Maybe then we will also have a reasonable influenza vaccination rate,” he added.

This article was translated from the Medscape German edition.

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

The fourth vaccination against COVID-19 is the subject of intense discussion. Immunity against new Omicron variants (currently BA.4 and BA.5) is getting weaker and weaker. Is another vaccination with the available vaccines worth it?

For Leif Erik Sander, MD, director of infectious diseases and pneumology at Charité University Medicine, Berlin, the latest data send a clear message. “The COVID-19 vaccination is still effective against Omicron. After three doses of the vaccine, it continues to prevent severe diseases, respiratory failures, and death,” he reported at the 62nd Congress of the German Pneumology and Respiratory Medicine Society in Leipzig.

The most recent data from the United Kingdom show that the vaccine’s effectiveness against Omicron decreases after just a few months, which speaks in favor of a fourth vaccination. “Omicron is a development that we did not anticipate occurring so early on,” said Dr. Sander.

In terms of phylogenetics, Omicron is far removed from the previous variants of concern. More than 30 mutations to the spike protein (the antigen that is vaccinated against) foster the loss of immunity.
 

Boosters broaden immunity

“The booster makes all the difference here,” emphasized Dr. Sander. Experiments at Charité Berlin show that after double vaccination, the vaccination sera from healthy young people no longer neutralizes Omicron. But a third vaccination confers a very good neutralizing titer, even against Omicron.

“The third vaccination broadens the humoral immune response against the spike protein so that conserved epitopes that are unchanged, even in Omicron, are addressed, with the result that you have neutralization capacity again,” the infectious diseases specialist explained.
 

Continued protection

However, data from the United Kingdom on vaccine effectiveness show where the limit lies. Initially, after three doses, vaccine effectiveness against symptomatic disease after Omicron infection is very good. This effectiveness decreases significantly over the course of the next few months. “Lots of people experience an Omicron infection despite the booster,” said Mr. Sander.

Nonetheless, the high incidence of Omicron infections in the recent past has not overwhelmed the health care system. “This is because the vaccine’s effectiveness against severe diseases that require hospitalization and against respiratory failure is still good in the at-risk population over the age of 65, once they have had their three vaccinations,” said Dr. Sander. The data also show that there is good protection of over 90%, even against mortality.
 

Waning observed

It could be said that currently, vaccination even continues to work against Omicron, says Dr. Sander. It prevents severe disease, respiratory failure, and death. Nonetheless, after just 3 months, a slight waning of immune protection can be observed in all three endpoints.

Therefore, the question arises as to whether a fourth vaccination is worthwhile. In Israel, “Delta was successfully eradicated with the third vaccination,” and now they are trying this again for Omicron with a fourth vaccination, reported Dr. Sander.
 

Fourth vaccination protective

The first investigations show that protection against severe disease can be increased once more. “For the over-60s, protection is almost quadrupled through the fourth vaccination,” says Dr. Sander. “However, this is still plagued with a lot of uncertainty; it is still not known how stable it is.”

There is hope on the basis of results of an as yet non–peer-reviewed study from Sweden, which is currently available only as a preprint. That study shows that a fourth vaccination in a high-risk population of care-home residents and people older than 80 years can halve overall mortality. “If this can be confirmed and replicated, it must be recommended quite extensively for this high-risk group,” said Dr. Sander. The Standing Committee on Vaccination in Germany is currently recommending that high-risk groups be vaccinated against COVID-19 for the fourth time. To date, though, this has only been implemented halfheartedly.
 

Propensity for mutation

Omicron keeps developing. Following BA.1 and the more infectious subvariant BA.2, BA.4 and BA.5 are spreading in Germany. “To date, there is no evidence that vaccine protection against severe diseases has changed as a result of BA.2 emerging,” said Dr. Sander.

However, the loss of immunity against BA.4 and BA.5 is more strongly pronounced. “If you were infected with BA.1, you are not immune to BA.5,” says Dr. Sander. Lessened immunity from BA.4 and BA.5 is even more pronounced. “Anyone who was infected with BA.1 is not immune to BA.5,” says Dr. Sander. The two clades not only have spike protein mutations shared by BA.2 but also additional spike protein mutations. According to the expert, it could well be that these strains will prevail because they are best able to avoid the immunity of the population.
 

Adapted vaccines feasible?

“Vaccines adapted to BA.1 were developed very early on and were also part of clinical research,” said Dr. Sander. The initial data indicate that additional antibody responses are being mobilized that may neutralize the new variants.

It was deduced from trials on monkeys that the available vaccines were so good that only small improvements were to be expected, said Dr. Sander.
 

Moderna’s adapted vaccine

The U.S. pharmaceutical company Moderna recently submitted the first results regarding its bivalent Omicron vaccine mRNA-1273.214, which is adapted to Omicron BA.1. Data from BioNTech are expected soon.

Moderna tested a booster that contains both the spike mRNA from the original vaccine and a new mRNA adapted to the Omicron variant BA.1. The experimental vaccine mRNA-1273.214 exhibited an eightfold increase in geometric mean neutralization titer against Omicron in study participants who were seronegative at the start, compared with the already-approved vaccine.

In its latest notice, Moderna did not publish any data on how effective the updated vaccine is against the virus variants BA.4 or BA.5. Data on clinical endpoints, such as hospitalization or mortality, are also not available.
 

Conservative epitopes

Should it be assumed that the development of vaccines will always lag the emergence of new subvariants? In this respect, Dr. Sander appears optimistic. “The immunological mechanism is clear, that various B cells and antibodies will be formed that are directed against conservative epitopes that have various variants. This is good news, since we do not want to protect against BA.1 now, just for BA.8 to emerge when the vaccine goes to market. We want to protect ourselves as broadly as possible, and it seems like it may be possible to do so with this vaccine.”

Double vaccination?

Dr. Sander anticipates that a fourth vaccination against COVID-19 will occur with the next wave of the coronavirus in September or October. He remarked that coupling it with the influenza vaccination should be considered.

The coronavirus pandemic has led to shifts in other seasonal waves of pathogens. In the summer, pediatric departments were unexpectedly inundated with children suffering from RSV infections. And while the flu season over the past 2 years has been almost absent, the influenza wave may occur significantly earlier than usual this year.

“In Australia, the influenza wave arrived much earlier this year than usual, which may of course also be fruitful for us,” said Dr. Sander. “Perhaps we will also get influenza as early as in September or October. I would then plead for vaccine centers to be allowed to vaccinate against both influenza and COVID-19 at the same time. Maybe then we will also have a reasonable influenza vaccination rate,” he added.

This article was translated from the Medscape German edition.

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

A new Scandinavian study has confirmed previous data showing increased rates of cerebral venous thrombosis and thrombocytopenia after the AstraZeneca COVID-19 vaccine.

The study also showed higher rates of several thromboembolic and thrombocytopenic outcomes after the Pfizer and Moderna mRNA vaccines, although these increases were less than the rates observed after the AstraZeneca vaccine, and sensitivity analyses were not consistent.

The researchers conclude that confirmatory analysis on the two mRNA vaccines by other methods are warranted.

The study was published in the June issue of JAMA Network Open.

“This study confirms what we know from other studies: that the AstraZeneca vaccine is associated with the rare but serious side effect of vaccine-induced immune thrombotic thrombocytopenia,” lead author Jacob Dag Berild, MD, Norwegian Institute of Public Health, Oslo, told this news organization.

“Reassuringly, no consistent association was observed between the Pfizer and Moderna mRNA vaccines and these rare complications,” he added.

Dr. Dag Berild noted that in the current study there was an excess of 1.6 events of cerebral venous thrombosis per 100,000 AstraZeneca vaccine doses, which is similar to what has been previously reported.

Asked how he saw these results affecting continued use of these vaccines, Dr. Dag Berild pointed out that the risk-benefit ratio of the vaccine depends on the risk of contracting COVID-19 and the risk for a severe outcome from COVID-19 weighed against the risk for an adverse event after vaccination.

“The European Medicines Agency has concluded that the overall risk-benefit ratio remains positive for the AstraZeneca vaccine, but Norway, Finland, and Denmark no longer use the AstraZeneca vaccine in their vaccination programs because of adequate availability of alternative vaccines. I think this is a reasonable decision,” he said.

For the current study, the researchers linked individual-level data separately from national population, patient, and vaccination registers in Norway, Finland, and Denmark. Patient registers were used to identify hospital visits and admissions related to thromboembolic and thrombocytopenic disease in all three countries.

The main outcomes were relative rates of coronary artery disease, coagulation disorders, and cerebrovascular disease in the 28-day period after vaccination, compared with the control period prior to vaccination.

The authors note that a strength of this study is the use of registers with full population coverage in three countries with universal health care, ensuring equal access to care for all permanent residents. At the end of the study period, from Jan. 1, 2020 to May 16, 2021, more than 5.3 million people in the three countries were vaccinated with one or two doses.

Another strength is the inherent adjustment for time-invariant confounders in the self-controlled case series design and the resulting control of confounders that can affect the more traditional observational studies when complete data for confounders are not available, they add.

Of the 265,339 hospital contacts, 43% were made by female patients and 93% by patients born in or before 1971, and 44% were for coronary artery disease, 21% for coagulation disorders, and 35% for cerebrovascular disease.

In the 28-day period after vaccination, there was an elevated rate of coronary artery disease after the Moderna vaccine (relative rate, 1.13) but not after the AstraZeneca (RR, 0.92) or Pfizer (RR, 0.96) vaccines.

There was an observed increase in the rate of coagulation disorders after all three vaccines (AstraZeneca RR, 2.01; Pfizer RR, 1.12; and Moderna RR, 1.26).

There was also an increase in the rate of cerebrovascular disease after all three vaccines (AstraZeneca RR, 1.32; Pfizer RR, 1.09; and Moderna RR, 1.21).

For individual diseases in the main outcomes, two notably high rates were observed after the AstraZeneca vaccine, with relative rates of 12.04 for cerebral venous thrombosis and 4.29 for thrombocytopenia, corresponding to 1.6 and 4.9 excess events per 100,000 doses, respectively.

The elevated risk after the AstraZeneca vaccine was consistent across all three countries and robust in sensitivity analyses.

The researchers report that they also observed statistically significant increases in hospital contacts for thrombocytopenic and thromboembolic events after the Pfizer and Moderna vaccines. However, the risk was smaller than after the AstraZeneca vaccine.

“Additionally, the national estimates varied, increased risk [was] observed only in the oldest cohorts, and sensitivity analysis checking underlying assumptions of the analyses were not consistent. Therefore, the overall and combined increased relative risks following the Pfizer and Moderna vaccinations should be interpreted with caution,” they say.

They note that their results with the AstraZeneca vaccine are in line with a comparison of observed and historic rates performed on partly the same population in Norway and Denmark and also with a Scottish national case-control study.

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

A new Scandinavian study has confirmed previous data showing increased rates of cerebral venous thrombosis and thrombocytopenia after the AstraZeneca COVID-19 vaccine.

The study also showed higher rates of several thromboembolic and thrombocytopenic outcomes after the Pfizer and Moderna mRNA vaccines, although these increases were less than the rates observed after the AstraZeneca vaccine, and sensitivity analyses were not consistent.

The researchers conclude that confirmatory analysis on the two mRNA vaccines by other methods are warranted.

The study was published in the June issue of JAMA Network Open.

“This study confirms what we know from other studies: that the AstraZeneca vaccine is associated with the rare but serious side effect of vaccine-induced immune thrombotic thrombocytopenia,” lead author Jacob Dag Berild, MD, Norwegian Institute of Public Health, Oslo, told this news organization.

“Reassuringly, no consistent association was observed between the Pfizer and Moderna mRNA vaccines and these rare complications,” he added.

Dr. Dag Berild noted that in the current study there was an excess of 1.6 events of cerebral venous thrombosis per 100,000 AstraZeneca vaccine doses, which is similar to what has been previously reported.

Asked how he saw these results affecting continued use of these vaccines, Dr. Dag Berild pointed out that the risk-benefit ratio of the vaccine depends on the risk of contracting COVID-19 and the risk for a severe outcome from COVID-19 weighed against the risk for an adverse event after vaccination.

“The European Medicines Agency has concluded that the overall risk-benefit ratio remains positive for the AstraZeneca vaccine, but Norway, Finland, and Denmark no longer use the AstraZeneca vaccine in their vaccination programs because of adequate availability of alternative vaccines. I think this is a reasonable decision,” he said.

For the current study, the researchers linked individual-level data separately from national population, patient, and vaccination registers in Norway, Finland, and Denmark. Patient registers were used to identify hospital visits and admissions related to thromboembolic and thrombocytopenic disease in all three countries.

The main outcomes were relative rates of coronary artery disease, coagulation disorders, and cerebrovascular disease in the 28-day period after vaccination, compared with the control period prior to vaccination.

The authors note that a strength of this study is the use of registers with full population coverage in three countries with universal health care, ensuring equal access to care for all permanent residents. At the end of the study period, from Jan. 1, 2020 to May 16, 2021, more than 5.3 million people in the three countries were vaccinated with one or two doses.

Another strength is the inherent adjustment for time-invariant confounders in the self-controlled case series design and the resulting control of confounders that can affect the more traditional observational studies when complete data for confounders are not available, they add.

Of the 265,339 hospital contacts, 43% were made by female patients and 93% by patients born in or before 1971, and 44% were for coronary artery disease, 21% for coagulation disorders, and 35% for cerebrovascular disease.

In the 28-day period after vaccination, there was an elevated rate of coronary artery disease after the Moderna vaccine (relative rate, 1.13) but not after the AstraZeneca (RR, 0.92) or Pfizer (RR, 0.96) vaccines.

There was an observed increase in the rate of coagulation disorders after all three vaccines (AstraZeneca RR, 2.01; Pfizer RR, 1.12; and Moderna RR, 1.26).

There was also an increase in the rate of cerebrovascular disease after all three vaccines (AstraZeneca RR, 1.32; Pfizer RR, 1.09; and Moderna RR, 1.21).

For individual diseases in the main outcomes, two notably high rates were observed after the AstraZeneca vaccine, with relative rates of 12.04 for cerebral venous thrombosis and 4.29 for thrombocytopenia, corresponding to 1.6 and 4.9 excess events per 100,000 doses, respectively.

The elevated risk after the AstraZeneca vaccine was consistent across all three countries and robust in sensitivity analyses.

The researchers report that they also observed statistically significant increases in hospital contacts for thrombocytopenic and thromboembolic events after the Pfizer and Moderna vaccines. However, the risk was smaller than after the AstraZeneca vaccine.

“Additionally, the national estimates varied, increased risk [was] observed only in the oldest cohorts, and sensitivity analysis checking underlying assumptions of the analyses were not consistent. Therefore, the overall and combined increased relative risks following the Pfizer and Moderna vaccinations should be interpreted with caution,” they say.

They note that their results with the AstraZeneca vaccine are in line with a comparison of observed and historic rates performed on partly the same population in Norway and Denmark and also with a Scottish national case-control study.

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

A new Scandinavian study has confirmed previous data showing increased rates of cerebral venous thrombosis and thrombocytopenia after the AstraZeneca COVID-19 vaccine.

The study also showed higher rates of several thromboembolic and thrombocytopenic outcomes after the Pfizer and Moderna mRNA vaccines, although these increases were less than the rates observed after the AstraZeneca vaccine, and sensitivity analyses were not consistent.

The researchers conclude that confirmatory analysis on the two mRNA vaccines by other methods are warranted.

The study was published in the June issue of JAMA Network Open.

“This study confirms what we know from other studies: that the AstraZeneca vaccine is associated with the rare but serious side effect of vaccine-induced immune thrombotic thrombocytopenia,” lead author Jacob Dag Berild, MD, Norwegian Institute of Public Health, Oslo, told this news organization.

“Reassuringly, no consistent association was observed between the Pfizer and Moderna mRNA vaccines and these rare complications,” he added.

Dr. Dag Berild noted that in the current study there was an excess of 1.6 events of cerebral venous thrombosis per 100,000 AstraZeneca vaccine doses, which is similar to what has been previously reported.

Asked how he saw these results affecting continued use of these vaccines, Dr. Dag Berild pointed out that the risk-benefit ratio of the vaccine depends on the risk of contracting COVID-19 and the risk for a severe outcome from COVID-19 weighed against the risk for an adverse event after vaccination.

“The European Medicines Agency has concluded that the overall risk-benefit ratio remains positive for the AstraZeneca vaccine, but Norway, Finland, and Denmark no longer use the AstraZeneca vaccine in their vaccination programs because of adequate availability of alternative vaccines. I think this is a reasonable decision,” he said.

For the current study, the researchers linked individual-level data separately from national population, patient, and vaccination registers in Norway, Finland, and Denmark. Patient registers were used to identify hospital visits and admissions related to thromboembolic and thrombocytopenic disease in all three countries.

The main outcomes were relative rates of coronary artery disease, coagulation disorders, and cerebrovascular disease in the 28-day period after vaccination, compared with the control period prior to vaccination.

The authors note that a strength of this study is the use of registers with full population coverage in three countries with universal health care, ensuring equal access to care for all permanent residents. At the end of the study period, from Jan. 1, 2020 to May 16, 2021, more than 5.3 million people in the three countries were vaccinated with one or two doses.

Another strength is the inherent adjustment for time-invariant confounders in the self-controlled case series design and the resulting control of confounders that can affect the more traditional observational studies when complete data for confounders are not available, they add.

Of the 265,339 hospital contacts, 43% were made by female patients and 93% by patients born in or before 1971, and 44% were for coronary artery disease, 21% for coagulation disorders, and 35% for cerebrovascular disease.

In the 28-day period after vaccination, there was an elevated rate of coronary artery disease after the Moderna vaccine (relative rate, 1.13) but not after the AstraZeneca (RR, 0.92) or Pfizer (RR, 0.96) vaccines.

There was an observed increase in the rate of coagulation disorders after all three vaccines (AstraZeneca RR, 2.01; Pfizer RR, 1.12; and Moderna RR, 1.26).

There was also an increase in the rate of cerebrovascular disease after all three vaccines (AstraZeneca RR, 1.32; Pfizer RR, 1.09; and Moderna RR, 1.21).

For individual diseases in the main outcomes, two notably high rates were observed after the AstraZeneca vaccine, with relative rates of 12.04 for cerebral venous thrombosis and 4.29 for thrombocytopenia, corresponding to 1.6 and 4.9 excess events per 100,000 doses, respectively.

The elevated risk after the AstraZeneca vaccine was consistent across all three countries and robust in sensitivity analyses.

The researchers report that they also observed statistically significant increases in hospital contacts for thrombocytopenic and thromboembolic events after the Pfizer and Moderna vaccines. However, the risk was smaller than after the AstraZeneca vaccine.

“Additionally, the national estimates varied, increased risk [was] observed only in the oldest cohorts, and sensitivity analysis checking underlying assumptions of the analyses were not consistent. Therefore, the overall and combined increased relative risks following the Pfizer and Moderna vaccinations should be interpreted with caution,” they say.

They note that their results with the AstraZeneca vaccine are in line with a comparison of observed and historic rates performed on partly the same population in Norway and Denmark and also with a Scottish national case-control study.

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

LONDON – Bulevirtide may not just treat but perhaps be a potential cure for hepatitis D in some patients, as was suggested at the annual International Liver Congress.

Data from an ongoing phase 3 trial showed that, after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable hepatitis delta virus (HDV) RNA levels and normalized ALT levels.

“The good message for our patients is that the initial data of the smaller phase 2 trials will really be confirmed, so the drug works,” Heiner Wedemeyer, MD, said at a media briefing ahead of his presentation at the meeting sponsored by the European Association for the Study of the Liver .

“It induces a decline in viral load and, very importantly for us as hepatologists, liver enzymes normalize, this is really good news” added Dr. Wedemeyer, who is the clinic director of the department of gastroenterology, hepatology, and endocrinology at Hannover (Germany) Medical School.

“This is really an almost historic moment for hepatology,” he said. “It’s the first time that these patients have an antiviral treatment; they are afraid of dying and now they have a hope.”

Giving his thoughts, Thomas Berg, MD, Secretary General of EASL, said: “We are entering into a golden age of hepatology science when it comes to viral hepatitis.

Dr. Berg, also of University Clinic Leipzig (Germany), added: “We have several million people worldwide living with viral hepatitis; we have a cure for hepatitis C but there’s no cure for hepatitis B or hepatitis D, so these data give me great hope that we have scientific momentum with us.”
 

Pivotal phase 3 study

The MYR301 trial is an important and pivotal study for bulevirtide, which is a first-in-class HDV entry inhibitor. While it was approved for use Europe in 2020 under the brand name Hepcludex, the drug remains investigational in the United States.

“We were really surprised that EMA [European Medicines Agency] went forward, granting approval because there was no alternative available at that time,” Dr. Wedemeyer said. That approval is conditional, however, and was based on the results of phase 2 studies with the proviso that further data needed would need to be provided. Hopefully, the phase 3 findings will mean that the drug will receive full official approval, he said.

Overall, 150 patients with chronic hepatitis D were recruited into the phase 3 study and randomized to receive one of two doses of bulevirtide (2 mg or 10 mg) for 144 weeks or delayed treatment for 48 weeks followed by the higher dose of the drug until the remainder of the treatment period. Bulevirtide was given as once-daily subcutaneous injection.

The mean age of participants was 41 years, the majority (82.7%) were White, and just under half already had liver cirrhosis. For inclusion, Dr. Wedemeyer said that they had to have compensated cirrhosis.

Just over half had received prior interferon therapy and almost two-thirds were receiving concomitant nucleos(t)ide (NUC) treatment.
 

Key results

The primary endpoint was defined as a combination of decreased HDV RNA (defined as undetectable or a 2 log or greater decrease) and normalized ALT (defined as 3.1 U/L or less in women and 4.1 U/L or less in men). This was assessed after 48 weeks’ treatment and was achieved by 45% of participants given the 2-mg dose of bulevirtide, 48% of those given the 10-mg dose, and by 2% of those who had delayed treatment (P < .0001 for both doses, compared with delayed treatment).

The treatment benefit was consistent across all subgroups of patients, including those with cirrhosis, Dr. Wedemeyer reported.

Looking at some of the secondary endpoints, he reported that, when considering only decreased HDV RNA, the rate of response was over 70% with both dose of bulevirtide at week 48, compared with just 4% for delayed treatment (P < .0001), although there was no significant difference in rates of undetectable HDV RNA between the two doses. ALT normalization rates were 51%-56% versus 12% for delayed treatment (P < .0001).

A further benefit was seen in liver stiffness, with values reduced by at least three points at week 48 with either dose of bulevirtide, compared with an increase of almost 1 point for delayed treatment.

As for side effects, one of the concerns for bulevirtide is an increase in serum bile acids, but when this occurred, it occurred early and remained steady over the course of treatment, with a less pronounced effect in the 2 mg–dosed group than the 10 mg–dosed group. There were no serious adverse reactions related to bulevirtide or any adverse event that led to stopping the drug.

“There are always questions that need to be answered,” Dr. Wedemeyer acknowledged. Indeed, it’s unclear for how long patients need to be treated and if treatment with interferon is needed. In the phase 2 studies (MYR202 and MYR203), bulevirtide was given at the same time as pegylated interferon alpha (peg-IFNa) or tenofovir, whereas in the phase 3 MYR301 trial, it was given as monotherapy.
 

Real-world experience

“We have already some real-world data in parallel to this phase 3 trial,” Dr. Wedemeyer said. “So, for us in the hepatitis D field, it is a really exciting time; [it’s] completely novel data and game-changing for patients.”

“The results are similar to our real life study, but in our real-life study, we have some patients treated with interferon and some not treated with interferon,” Hélène Fontaine, MD, of Hôpital Cochin in Paris, observed in an interview.

She reported preliminary results from the prospective BuleDelta cohort, which showed a virologic response rate of 58% and ALT normalization in 46% of patients.

“Virologic response was achieved in more patients receiving bulevirtide in combination with interferon,” she said. Indeed, 84% of patient who received peg-IFNa versus 39% of those who did not achieved a virologic response. However, rates of ALT normalization were more frequent in those received bulevirtide monotherapy than in combination with peg-IFN1 (54% vs. 35%).

A greater benefit of combining bulevirtide with interferon therapy was also seen in another real-world study presented by Victor de Lédinghen, MD, PhD, of Bordeaux (France) University Hospital. After 18 months of treatment, bulevirtide plus peg-IFNa was associated with undetectable HDV RNA in 57% of patients versus 33% of those given the drug as monotherapy.

“Of course, if you add interferon, it’s better than without but you cannot use interferon in all patients,” he observed in an interview.

Results are good but could be better, he suggested, noting that the results are dependent on patients injecting themselves correctly on a daily basis.

At the media briefing Dr. Wedemeyer also commented on how bulevirtide must be delivered.

“The only, let’s say, disadvantage is that it has to be injected because it’s a peptide, which requires daily injections, but patients managed very well,” Dr. Wedemeyer said.

“There is some evidence from single cases that we may stop treatment and that the virus does not come back,” he said, but stressed that patients should not stop treatment on their own as the risk is not known.

“For patients with advanced disease I consider this as a maintenance treatment,” Dr. Wedemeyer said, at least for the time being.

The MYR3201 study was funded by Gilead Sciences. The BuleDelta cohort is sponsored by the ANRS Maladies Infectieuses Emergencies. Dr. Wedemeyer acknowledged research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences and MYR as well as having ties to multiple pharmaceutical and biotechnology companies. Dr. Berg, Dr. Fontaine, and Dr. de Lédinghen had no conflicts of interest to report.
 

LONDON – Bulevirtide may not just treat but perhaps be a potential cure for hepatitis D in some patients, as was suggested at the annual International Liver Congress.

Data from an ongoing phase 3 trial showed that, after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable hepatitis delta virus (HDV) RNA levels and normalized ALT levels.

“The good message for our patients is that the initial data of the smaller phase 2 trials will really be confirmed, so the drug works,” Heiner Wedemeyer, MD, said at a media briefing ahead of his presentation at the meeting sponsored by the European Association for the Study of the Liver .

“It induces a decline in viral load and, very importantly for us as hepatologists, liver enzymes normalize, this is really good news” added Dr. Wedemeyer, who is the clinic director of the department of gastroenterology, hepatology, and endocrinology at Hannover (Germany) Medical School.

“This is really an almost historic moment for hepatology,” he said. “It’s the first time that these patients have an antiviral treatment; they are afraid of dying and now they have a hope.”

Giving his thoughts, Thomas Berg, MD, Secretary General of EASL, said: “We are entering into a golden age of hepatology science when it comes to viral hepatitis.

Dr. Berg, also of University Clinic Leipzig (Germany), added: “We have several million people worldwide living with viral hepatitis; we have a cure for hepatitis C but there’s no cure for hepatitis B or hepatitis D, so these data give me great hope that we have scientific momentum with us.”
 

Pivotal phase 3 study

The MYR301 trial is an important and pivotal study for bulevirtide, which is a first-in-class HDV entry inhibitor. While it was approved for use Europe in 2020 under the brand name Hepcludex, the drug remains investigational in the United States.

“We were really surprised that EMA [European Medicines Agency] went forward, granting approval because there was no alternative available at that time,” Dr. Wedemeyer said. That approval is conditional, however, and was based on the results of phase 2 studies with the proviso that further data needed would need to be provided. Hopefully, the phase 3 findings will mean that the drug will receive full official approval, he said.

Overall, 150 patients with chronic hepatitis D were recruited into the phase 3 study and randomized to receive one of two doses of bulevirtide (2 mg or 10 mg) for 144 weeks or delayed treatment for 48 weeks followed by the higher dose of the drug until the remainder of the treatment period. Bulevirtide was given as once-daily subcutaneous injection.

The mean age of participants was 41 years, the majority (82.7%) were White, and just under half already had liver cirrhosis. For inclusion, Dr. Wedemeyer said that they had to have compensated cirrhosis.

Just over half had received prior interferon therapy and almost two-thirds were receiving concomitant nucleos(t)ide (NUC) treatment.
 

Key results

The primary endpoint was defined as a combination of decreased HDV RNA (defined as undetectable or a 2 log or greater decrease) and normalized ALT (defined as 3.1 U/L or less in women and 4.1 U/L or less in men). This was assessed after 48 weeks’ treatment and was achieved by 45% of participants given the 2-mg dose of bulevirtide, 48% of those given the 10-mg dose, and by 2% of those who had delayed treatment (P < .0001 for both doses, compared with delayed treatment).

The treatment benefit was consistent across all subgroups of patients, including those with cirrhosis, Dr. Wedemeyer reported.

Looking at some of the secondary endpoints, he reported that, when considering only decreased HDV RNA, the rate of response was over 70% with both dose of bulevirtide at week 48, compared with just 4% for delayed treatment (P < .0001), although there was no significant difference in rates of undetectable HDV RNA between the two doses. ALT normalization rates were 51%-56% versus 12% for delayed treatment (P < .0001).

A further benefit was seen in liver stiffness, with values reduced by at least three points at week 48 with either dose of bulevirtide, compared with an increase of almost 1 point for delayed treatment.

As for side effects, one of the concerns for bulevirtide is an increase in serum bile acids, but when this occurred, it occurred early and remained steady over the course of treatment, with a less pronounced effect in the 2 mg–dosed group than the 10 mg–dosed group. There were no serious adverse reactions related to bulevirtide or any adverse event that led to stopping the drug.

“There are always questions that need to be answered,” Dr. Wedemeyer acknowledged. Indeed, it’s unclear for how long patients need to be treated and if treatment with interferon is needed. In the phase 2 studies (MYR202 and MYR203), bulevirtide was given at the same time as pegylated interferon alpha (peg-IFNa) or tenofovir, whereas in the phase 3 MYR301 trial, it was given as monotherapy.
 

Real-world experience

“We have already some real-world data in parallel to this phase 3 trial,” Dr. Wedemeyer said. “So, for us in the hepatitis D field, it is a really exciting time; [it’s] completely novel data and game-changing for patients.”

“The results are similar to our real life study, but in our real-life study, we have some patients treated with interferon and some not treated with interferon,” Hélène Fontaine, MD, of Hôpital Cochin in Paris, observed in an interview.

She reported preliminary results from the prospective BuleDelta cohort, which showed a virologic response rate of 58% and ALT normalization in 46% of patients.

“Virologic response was achieved in more patients receiving bulevirtide in combination with interferon,” she said. Indeed, 84% of patient who received peg-IFNa versus 39% of those who did not achieved a virologic response. However, rates of ALT normalization were more frequent in those received bulevirtide monotherapy than in combination with peg-IFN1 (54% vs. 35%).

A greater benefit of combining bulevirtide with interferon therapy was also seen in another real-world study presented by Victor de Lédinghen, MD, PhD, of Bordeaux (France) University Hospital. After 18 months of treatment, bulevirtide plus peg-IFNa was associated with undetectable HDV RNA in 57% of patients versus 33% of those given the drug as monotherapy.

“Of course, if you add interferon, it’s better than without but you cannot use interferon in all patients,” he observed in an interview.

Results are good but could be better, he suggested, noting that the results are dependent on patients injecting themselves correctly on a daily basis.

At the media briefing Dr. Wedemeyer also commented on how bulevirtide must be delivered.

“The only, let’s say, disadvantage is that it has to be injected because it’s a peptide, which requires daily injections, but patients managed very well,” Dr. Wedemeyer said.

“There is some evidence from single cases that we may stop treatment and that the virus does not come back,” he said, but stressed that patients should not stop treatment on their own as the risk is not known.

“For patients with advanced disease I consider this as a maintenance treatment,” Dr. Wedemeyer said, at least for the time being.

The MYR3201 study was funded by Gilead Sciences. The BuleDelta cohort is sponsored by the ANRS Maladies Infectieuses Emergencies. Dr. Wedemeyer acknowledged research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences and MYR as well as having ties to multiple pharmaceutical and biotechnology companies. Dr. Berg, Dr. Fontaine, and Dr. de Lédinghen had no conflicts of interest to report.
 

LONDON – Bulevirtide may not just treat but perhaps be a potential cure for hepatitis D in some patients, as was suggested at the annual International Liver Congress.

Data from an ongoing phase 3 trial showed that, after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable hepatitis delta virus (HDV) RNA levels and normalized ALT levels.

“The good message for our patients is that the initial data of the smaller phase 2 trials will really be confirmed, so the drug works,” Heiner Wedemeyer, MD, said at a media briefing ahead of his presentation at the meeting sponsored by the European Association for the Study of the Liver .

“It induces a decline in viral load and, very importantly for us as hepatologists, liver enzymes normalize, this is really good news” added Dr. Wedemeyer, who is the clinic director of the department of gastroenterology, hepatology, and endocrinology at Hannover (Germany) Medical School.

“This is really an almost historic moment for hepatology,” he said. “It’s the first time that these patients have an antiviral treatment; they are afraid of dying and now they have a hope.”

Giving his thoughts, Thomas Berg, MD, Secretary General of EASL, said: “We are entering into a golden age of hepatology science when it comes to viral hepatitis.

Dr. Berg, also of University Clinic Leipzig (Germany), added: “We have several million people worldwide living with viral hepatitis; we have a cure for hepatitis C but there’s no cure for hepatitis B or hepatitis D, so these data give me great hope that we have scientific momentum with us.”
 

Pivotal phase 3 study

The MYR301 trial is an important and pivotal study for bulevirtide, which is a first-in-class HDV entry inhibitor. While it was approved for use Europe in 2020 under the brand name Hepcludex, the drug remains investigational in the United States.

“We were really surprised that EMA [European Medicines Agency] went forward, granting approval because there was no alternative available at that time,” Dr. Wedemeyer said. That approval is conditional, however, and was based on the results of phase 2 studies with the proviso that further data needed would need to be provided. Hopefully, the phase 3 findings will mean that the drug will receive full official approval, he said.

Overall, 150 patients with chronic hepatitis D were recruited into the phase 3 study and randomized to receive one of two doses of bulevirtide (2 mg or 10 mg) for 144 weeks or delayed treatment for 48 weeks followed by the higher dose of the drug until the remainder of the treatment period. Bulevirtide was given as once-daily subcutaneous injection.

The mean age of participants was 41 years, the majority (82.7%) were White, and just under half already had liver cirrhosis. For inclusion, Dr. Wedemeyer said that they had to have compensated cirrhosis.

Just over half had received prior interferon therapy and almost two-thirds were receiving concomitant nucleos(t)ide (NUC) treatment.
 

Key results

The primary endpoint was defined as a combination of decreased HDV RNA (defined as undetectable or a 2 log or greater decrease) and normalized ALT (defined as 3.1 U/L or less in women and 4.1 U/L or less in men). This was assessed after 48 weeks’ treatment and was achieved by 45% of participants given the 2-mg dose of bulevirtide, 48% of those given the 10-mg dose, and by 2% of those who had delayed treatment (P < .0001 for both doses, compared with delayed treatment).

The treatment benefit was consistent across all subgroups of patients, including those with cirrhosis, Dr. Wedemeyer reported.

Looking at some of the secondary endpoints, he reported that, when considering only decreased HDV RNA, the rate of response was over 70% with both dose of bulevirtide at week 48, compared with just 4% for delayed treatment (P < .0001), although there was no significant difference in rates of undetectable HDV RNA between the two doses. ALT normalization rates were 51%-56% versus 12% for delayed treatment (P < .0001).

A further benefit was seen in liver stiffness, with values reduced by at least three points at week 48 with either dose of bulevirtide, compared with an increase of almost 1 point for delayed treatment.

As for side effects, one of the concerns for bulevirtide is an increase in serum bile acids, but when this occurred, it occurred early and remained steady over the course of treatment, with a less pronounced effect in the 2 mg–dosed group than the 10 mg–dosed group. There were no serious adverse reactions related to bulevirtide or any adverse event that led to stopping the drug.

“There are always questions that need to be answered,” Dr. Wedemeyer acknowledged. Indeed, it’s unclear for how long patients need to be treated and if treatment with interferon is needed. In the phase 2 studies (MYR202 and MYR203), bulevirtide was given at the same time as pegylated interferon alpha (peg-IFNa) or tenofovir, whereas in the phase 3 MYR301 trial, it was given as monotherapy.
 

Real-world experience

“We have already some real-world data in parallel to this phase 3 trial,” Dr. Wedemeyer said. “So, for us in the hepatitis D field, it is a really exciting time; [it’s] completely novel data and game-changing for patients.”

“The results are similar to our real life study, but in our real-life study, we have some patients treated with interferon and some not treated with interferon,” Hélène Fontaine, MD, of Hôpital Cochin in Paris, observed in an interview.

She reported preliminary results from the prospective BuleDelta cohort, which showed a virologic response rate of 58% and ALT normalization in 46% of patients.

“Virologic response was achieved in more patients receiving bulevirtide in combination with interferon,” she said. Indeed, 84% of patient who received peg-IFNa versus 39% of those who did not achieved a virologic response. However, rates of ALT normalization were more frequent in those received bulevirtide monotherapy than in combination with peg-IFN1 (54% vs. 35%).

A greater benefit of combining bulevirtide with interferon therapy was also seen in another real-world study presented by Victor de Lédinghen, MD, PhD, of Bordeaux (France) University Hospital. After 18 months of treatment, bulevirtide plus peg-IFNa was associated with undetectable HDV RNA in 57% of patients versus 33% of those given the drug as monotherapy.

“Of course, if you add interferon, it’s better than without but you cannot use interferon in all patients,” he observed in an interview.

Results are good but could be better, he suggested, noting that the results are dependent on patients injecting themselves correctly on a daily basis.

At the media briefing Dr. Wedemeyer also commented on how bulevirtide must be delivered.

“The only, let’s say, disadvantage is that it has to be injected because it’s a peptide, which requires daily injections, but patients managed very well,” Dr. Wedemeyer said.

“There is some evidence from single cases that we may stop treatment and that the virus does not come back,” he said, but stressed that patients should not stop treatment on their own as the risk is not known.

“For patients with advanced disease I consider this as a maintenance treatment,” Dr. Wedemeyer said, at least for the time being.

The MYR3201 study was funded by Gilead Sciences. The BuleDelta cohort is sponsored by the ANRS Maladies Infectieuses Emergencies. Dr. Wedemeyer acknowledged research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences and MYR as well as having ties to multiple pharmaceutical and biotechnology companies. Dr. Berg, Dr. Fontaine, and Dr. de Lédinghen had no conflicts of interest to report.
 

Ask the sibling of any celebrity and they’ll tell you they don’t get anywhere near the same attention. The same is true for coronaviruses – the one that causes COVID-19 has been in the spotlight for more than 2 years now, while the others at the moment circulate in relative obscurity.

With the knowledge that any of the other coronaviruses could pose a serious future threat, Pfizer and its partner BioNTech announced plans on June 29 to develop a vaccine that will work against SARS-CoV-2 (the virus that causes COVID-19) and the entire class, or family, of related coronaviruses.

Trials in people of this “pan-coronavirus” vaccine are scheduled to start this fall, Reuters reported. The aim of this universal vaccine is to lessen the threat from new variants before they emerge – to provide “durable variant protection.”

“I applaud the sentiment that is long overdue,” said Eric Topol, MD, when asked to comment. “It is crucial that we get ahead of the virus, and the best way is to develop pan-betacoronavirus vaccines that are variant-proof.”

“We had potential to get them into clinical trials many months ago, but this is the first sign it may happen,” said Dr. Topol, executive vice president of Scripps Research and editor-in-chief for Medscape, WebMD’s sister site for health care professionals.

SARS-CoV-2 is not the first troublemaker in the coronavirus family. SARS, a coronavirus that causes acute respiratory syndrome, emerged in late 2002. A decade later, officials sounded the alarm about the coronavirus behind Middle East respiratory syndrome (MERS).

The coronavirus family is large, but only seven coronavirus types can infect humans, the CDC reports. Most cause mild to moderate upper respiratory tract infections, although some people can get pneumonia or bronchiolitis.

Unless you’re a virologist, immunologist, or public health official, you may be unaware that coronaviruses are one of the causes of the common cold, for example.

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

Ask the sibling of any celebrity and they’ll tell you they don’t get anywhere near the same attention. The same is true for coronaviruses – the one that causes COVID-19 has been in the spotlight for more than 2 years now, while the others at the moment circulate in relative obscurity.

With the knowledge that any of the other coronaviruses could pose a serious future threat, Pfizer and its partner BioNTech announced plans on June 29 to develop a vaccine that will work against SARS-CoV-2 (the virus that causes COVID-19) and the entire class, or family, of related coronaviruses.

Trials in people of this “pan-coronavirus” vaccine are scheduled to start this fall, Reuters reported. The aim of this universal vaccine is to lessen the threat from new variants before they emerge – to provide “durable variant protection.”

“I applaud the sentiment that is long overdue,” said Eric Topol, MD, when asked to comment. “It is crucial that we get ahead of the virus, and the best way is to develop pan-betacoronavirus vaccines that are variant-proof.”

“We had potential to get them into clinical trials many months ago, but this is the first sign it may happen,” said Dr. Topol, executive vice president of Scripps Research and editor-in-chief for Medscape, WebMD’s sister site for health care professionals.

SARS-CoV-2 is not the first troublemaker in the coronavirus family. SARS, a coronavirus that causes acute respiratory syndrome, emerged in late 2002. A decade later, officials sounded the alarm about the coronavirus behind Middle East respiratory syndrome (MERS).

The coronavirus family is large, but only seven coronavirus types can infect humans, the CDC reports. Most cause mild to moderate upper respiratory tract infections, although some people can get pneumonia or bronchiolitis.

Unless you’re a virologist, immunologist, or public health official, you may be unaware that coronaviruses are one of the causes of the common cold, for example.

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

Ask the sibling of any celebrity and they’ll tell you they don’t get anywhere near the same attention. The same is true for coronaviruses – the one that causes COVID-19 has been in the spotlight for more than 2 years now, while the others at the moment circulate in relative obscurity.

With the knowledge that any of the other coronaviruses could pose a serious future threat, Pfizer and its partner BioNTech announced plans on June 29 to develop a vaccine that will work against SARS-CoV-2 (the virus that causes COVID-19) and the entire class, or family, of related coronaviruses.

Trials in people of this “pan-coronavirus” vaccine are scheduled to start this fall, Reuters reported. The aim of this universal vaccine is to lessen the threat from new variants before they emerge – to provide “durable variant protection.”

“I applaud the sentiment that is long overdue,” said Eric Topol, MD, when asked to comment. “It is crucial that we get ahead of the virus, and the best way is to develop pan-betacoronavirus vaccines that are variant-proof.”

“We had potential to get them into clinical trials many months ago, but this is the first sign it may happen,” said Dr. Topol, executive vice president of Scripps Research and editor-in-chief for Medscape, WebMD’s sister site for health care professionals.

SARS-CoV-2 is not the first troublemaker in the coronavirus family. SARS, a coronavirus that causes acute respiratory syndrome, emerged in late 2002. A decade later, officials sounded the alarm about the coronavirus behind Middle East respiratory syndrome (MERS).

The coronavirus family is large, but only seven coronavirus types can infect humans, the CDC reports. Most cause mild to moderate upper respiratory tract infections, although some people can get pneumonia or bronchiolitis.

Unless you’re a virologist, immunologist, or public health official, you may be unaware that coronaviruses are one of the causes of the common cold, for example.

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