Hepatitis

Purpose

Examine hepatitis B virus (HBV) testing in veterans receiving systemic anticancer treatment (SACT) in the Veterans Health Administration (VHA).

Background

HBV reactivation is reported in patients with chronic (HB surface antigen, HBsAg, positive) or prior (HB core antibody, HBcAb, positive) HBV infection, who receive SACT. A recent American Society of Clinical Oncology provisional clinical opinion update recommended HBV screening for all patients prior to initiation of SACT (excluding hormonal therapy). HBV testing and the incidence of hepatitis in veterans receiving SACT in the VHA has not been reported.

Methods/Data Analysis

VHA EHR data were used to identify veterans receiving SACT (01/2010-12/2021). Testing for HBsAg, HBcAb and alanine aminotransferase (ALT) was extracted. Patients known to have HBV or elevated ALT prior to first SACT, and those receiving anti-CD20 were excluded. Patients were followed until two years after the last SACT or 12/2021, whichever occurred first. Patients receiving intravenous SACT and those receiving oral SACT are described separately.

Results

Between 2010 and 2021, 215,395 veterans received an intravenous SACT, while 80,752 veterans received an oral SACT. Of patients treated with an SACT, 80% had no evidence of HBsAg or HBcAb testing prior to treatment initiation, and 8-12% experienced at least one elevated ALT between treatment initiation and two years after the last SACT. There was no evidence of increased ALT elevation in patients who were not tested compared to those that were tested prior to treatment initiation. In patients with at least one ALT elevation, approximately 30% were tested for HBV and of these, 3% tested positive.

Conclusions/Implications

Most veterans receiving SACT are not tested for HBV prior to treatment initiation, and do not experience elevated ALTs. In patients with elevated ALT during or subsequent to SACT, the majority are not tested for HBV. Veterans that are tested reveal an HBV prevalence of about 10%. Our results suggest that HBV testing prior to SACT initiation should not be at the expense of delaying treatment, given the magnitude of proposed change from current practice and the anticipated low probability of benefit.

Purpose

Examine hepatitis B virus (HBV) testing in veterans receiving systemic anticancer treatment (SACT) in the Veterans Health Administration (VHA).

Background

HBV reactivation is reported in patients with chronic (HB surface antigen, HBsAg, positive) or prior (HB core antibody, HBcAb, positive) HBV infection, who receive SACT. A recent American Society of Clinical Oncology provisional clinical opinion update recommended HBV screening for all patients prior to initiation of SACT (excluding hormonal therapy). HBV testing and the incidence of hepatitis in veterans receiving SACT in the VHA has not been reported.

Methods/Data Analysis

VHA EHR data were used to identify veterans receiving SACT (01/2010-12/2021). Testing for HBsAg, HBcAb and alanine aminotransferase (ALT) was extracted. Patients known to have HBV or elevated ALT prior to first SACT, and those receiving anti-CD20 were excluded. Patients were followed until two years after the last SACT or 12/2021, whichever occurred first. Patients receiving intravenous SACT and those receiving oral SACT are described separately.

Results

Between 2010 and 2021, 215,395 veterans received an intravenous SACT, while 80,752 veterans received an oral SACT. Of patients treated with an SACT, 80% had no evidence of HBsAg or HBcAb testing prior to treatment initiation, and 8-12% experienced at least one elevated ALT between treatment initiation and two years after the last SACT. There was no evidence of increased ALT elevation in patients who were not tested compared to those that were tested prior to treatment initiation. In patients with at least one ALT elevation, approximately 30% were tested for HBV and of these, 3% tested positive.

Conclusions/Implications

Most veterans receiving SACT are not tested for HBV prior to treatment initiation, and do not experience elevated ALTs. In patients with elevated ALT during or subsequent to SACT, the majority are not tested for HBV. Veterans that are tested reveal an HBV prevalence of about 10%. Our results suggest that HBV testing prior to SACT initiation should not be at the expense of delaying treatment, given the magnitude of proposed change from current practice and the anticipated low probability of benefit.

Purpose

Examine hepatitis B virus (HBV) testing in veterans receiving systemic anticancer treatment (SACT) in the Veterans Health Administration (VHA).

Background

HBV reactivation is reported in patients with chronic (HB surface antigen, HBsAg, positive) or prior (HB core antibody, HBcAb, positive) HBV infection, who receive SACT. A recent American Society of Clinical Oncology provisional clinical opinion update recommended HBV screening for all patients prior to initiation of SACT (excluding hormonal therapy). HBV testing and the incidence of hepatitis in veterans receiving SACT in the VHA has not been reported.

Methods/Data Analysis

VHA EHR data were used to identify veterans receiving SACT (01/2010-12/2021). Testing for HBsAg, HBcAb and alanine aminotransferase (ALT) was extracted. Patients known to have HBV or elevated ALT prior to first SACT, and those receiving anti-CD20 were excluded. Patients were followed until two years after the last SACT or 12/2021, whichever occurred first. Patients receiving intravenous SACT and those receiving oral SACT are described separately.

Results

Between 2010 and 2021, 215,395 veterans received an intravenous SACT, while 80,752 veterans received an oral SACT. Of patients treated with an SACT, 80% had no evidence of HBsAg or HBcAb testing prior to treatment initiation, and 8-12% experienced at least one elevated ALT between treatment initiation and two years after the last SACT. There was no evidence of increased ALT elevation in patients who were not tested compared to those that were tested prior to treatment initiation. In patients with at least one ALT elevation, approximately 30% were tested for HBV and of these, 3% tested positive.

Conclusions/Implications

Most veterans receiving SACT are not tested for HBV prior to treatment initiation, and do not experience elevated ALTs. In patients with elevated ALT during or subsequent to SACT, the majority are not tested for HBV. Veterans that are tested reveal an HBV prevalence of about 10%. Our results suggest that HBV testing prior to SACT initiation should not be at the expense of delaying treatment, given the magnitude of proposed change from current practice and the anticipated low probability of benefit.

Fewer than 1 in 3 people infected with hepatitis C virus (HCV) begin receiving treatment within a year of their diagnosis, according to a new report by the Centers for Disease Control and Prevention.

Although HCV infection can be cured in more than 95% of patients with safe, oral medication, many barriers prevent people from receiving the care they need, experts say. These include insurance restrictions and the need for specialist visits.

“If we are going to make an impact against hepatitis C, we need to connect more people to treatments and reduce disparities of access to diagnosis and treatment,” said Carolyn Wester, MD, MPH, director of the CDC’s Division of Viral Hepatitis, during an Aug. 9 press call. “People shouldn’t have to jump over hurdles to access lifesaving treatments.”

The CDC report was published  in Vital Signs.

An estimated 2.2 million Americans are living with HCV infection. The most recent data indicate that new infections increased more than threefold from 2011 to 2019. HCV transmission usually occurs through contact with the blood of an infected person. Today, most people become infected with the virus by sharing needles, syringes, and other equipment used to inject drugs, according to the CDC.

The researchers used a nationwide administrative claims database to identify more than 47,600 adults diagnosed with HCV infection from Jan. 30, 2019 through Oct. 31, 2020. Most patients (79%) were Medicaid recipients, 7% were Medicare patients, and 14% had private insurance. CDC researchers found that just 23% of Medicaid recipients, 28% of Medicare patients, and 35% of patients with private insurance began receiving direct-acting antiviral agents (DAAs) within 360 days of receiving a positive HCV test result. Of those who did receive treatment, most (from 75% to 84%) began receiving treatment within 180 days of their diagnosis.

Among people on Medicaid plans, patients who lived in states with treatment restrictions were 23% less likely to receive timely treatment (adjusted odds ratio, 0.77; 95% confidence interval, 0.74-0.81), compared with those living in states with no restrictions. Medicaid patients who were Black or of another race other than White were also less likely than White patients to be treated for HCV within the same year as their diagnosis. The lowest rates of treatment were among adults younger than 40 years, regardless of insurance type. This age group had the highest rates of new infections.

Actual treatment percentages may be even smaller than the number captured in this study, because the study included patients with continuous insurance coverage, Dr. Wester said, “so in many ways, [these] are the individuals who are set up to have the best access to care and treatment.”

Dr. Wester mentioned several steps that could improve access to DAAs for patients with HCV infection:

• Provide treatment outside of specialist offices, such as primary care and community clinics, substance use treatment centers, and syringe services programs.
• Increase the number of primary care providers offering hepatitis C treatment.
• Provide treatment in as few visits as possible.
• Eliminate restrictions by insurance providers on treatment.

A ‘health injustice’

While DAA treatments are effective, they are also expensive. Generic medications cost around $24,000 for a 12-week course, and some brand-name drugs are estimated to cost more than three times that amount. Many insurance companies, therefore, have treatment restrictions in place, including the following:

• There must be evidence of liver fibrosis for a patient to be treated.
• The doctor prescribing treatment must be a liver specialist or an infectious disease specialist.
• The patient must meet sobriety requirements.
• Treatment requires preauthorization approval from insurance carriers.

These criteria prevent patients from getting the care that they need, said Jonathan Mermin, MD, MPH, director of the CDC’s National Center for HIV, Viral Hepatitis, STD, and TB Prevention, during the press call. “Restricting access to hepatitis C treatment turns an infectious disease into a health injustice,” he added.

Oluwaseun Falade-Nwulia, MBBS, MPH, an infectious disease specialist and assistant professor of medicine at the Johns Hopkins University School of Medicine, Baltimore, emphasized the importance of removing barriers to HCV treatment and expanding HCV care out of specialist offices. She noted that treatment for HCV infection should begin immediately after a patient’s diagnosis. Previously, guidelines recommended waiting 6 months from the time a patient was diagnosed with HCV to begin treatment to see whether the patient’s body could clear the infection on its own. Now, guidelines recommend that after a diagnosis of acute HCV, “HCV treatment should be initiated without awaiting spontaneous resolution.” But some insurance companies still ask for evidence that a patient has been infected for at least 6 months before approving therapy, Dr. Falade-Nwulia noted.

“We have a system that has so many structural barriers for patients who we know already have so many social determinants of health working against them to access any health care,” she said. “I think it’s doubly devastating that patients that can actually get to a provider and get a prescription may still not have access to [the medication] because of structural barriers, such as restrictions based on a need to prove chronicity.”

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

Fewer than 1 in 3 people infected with hepatitis C virus (HCV) begin receiving treatment within a year of their diagnosis, according to a new report by the Centers for Disease Control and Prevention.

Although HCV infection can be cured in more than 95% of patients with safe, oral medication, many barriers prevent people from receiving the care they need, experts say. These include insurance restrictions and the need for specialist visits.

“If we are going to make an impact against hepatitis C, we need to connect more people to treatments and reduce disparities of access to diagnosis and treatment,” said Carolyn Wester, MD, MPH, director of the CDC’s Division of Viral Hepatitis, during an Aug. 9 press call. “People shouldn’t have to jump over hurdles to access lifesaving treatments.”

The CDC report was published  in Vital Signs.

An estimated 2.2 million Americans are living with HCV infection. The most recent data indicate that new infections increased more than threefold from 2011 to 2019. HCV transmission usually occurs through contact with the blood of an infected person. Today, most people become infected with the virus by sharing needles, syringes, and other equipment used to inject drugs, according to the CDC.

The researchers used a nationwide administrative claims database to identify more than 47,600 adults diagnosed with HCV infection from Jan. 30, 2019 through Oct. 31, 2020. Most patients (79%) were Medicaid recipients, 7% were Medicare patients, and 14% had private insurance. CDC researchers found that just 23% of Medicaid recipients, 28% of Medicare patients, and 35% of patients with private insurance began receiving direct-acting antiviral agents (DAAs) within 360 days of receiving a positive HCV test result. Of those who did receive treatment, most (from 75% to 84%) began receiving treatment within 180 days of their diagnosis.

Among people on Medicaid plans, patients who lived in states with treatment restrictions were 23% less likely to receive timely treatment (adjusted odds ratio, 0.77; 95% confidence interval, 0.74-0.81), compared with those living in states with no restrictions. Medicaid patients who were Black or of another race other than White were also less likely than White patients to be treated for HCV within the same year as their diagnosis. The lowest rates of treatment were among adults younger than 40 years, regardless of insurance type. This age group had the highest rates of new infections.

Actual treatment percentages may be even smaller than the number captured in this study, because the study included patients with continuous insurance coverage, Dr. Wester said, “so in many ways, [these] are the individuals who are set up to have the best access to care and treatment.”

Dr. Wester mentioned several steps that could improve access to DAAs for patients with HCV infection:

• Provide treatment outside of specialist offices, such as primary care and community clinics, substance use treatment centers, and syringe services programs.
• Increase the number of primary care providers offering hepatitis C treatment.
• Provide treatment in as few visits as possible.
• Eliminate restrictions by insurance providers on treatment.

A ‘health injustice’

While DAA treatments are effective, they are also expensive. Generic medications cost around $24,000 for a 12-week course, and some brand-name drugs are estimated to cost more than three times that amount. Many insurance companies, therefore, have treatment restrictions in place, including the following:

• There must be evidence of liver fibrosis for a patient to be treated.
• The doctor prescribing treatment must be a liver specialist or an infectious disease specialist.
• The patient must meet sobriety requirements.
• Treatment requires preauthorization approval from insurance carriers.

These criteria prevent patients from getting the care that they need, said Jonathan Mermin, MD, MPH, director of the CDC’s National Center for HIV, Viral Hepatitis, STD, and TB Prevention, during the press call. “Restricting access to hepatitis C treatment turns an infectious disease into a health injustice,” he added.

Oluwaseun Falade-Nwulia, MBBS, MPH, an infectious disease specialist and assistant professor of medicine at the Johns Hopkins University School of Medicine, Baltimore, emphasized the importance of removing barriers to HCV treatment and expanding HCV care out of specialist offices. She noted that treatment for HCV infection should begin immediately after a patient’s diagnosis. Previously, guidelines recommended waiting 6 months from the time a patient was diagnosed with HCV to begin treatment to see whether the patient’s body could clear the infection on its own. Now, guidelines recommend that after a diagnosis of acute HCV, “HCV treatment should be initiated without awaiting spontaneous resolution.” But some insurance companies still ask for evidence that a patient has been infected for at least 6 months before approving therapy, Dr. Falade-Nwulia noted.

“We have a system that has so many structural barriers for patients who we know already have so many social determinants of health working against them to access any health care,” she said. “I think it’s doubly devastating that patients that can actually get to a provider and get a prescription may still not have access to [the medication] because of structural barriers, such as restrictions based on a need to prove chronicity.”

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

Fewer than 1 in 3 people infected with hepatitis C virus (HCV) begin receiving treatment within a year of their diagnosis, according to a new report by the Centers for Disease Control and Prevention.

Although HCV infection can be cured in more than 95% of patients with safe, oral medication, many barriers prevent people from receiving the care they need, experts say. These include insurance restrictions and the need for specialist visits.

“If we are going to make an impact against hepatitis C, we need to connect more people to treatments and reduce disparities of access to diagnosis and treatment,” said Carolyn Wester, MD, MPH, director of the CDC’s Division of Viral Hepatitis, during an Aug. 9 press call. “People shouldn’t have to jump over hurdles to access lifesaving treatments.”

The CDC report was published  in Vital Signs.

An estimated 2.2 million Americans are living with HCV infection. The most recent data indicate that new infections increased more than threefold from 2011 to 2019. HCV transmission usually occurs through contact with the blood of an infected person. Today, most people become infected with the virus by sharing needles, syringes, and other equipment used to inject drugs, according to the CDC.

The researchers used a nationwide administrative claims database to identify more than 47,600 adults diagnosed with HCV infection from Jan. 30, 2019 through Oct. 31, 2020. Most patients (79%) were Medicaid recipients, 7% were Medicare patients, and 14% had private insurance. CDC researchers found that just 23% of Medicaid recipients, 28% of Medicare patients, and 35% of patients with private insurance began receiving direct-acting antiviral agents (DAAs) within 360 days of receiving a positive HCV test result. Of those who did receive treatment, most (from 75% to 84%) began receiving treatment within 180 days of their diagnosis.

Among people on Medicaid plans, patients who lived in states with treatment restrictions were 23% less likely to receive timely treatment (adjusted odds ratio, 0.77; 95% confidence interval, 0.74-0.81), compared with those living in states with no restrictions. Medicaid patients who were Black or of another race other than White were also less likely than White patients to be treated for HCV within the same year as their diagnosis. The lowest rates of treatment were among adults younger than 40 years, regardless of insurance type. This age group had the highest rates of new infections.

Actual treatment percentages may be even smaller than the number captured in this study, because the study included patients with continuous insurance coverage, Dr. Wester said, “so in many ways, [these] are the individuals who are set up to have the best access to care and treatment.”

Dr. Wester mentioned several steps that could improve access to DAAs for patients with HCV infection:

• Provide treatment outside of specialist offices, such as primary care and community clinics, substance use treatment centers, and syringe services programs.
• Increase the number of primary care providers offering hepatitis C treatment.
• Provide treatment in as few visits as possible.
• Eliminate restrictions by insurance providers on treatment.

A ‘health injustice’

While DAA treatments are effective, they are also expensive. Generic medications cost around $24,000 for a 12-week course, and some brand-name drugs are estimated to cost more than three times that amount. Many insurance companies, therefore, have treatment restrictions in place, including the following:

• There must be evidence of liver fibrosis for a patient to be treated.
• The doctor prescribing treatment must be a liver specialist or an infectious disease specialist.
• The patient must meet sobriety requirements.
• Treatment requires preauthorization approval from insurance carriers.

These criteria prevent patients from getting the care that they need, said Jonathan Mermin, MD, MPH, director of the CDC’s National Center for HIV, Viral Hepatitis, STD, and TB Prevention, during the press call. “Restricting access to hepatitis C treatment turns an infectious disease into a health injustice,” he added.

Oluwaseun Falade-Nwulia, MBBS, MPH, an infectious disease specialist and assistant professor of medicine at the Johns Hopkins University School of Medicine, Baltimore, emphasized the importance of removing barriers to HCV treatment and expanding HCV care out of specialist offices. She noted that treatment for HCV infection should begin immediately after a patient’s diagnosis. Previously, guidelines recommended waiting 6 months from the time a patient was diagnosed with HCV to begin treatment to see whether the patient’s body could clear the infection on its own. Now, guidelines recommend that after a diagnosis of acute HCV, “HCV treatment should be initiated without awaiting spontaneous resolution.” But some insurance companies still ask for evidence that a patient has been infected for at least 6 months before approving therapy, Dr. Falade-Nwulia noted.

“We have a system that has so many structural barriers for patients who we know already have so many social determinants of health working against them to access any health care,” she said. “I think it’s doubly devastating that patients that can actually get to a provider and get a prescription may still not have access to [the medication] because of structural barriers, such as restrictions based on a need to prove chronicity.”

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

Reinfection rates are low after treating hepatitis C virus in people taking opioid agonist therapy (OAT), even among those who still inject drugs, according to a new study.

The findings, which are based on prospective data from 13 countries, including the United States, and were published in Annals of Internal Medicine (2022 Aug 8. doi: 10.7326/M21-4119), should encourage physicians to treat HCV in people with a history of injection drug use, said lead author Jason Grebely, PhD. They should also pressure payers to lift reimbursement restrictions on the same population.

“Direct-acting antiviral medications for HCV infection are safe and effective among people receiving OAT and people with recent injecting-drug use,” the investigators wrote. “Concerns remain, however, that HCV reinfection may reduce the benefits of cure among people who inject drugs and compromise HCV elimination efforts.”

They explored these concerns through a 3-year extension of the phase 3 CO-STAR trial that evaluated elbasvir and grazoprevir in people consistently taking OAT. Participants in the CO-STAR trial, which had a 96% sustained virologic response rate among those who completed therapy, could elect to participate in the present study, offering a prospective look at long-term reinfection.

Out of 296 participants in the CO-STAR trial, 286 were evaluable for reinfection and 199 enrolled in the present extension. The majority were White (79.4%) and male (75.9%), with most taking methadone (79%), followed by buprenorphine (20%). At 6 months, 40 out of 191 respondents (21%) reported injection-drug use in the previous month. At the 3-year mark, 26 out of 142 respondents (18%) disclosed injection-drug use in the previous month.

For all participants in the CO-STAR trial, the overall rate of reinfection at 3 years was 1.7 per 100 person-years (95% confidence interval, 0.8-3.0), which is lower than the rate reported in systematic reviews (3.8 per 100 person-years), according to the investigators.

In the extension analysis, the 3-year reinfection rate was lower still, at 1.2 per 100 person-years. The rate was slightly higher among people who reported injection-drug use in the previous month (1.9 per 100 person-years), and slightly lower among those who did not report injection-drug use in the prior month (0.5 per 100 person-years). More pronounced differences in reinfection were observed among participants who shared needles (6.4 per 100 person-years), versus those who didn’t share needles (1.5 per 100 person years).
 

Low reinfection rate may help facilitate removal of reimbursement restrictions

“Most of the reinfections in this study occurred within 24 weeks of completing treatment, suggesting that this is a key period for optimizing treatment of opioid use disorder and for providing access to needle and syringe programs that have documented benefits in preventing HCV transmission,” the investigators wrote.

This is one of the largest observational studies of its kind to date, bolstered by “excellent study retention” and a “well-characterized cohort,” with findings that should prompt real-world action, said Dr. Grebely, who is head of the hepatitis C and drug use group in the viral hepatitis clinical research program at the Kirby Institute, University of New South Wales, Sydney.

“Given that reinfection has often been cited ... by some providers as a reason for not offering treatment to people receiving OAT, the low reinfection rate in this study will be incredibly important for guiding practice and ensuring therapy is not withheld from this group,” Dr. Grebely said in an interview. “In terms of policy implications, these data may also help to facilitate the removal of reimbursement restrictions based on recent drug/alcohol use criteria that are in place among many payers in the United States.”
 

More research needed to determine optimal intervention strategies

Carl Latkin, PhD, professor and vice chair of the department of health, behavior, and society at Johns Hopkins University, Baltimore, called the present publication a “great article and well-done study with long-term follow-up.”

Dr. Latkin, who investigates biobehavioral interventions for disadvantaged communities, said the reported rate of reinfection is “very low among a group of current and former injectors.”

Affirming Dr. Grebely’s call for supportive practices by physicians and payers, Dr. Latkin said: “The study highlights the importance of improving access to medication for opioid use disorder. This level of treatment adherence in this group is much higher than for many other medications. Given these data, it would be difficult for payers to have a rational reason for blanket restrictions for HCV treatment among people who use drugs.”

Dr. Latkin explained that “it isn’t simply injection drug use per se” that drives HCV reinfection; instead, he cited social factors, such as lack of housing, as well as withdrawal symptoms, especially among those without access to medications for opioid use disorder (MOUD).

Dr. Latkin and Grebely also agreed that more research is needed to determine optimal intervention strategies.

Dr. Grebely called for one to enhance HCV testing and linkage to care, a topic he covered in a recent review article (Lancet Gastroenterol Hepatol. 2022 May;7[5]:426-45.).

Dr. Latkin said that, while it’s clear that “syringe services programs, accessible HCV treatment, and MOUD are needed,” it is unclear how much coverage is necessary for a given population.

Findings support critical nature of needle and syringe exchange programs

Sarah M. Kattakuzhy, MD, an associate professor in the division of clinical care & research at the Institute of Human Virology, University of Maryland, Baltimore, agreed that the findings “support the critical nature of needle and syringe exchange programs.”

“As most cities in the United States fall well below the high coverage needle and syringe program threshold required to maximally prevent disease transmission, the study serves as a push toward an evidence-based harm reduction policy,” she said.

Dr. Kattakuzhy he added that the study “supports the need to longitudinally engage individuals after HCV treatment to monitor reinfection risk behaviors and test for reinfection,” she continued.

When it came to translating all the data to populations in the United States, she offered a more guarded view.

“Critically, the study population included only individuals who were engaged with OAT and adherent for 3 or more months, selecting to a population of individuals with high adherence and engagement in care,” Dr. Kattakuzhy said in an interview. “As such, the study findings are not applicable to other cross sections of the drug-using community, including individuals not engaged in OAT, and cohorts with higher rates of ongoing injection drug use. Furthermore, there are known genetic impacts on spontaneous clearance, and emerging data on the immunology of reinfection.

“Studies with a focus on less engaged, higher-risk, and minority populations with active drug use are required to answer the remaining questions in HCV reinfection,” she said.

The study was supported by Merck, the Australian Government Department of Health, and the Australian National Health and Medical Research Council. Dr. Grebely disclosed receiving funding from Cepheid, the manufacturer of the Xpert HCV assay. The other investigators disclosed additional relationships with Gilead, AbbVie, Cepheid, and others. Dr. Latkin and Dr. Kattakuzhy disclosed no relevant conflicts of interest.

Reinfection rates are low after treating hepatitis C virus in people taking opioid agonist therapy (OAT), even among those who still inject drugs, according to a new study.

The findings, which are based on prospective data from 13 countries, including the United States, and were published in Annals of Internal Medicine (2022 Aug 8. doi: 10.7326/M21-4119), should encourage physicians to treat HCV in people with a history of injection drug use, said lead author Jason Grebely, PhD. They should also pressure payers to lift reimbursement restrictions on the same population.

“Direct-acting antiviral medications for HCV infection are safe and effective among people receiving OAT and people with recent injecting-drug use,” the investigators wrote. “Concerns remain, however, that HCV reinfection may reduce the benefits of cure among people who inject drugs and compromise HCV elimination efforts.”

They explored these concerns through a 3-year extension of the phase 3 CO-STAR trial that evaluated elbasvir and grazoprevir in people consistently taking OAT. Participants in the CO-STAR trial, which had a 96% sustained virologic response rate among those who completed therapy, could elect to participate in the present study, offering a prospective look at long-term reinfection.

Out of 296 participants in the CO-STAR trial, 286 were evaluable for reinfection and 199 enrolled in the present extension. The majority were White (79.4%) and male (75.9%), with most taking methadone (79%), followed by buprenorphine (20%). At 6 months, 40 out of 191 respondents (21%) reported injection-drug use in the previous month. At the 3-year mark, 26 out of 142 respondents (18%) disclosed injection-drug use in the previous month.

For all participants in the CO-STAR trial, the overall rate of reinfection at 3 years was 1.7 per 100 person-years (95% confidence interval, 0.8-3.0), which is lower than the rate reported in systematic reviews (3.8 per 100 person-years), according to the investigators.

In the extension analysis, the 3-year reinfection rate was lower still, at 1.2 per 100 person-years. The rate was slightly higher among people who reported injection-drug use in the previous month (1.9 per 100 person-years), and slightly lower among those who did not report injection-drug use in the prior month (0.5 per 100 person-years). More pronounced differences in reinfection were observed among participants who shared needles (6.4 per 100 person-years), versus those who didn’t share needles (1.5 per 100 person years).
 

Low reinfection rate may help facilitate removal of reimbursement restrictions

“Most of the reinfections in this study occurred within 24 weeks of completing treatment, suggesting that this is a key period for optimizing treatment of opioid use disorder and for providing access to needle and syringe programs that have documented benefits in preventing HCV transmission,” the investigators wrote.

This is one of the largest observational studies of its kind to date, bolstered by “excellent study retention” and a “well-characterized cohort,” with findings that should prompt real-world action, said Dr. Grebely, who is head of the hepatitis C and drug use group in the viral hepatitis clinical research program at the Kirby Institute, University of New South Wales, Sydney.

“Given that reinfection has often been cited ... by some providers as a reason for not offering treatment to people receiving OAT, the low reinfection rate in this study will be incredibly important for guiding practice and ensuring therapy is not withheld from this group,” Dr. Grebely said in an interview. “In terms of policy implications, these data may also help to facilitate the removal of reimbursement restrictions based on recent drug/alcohol use criteria that are in place among many payers in the United States.”
 

More research needed to determine optimal intervention strategies

Carl Latkin, PhD, professor and vice chair of the department of health, behavior, and society at Johns Hopkins University, Baltimore, called the present publication a “great article and well-done study with long-term follow-up.”

Dr. Latkin, who investigates biobehavioral interventions for disadvantaged communities, said the reported rate of reinfection is “very low among a group of current and former injectors.”

Affirming Dr. Grebely’s call for supportive practices by physicians and payers, Dr. Latkin said: “The study highlights the importance of improving access to medication for opioid use disorder. This level of treatment adherence in this group is much higher than for many other medications. Given these data, it would be difficult for payers to have a rational reason for blanket restrictions for HCV treatment among people who use drugs.”

Dr. Latkin explained that “it isn’t simply injection drug use per se” that drives HCV reinfection; instead, he cited social factors, such as lack of housing, as well as withdrawal symptoms, especially among those without access to medications for opioid use disorder (MOUD).

Dr. Latkin and Grebely also agreed that more research is needed to determine optimal intervention strategies.

Dr. Grebely called for one to enhance HCV testing and linkage to care, a topic he covered in a recent review article (Lancet Gastroenterol Hepatol. 2022 May;7[5]:426-45.).

Dr. Latkin said that, while it’s clear that “syringe services programs, accessible HCV treatment, and MOUD are needed,” it is unclear how much coverage is necessary for a given population.

Findings support critical nature of needle and syringe exchange programs

Sarah M. Kattakuzhy, MD, an associate professor in the division of clinical care & research at the Institute of Human Virology, University of Maryland, Baltimore, agreed that the findings “support the critical nature of needle and syringe exchange programs.”

“As most cities in the United States fall well below the high coverage needle and syringe program threshold required to maximally prevent disease transmission, the study serves as a push toward an evidence-based harm reduction policy,” she said.

Dr. Kattakuzhy he added that the study “supports the need to longitudinally engage individuals after HCV treatment to monitor reinfection risk behaviors and test for reinfection,” she continued.

When it came to translating all the data to populations in the United States, she offered a more guarded view.

“Critically, the study population included only individuals who were engaged with OAT and adherent for 3 or more months, selecting to a population of individuals with high adherence and engagement in care,” Dr. Kattakuzhy said in an interview. “As such, the study findings are not applicable to other cross sections of the drug-using community, including individuals not engaged in OAT, and cohorts with higher rates of ongoing injection drug use. Furthermore, there are known genetic impacts on spontaneous clearance, and emerging data on the immunology of reinfection.

“Studies with a focus on less engaged, higher-risk, and minority populations with active drug use are required to answer the remaining questions in HCV reinfection,” she said.

The study was supported by Merck, the Australian Government Department of Health, and the Australian National Health and Medical Research Council. Dr. Grebely disclosed receiving funding from Cepheid, the manufacturer of the Xpert HCV assay. The other investigators disclosed additional relationships with Gilead, AbbVie, Cepheid, and others. Dr. Latkin and Dr. Kattakuzhy disclosed no relevant conflicts of interest.

Reinfection rates are low after treating hepatitis C virus in people taking opioid agonist therapy (OAT), even among those who still inject drugs, according to a new study.

The findings, which are based on prospective data from 13 countries, including the United States, and were published in Annals of Internal Medicine (2022 Aug 8. doi: 10.7326/M21-4119), should encourage physicians to treat HCV in people with a history of injection drug use, said lead author Jason Grebely, PhD. They should also pressure payers to lift reimbursement restrictions on the same population.

“Direct-acting antiviral medications for HCV infection are safe and effective among people receiving OAT and people with recent injecting-drug use,” the investigators wrote. “Concerns remain, however, that HCV reinfection may reduce the benefits of cure among people who inject drugs and compromise HCV elimination efforts.”

They explored these concerns through a 3-year extension of the phase 3 CO-STAR trial that evaluated elbasvir and grazoprevir in people consistently taking OAT. Participants in the CO-STAR trial, which had a 96% sustained virologic response rate among those who completed therapy, could elect to participate in the present study, offering a prospective look at long-term reinfection.

Out of 296 participants in the CO-STAR trial, 286 were evaluable for reinfection and 199 enrolled in the present extension. The majority were White (79.4%) and male (75.9%), with most taking methadone (79%), followed by buprenorphine (20%). At 6 months, 40 out of 191 respondents (21%) reported injection-drug use in the previous month. At the 3-year mark, 26 out of 142 respondents (18%) disclosed injection-drug use in the previous month.

For all participants in the CO-STAR trial, the overall rate of reinfection at 3 years was 1.7 per 100 person-years (95% confidence interval, 0.8-3.0), which is lower than the rate reported in systematic reviews (3.8 per 100 person-years), according to the investigators.

In the extension analysis, the 3-year reinfection rate was lower still, at 1.2 per 100 person-years. The rate was slightly higher among people who reported injection-drug use in the previous month (1.9 per 100 person-years), and slightly lower among those who did not report injection-drug use in the prior month (0.5 per 100 person-years). More pronounced differences in reinfection were observed among participants who shared needles (6.4 per 100 person-years), versus those who didn’t share needles (1.5 per 100 person years).
 

Low reinfection rate may help facilitate removal of reimbursement restrictions

“Most of the reinfections in this study occurred within 24 weeks of completing treatment, suggesting that this is a key period for optimizing treatment of opioid use disorder and for providing access to needle and syringe programs that have documented benefits in preventing HCV transmission,” the investigators wrote.

This is one of the largest observational studies of its kind to date, bolstered by “excellent study retention” and a “well-characterized cohort,” with findings that should prompt real-world action, said Dr. Grebely, who is head of the hepatitis C and drug use group in the viral hepatitis clinical research program at the Kirby Institute, University of New South Wales, Sydney.

“Given that reinfection has often been cited ... by some providers as a reason for not offering treatment to people receiving OAT, the low reinfection rate in this study will be incredibly important for guiding practice and ensuring therapy is not withheld from this group,” Dr. Grebely said in an interview. “In terms of policy implications, these data may also help to facilitate the removal of reimbursement restrictions based on recent drug/alcohol use criteria that are in place among many payers in the United States.”
 

More research needed to determine optimal intervention strategies

Carl Latkin, PhD, professor and vice chair of the department of health, behavior, and society at Johns Hopkins University, Baltimore, called the present publication a “great article and well-done study with long-term follow-up.”

Dr. Latkin, who investigates biobehavioral interventions for disadvantaged communities, said the reported rate of reinfection is “very low among a group of current and former injectors.”

Affirming Dr. Grebely’s call for supportive practices by physicians and payers, Dr. Latkin said: “The study highlights the importance of improving access to medication for opioid use disorder. This level of treatment adherence in this group is much higher than for many other medications. Given these data, it would be difficult for payers to have a rational reason for blanket restrictions for HCV treatment among people who use drugs.”

Dr. Latkin explained that “it isn’t simply injection drug use per se” that drives HCV reinfection; instead, he cited social factors, such as lack of housing, as well as withdrawal symptoms, especially among those without access to medications for opioid use disorder (MOUD).

Dr. Latkin and Grebely also agreed that more research is needed to determine optimal intervention strategies.

Dr. Grebely called for one to enhance HCV testing and linkage to care, a topic he covered in a recent review article (Lancet Gastroenterol Hepatol. 2022 May;7[5]:426-45.).

Dr. Latkin said that, while it’s clear that “syringe services programs, accessible HCV treatment, and MOUD are needed,” it is unclear how much coverage is necessary for a given population.

Findings support critical nature of needle and syringe exchange programs

Sarah M. Kattakuzhy, MD, an associate professor in the division of clinical care & research at the Institute of Human Virology, University of Maryland, Baltimore, agreed that the findings “support the critical nature of needle and syringe exchange programs.”

“As most cities in the United States fall well below the high coverage needle and syringe program threshold required to maximally prevent disease transmission, the study serves as a push toward an evidence-based harm reduction policy,” she said.

Dr. Kattakuzhy he added that the study “supports the need to longitudinally engage individuals after HCV treatment to monitor reinfection risk behaviors and test for reinfection,” she continued.

When it came to translating all the data to populations in the United States, she offered a more guarded view.

“Critically, the study population included only individuals who were engaged with OAT and adherent for 3 or more months, selecting to a population of individuals with high adherence and engagement in care,” Dr. Kattakuzhy said in an interview. “As such, the study findings are not applicable to other cross sections of the drug-using community, including individuals not engaged in OAT, and cohorts with higher rates of ongoing injection drug use. Furthermore, there are known genetic impacts on spontaneous clearance, and emerging data on the immunology of reinfection.

“Studies with a focus on less engaged, higher-risk, and minority populations with active drug use are required to answer the remaining questions in HCV reinfection,” she said.

The study was supported by Merck, the Australian Government Department of Health, and the Australian National Health and Medical Research Council. Dr. Grebely disclosed receiving funding from Cepheid, the manufacturer of the Xpert HCV assay. The other investigators disclosed additional relationships with Gilead, AbbVie, Cepheid, and others. Dr. Latkin and Dr. Kattakuzhy disclosed no relevant conflicts of interest.

Hepatocellular carcinoma risk declines after direct-acting antiviral treatment but remains high enough to justify screening for at least 7 years after hepatitis C cure, according to a new report.

Among patients with cirrhosis and fibrosis-4 (FIB-4) scores of 3.25 or higher, the incidence of hepatocellular carcinoma appeared to decline progressively each year up to 7 years after a sustained virologic response, although the rate remained above the 1% per year threshold that warrants screening.

“The majority of patients with hepatitis C have been treated and cured in the United States,” George Ioannou, MD, the senior study author and professor of medicine at the University of Washington, Seattle, said in an interview. “After hepatitis C eradication, these patients generally do very well from the liver standpoint, but the one thing they have to continue worrying about is development of liver cancer.”

Dr. Ioannou, who is also director of hepatology at the Veterans Affairs Puget Sound Health Care System, Seattle, noted that patients may be screened “indefinitely,” which places a burden on the patients and the health care system.

“We are still not sure to what extent the risk of liver cancer declines after hepatitis C eradication as more and more time accrues,” he said. “In those who had cirrhosis of the liver prior to hepatitis C cure, we are still not certain if there is a time point after hepatitis C cure when we can tell a patient that their risk of liver cancer is now very low and we no longer need to keep screening for liver cancer.”

The study was published online in Gastroenterology.
 

Risk calculations

In a previous study, Dr. Ioannou and colleagues found that hepatocellular carcinoma risk declined during the first 4 years of follow-up after a sustained virologic response from direct-acting antiviral medications. But the follow-up time wasn’t long enough to determine whether the cancer risk continues to decline to levels low enough to forgo screening.

In this study, Dr. Ioannou and colleagues extended the follow-up to 7 years. They were curious to see whether the cancer risk declines enough to drop the screening requirement, particularly as related to pretreatment cirrhosis and fibrosis-4 scores.

The research team analyzed electronic health records from the Veterans Affairs Corporate Data Warehouse, a national repository of Veterans Health Administration records developed specifically for research purposes.

The researchers included 29,033 patients in the Veterans Affairs health care system who had been infected with hepatitis C virus and were treated with direct-acting antivirals between January 2013 and December 2015. The patients had a sustained virologic response, which is defined as a viral load below the lower limit of detection at least 12 weeks after therapy completion.

The patients were followed for incident hepatocellular carcinoma until December 2021. The researchers then calculated the annual incidence during each year of follow-up after treatment.

About 96.6% of patients were men, and 52.2% were non-Hispanic White persons. The average age was 61 years. The most common conditions were alcohol use disorder (43.7%), substance use disorder (37.7%), and diabetes (28.9%).

Among the 7,533 patients with pretreatment cirrhosis, 948 (12.6%) developed hepatocellular carcinoma during a mean follow-up period of 4.9 years. Among patients with FIB-4 scores of 3.25 or higher, the annual incidence decreased from 3.8% in the first year to 1.4% in the seventh year but remained substantial up to 7 years after sustained virologic response. Among patients with both cirrhosis and a high FIB-4 score, the annual rate ranged from 0.7% to 1.3% and didn’t change significantly over time.

Among the 21,500 patients without pretreatment cirrhosis, 541 (or 2.5%) developed hepatocellular carcinoma during a mean follow-up period of 5.4 years. The incidence rate was significantly higher for patients with high FIB-4 scores. Among patients without cirrhosis but who had a high FIB-4 score, the annual rate remained stable but substantial (from 0.8% to 1.3%) for up to 7 years.

In a subgroup analysis that examined incidence according to changes in FIB-4 scores before and after treatment, the rate remained high among those with cirrhosis regardless of a score change. Among those without cirrhosis but who had a persistently high FIB-4 score, the incidence was high. In those without cirrhosis whose FIB-4 score dropped, the incidence was lower.

“The study demonstrates a clear decline in the risk of liver cancer over time after hepatitis C cure in the highest-risk group. This is very positive news for patients,” Dr. Ioannou said. “However, even with that decline in risk up to 7 years after eradication of hepatitis C with direct-acting antivirals, the risk is still high enough to warrant liver cancer screening.”
 

Future concerns

For a follow-up study, Dr. Ioannou and colleagues plan to adjust their analyses for other factors that influence the risk of liver cancer, such as age and nonalcoholic fatty liver disease. Other studies could increase the follow-up time beyond 7 years and assess how changes in diabetes, weight management, and alcohol use might affect liver cancer risk.

“With the availability of safe and effective direct-acting antiviral treatments, a growing number of patients have been or will be treated and cured of their hepatitis C infection,” Nicole Kim, MD, one of the lead authors and a transplant hepatology fellow at the University of Washington, Seattle, told this news organization.

“It is therefore important for us to develop a better understanding of how liver cancer risk might change after treatment, so we can improve the care we provide to this patient population,” she said.

The results require validation in nonveteran cohorts, the study authors write, as well as follow-up after the COVID-19 pandemic, when screening and diagnostic practices were restricted.

“Several studies have demonstrated that HCC [hepatocellular carcinoma] surveillance is underused in clinical practice, including in patients after [sustained virologic response],” Amit Singal, MD, clinical chief of hepatology and medical director of the liver tumor program at the University of Texas Southwestern Medical Center, told this news organization.

Dr. Singal, who wasn’t involved with this study, is evaluating several intervention strategies to increase surveillance utilization. His research group is conducting a multicenter randomized trial using mailed outreach invitations and is also evaluating a biomarker, PLSec-AFP, to identify patients with the highest risks who may warrant more intensive surveillance strategies.

“We have recently validated the performance of this biomarker in a large cohort of patients with cirrhosis, including some with cured hepatitis C virus infection,” he said.

The study was funded by an NIH/NCI grant and a VA CSR under Dr. Ioannou. The manuscript writing was supported by the NIH under Dr. Kim and co-author Philip Vutien. Dr. Singal has disclosed no relevant financial relationships.

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

Hepatocellular carcinoma risk declines after direct-acting antiviral treatment but remains high enough to justify screening for at least 7 years after hepatitis C cure, according to a new report.

Among patients with cirrhosis and fibrosis-4 (FIB-4) scores of 3.25 or higher, the incidence of hepatocellular carcinoma appeared to decline progressively each year up to 7 years after a sustained virologic response, although the rate remained above the 1% per year threshold that warrants screening.

“The majority of patients with hepatitis C have been treated and cured in the United States,” George Ioannou, MD, the senior study author and professor of medicine at the University of Washington, Seattle, said in an interview. “After hepatitis C eradication, these patients generally do very well from the liver standpoint, but the one thing they have to continue worrying about is development of liver cancer.”

Dr. Ioannou, who is also director of hepatology at the Veterans Affairs Puget Sound Health Care System, Seattle, noted that patients may be screened “indefinitely,” which places a burden on the patients and the health care system.

“We are still not sure to what extent the risk of liver cancer declines after hepatitis C eradication as more and more time accrues,” he said. “In those who had cirrhosis of the liver prior to hepatitis C cure, we are still not certain if there is a time point after hepatitis C cure when we can tell a patient that their risk of liver cancer is now very low and we no longer need to keep screening for liver cancer.”

The study was published online in Gastroenterology.
 

Risk calculations

In a previous study, Dr. Ioannou and colleagues found that hepatocellular carcinoma risk declined during the first 4 years of follow-up after a sustained virologic response from direct-acting antiviral medications. But the follow-up time wasn’t long enough to determine whether the cancer risk continues to decline to levels low enough to forgo screening.

In this study, Dr. Ioannou and colleagues extended the follow-up to 7 years. They were curious to see whether the cancer risk declines enough to drop the screening requirement, particularly as related to pretreatment cirrhosis and fibrosis-4 scores.

The research team analyzed electronic health records from the Veterans Affairs Corporate Data Warehouse, a national repository of Veterans Health Administration records developed specifically for research purposes.

The researchers included 29,033 patients in the Veterans Affairs health care system who had been infected with hepatitis C virus and were treated with direct-acting antivirals between January 2013 and December 2015. The patients had a sustained virologic response, which is defined as a viral load below the lower limit of detection at least 12 weeks after therapy completion.

The patients were followed for incident hepatocellular carcinoma until December 2021. The researchers then calculated the annual incidence during each year of follow-up after treatment.

About 96.6% of patients were men, and 52.2% were non-Hispanic White persons. The average age was 61 years. The most common conditions were alcohol use disorder (43.7%), substance use disorder (37.7%), and diabetes (28.9%).

Among the 7,533 patients with pretreatment cirrhosis, 948 (12.6%) developed hepatocellular carcinoma during a mean follow-up period of 4.9 years. Among patients with FIB-4 scores of 3.25 or higher, the annual incidence decreased from 3.8% in the first year to 1.4% in the seventh year but remained substantial up to 7 years after sustained virologic response. Among patients with both cirrhosis and a high FIB-4 score, the annual rate ranged from 0.7% to 1.3% and didn’t change significantly over time.

Among the 21,500 patients without pretreatment cirrhosis, 541 (or 2.5%) developed hepatocellular carcinoma during a mean follow-up period of 5.4 years. The incidence rate was significantly higher for patients with high FIB-4 scores. Among patients without cirrhosis but who had a high FIB-4 score, the annual rate remained stable but substantial (from 0.8% to 1.3%) for up to 7 years.

In a subgroup analysis that examined incidence according to changes in FIB-4 scores before and after treatment, the rate remained high among those with cirrhosis regardless of a score change. Among those without cirrhosis but who had a persistently high FIB-4 score, the incidence was high. In those without cirrhosis whose FIB-4 score dropped, the incidence was lower.

“The study demonstrates a clear decline in the risk of liver cancer over time after hepatitis C cure in the highest-risk group. This is very positive news for patients,” Dr. Ioannou said. “However, even with that decline in risk up to 7 years after eradication of hepatitis C with direct-acting antivirals, the risk is still high enough to warrant liver cancer screening.”
 

Future concerns

For a follow-up study, Dr. Ioannou and colleagues plan to adjust their analyses for other factors that influence the risk of liver cancer, such as age and nonalcoholic fatty liver disease. Other studies could increase the follow-up time beyond 7 years and assess how changes in diabetes, weight management, and alcohol use might affect liver cancer risk.

“With the availability of safe and effective direct-acting antiviral treatments, a growing number of patients have been or will be treated and cured of their hepatitis C infection,” Nicole Kim, MD, one of the lead authors and a transplant hepatology fellow at the University of Washington, Seattle, told this news organization.

“It is therefore important for us to develop a better understanding of how liver cancer risk might change after treatment, so we can improve the care we provide to this patient population,” she said.

The results require validation in nonveteran cohorts, the study authors write, as well as follow-up after the COVID-19 pandemic, when screening and diagnostic practices were restricted.

“Several studies have demonstrated that HCC [hepatocellular carcinoma] surveillance is underused in clinical practice, including in patients after [sustained virologic response],” Amit Singal, MD, clinical chief of hepatology and medical director of the liver tumor program at the University of Texas Southwestern Medical Center, told this news organization.

Dr. Singal, who wasn’t involved with this study, is evaluating several intervention strategies to increase surveillance utilization. His research group is conducting a multicenter randomized trial using mailed outreach invitations and is also evaluating a biomarker, PLSec-AFP, to identify patients with the highest risks who may warrant more intensive surveillance strategies.

“We have recently validated the performance of this biomarker in a large cohort of patients with cirrhosis, including some with cured hepatitis C virus infection,” he said.

The study was funded by an NIH/NCI grant and a VA CSR under Dr. Ioannou. The manuscript writing was supported by the NIH under Dr. Kim and co-author Philip Vutien. Dr. Singal has disclosed no relevant financial relationships.

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

Hepatocellular carcinoma risk declines after direct-acting antiviral treatment but remains high enough to justify screening for at least 7 years after hepatitis C cure, according to a new report.

Among patients with cirrhosis and fibrosis-4 (FIB-4) scores of 3.25 or higher, the incidence of hepatocellular carcinoma appeared to decline progressively each year up to 7 years after a sustained virologic response, although the rate remained above the 1% per year threshold that warrants screening.

“The majority of patients with hepatitis C have been treated and cured in the United States,” George Ioannou, MD, the senior study author and professor of medicine at the University of Washington, Seattle, said in an interview. “After hepatitis C eradication, these patients generally do very well from the liver standpoint, but the one thing they have to continue worrying about is development of liver cancer.”

Dr. Ioannou, who is also director of hepatology at the Veterans Affairs Puget Sound Health Care System, Seattle, noted that patients may be screened “indefinitely,” which places a burden on the patients and the health care system.

“We are still not sure to what extent the risk of liver cancer declines after hepatitis C eradication as more and more time accrues,” he said. “In those who had cirrhosis of the liver prior to hepatitis C cure, we are still not certain if there is a time point after hepatitis C cure when we can tell a patient that their risk of liver cancer is now very low and we no longer need to keep screening for liver cancer.”

The study was published online in Gastroenterology.
 

Risk calculations

In a previous study, Dr. Ioannou and colleagues found that hepatocellular carcinoma risk declined during the first 4 years of follow-up after a sustained virologic response from direct-acting antiviral medications. But the follow-up time wasn’t long enough to determine whether the cancer risk continues to decline to levels low enough to forgo screening.

In this study, Dr. Ioannou and colleagues extended the follow-up to 7 years. They were curious to see whether the cancer risk declines enough to drop the screening requirement, particularly as related to pretreatment cirrhosis and fibrosis-4 scores.

The research team analyzed electronic health records from the Veterans Affairs Corporate Data Warehouse, a national repository of Veterans Health Administration records developed specifically for research purposes.

The researchers included 29,033 patients in the Veterans Affairs health care system who had been infected with hepatitis C virus and were treated with direct-acting antivirals between January 2013 and December 2015. The patients had a sustained virologic response, which is defined as a viral load below the lower limit of detection at least 12 weeks after therapy completion.

The patients were followed for incident hepatocellular carcinoma until December 2021. The researchers then calculated the annual incidence during each year of follow-up after treatment.

About 96.6% of patients were men, and 52.2% were non-Hispanic White persons. The average age was 61 years. The most common conditions were alcohol use disorder (43.7%), substance use disorder (37.7%), and diabetes (28.9%).

Among the 7,533 patients with pretreatment cirrhosis, 948 (12.6%) developed hepatocellular carcinoma during a mean follow-up period of 4.9 years. Among patients with FIB-4 scores of 3.25 or higher, the annual incidence decreased from 3.8% in the first year to 1.4% in the seventh year but remained substantial up to 7 years after sustained virologic response. Among patients with both cirrhosis and a high FIB-4 score, the annual rate ranged from 0.7% to 1.3% and didn’t change significantly over time.

Among the 21,500 patients without pretreatment cirrhosis, 541 (or 2.5%) developed hepatocellular carcinoma during a mean follow-up period of 5.4 years. The incidence rate was significantly higher for patients with high FIB-4 scores. Among patients without cirrhosis but who had a high FIB-4 score, the annual rate remained stable but substantial (from 0.8% to 1.3%) for up to 7 years.

In a subgroup analysis that examined incidence according to changes in FIB-4 scores before and after treatment, the rate remained high among those with cirrhosis regardless of a score change. Among those without cirrhosis but who had a persistently high FIB-4 score, the incidence was high. In those without cirrhosis whose FIB-4 score dropped, the incidence was lower.

“The study demonstrates a clear decline in the risk of liver cancer over time after hepatitis C cure in the highest-risk group. This is very positive news for patients,” Dr. Ioannou said. “However, even with that decline in risk up to 7 years after eradication of hepatitis C with direct-acting antivirals, the risk is still high enough to warrant liver cancer screening.”
 

Future concerns

For a follow-up study, Dr. Ioannou and colleagues plan to adjust their analyses for other factors that influence the risk of liver cancer, such as age and nonalcoholic fatty liver disease. Other studies could increase the follow-up time beyond 7 years and assess how changes in diabetes, weight management, and alcohol use might affect liver cancer risk.

“With the availability of safe and effective direct-acting antiviral treatments, a growing number of patients have been or will be treated and cured of their hepatitis C infection,” Nicole Kim, MD, one of the lead authors and a transplant hepatology fellow at the University of Washington, Seattle, told this news organization.

“It is therefore important for us to develop a better understanding of how liver cancer risk might change after treatment, so we can improve the care we provide to this patient population,” she said.

The results require validation in nonveteran cohorts, the study authors write, as well as follow-up after the COVID-19 pandemic, when screening and diagnostic practices were restricted.

“Several studies have demonstrated that HCC [hepatocellular carcinoma] surveillance is underused in clinical practice, including in patients after [sustained virologic response],” Amit Singal, MD, clinical chief of hepatology and medical director of the liver tumor program at the University of Texas Southwestern Medical Center, told this news organization.

Dr. Singal, who wasn’t involved with this study, is evaluating several intervention strategies to increase surveillance utilization. His research group is conducting a multicenter randomized trial using mailed outreach invitations and is also evaluating a biomarker, PLSec-AFP, to identify patients with the highest risks who may warrant more intensive surveillance strategies.

“We have recently validated the performance of this biomarker in a large cohort of patients with cirrhosis, including some with cured hepatitis C virus infection,” he said.

The study was funded by an NIH/NCI grant and a VA CSR under Dr. Ioannou. The manuscript writing was supported by the NIH under Dr. Kim and co-author Philip Vutien. Dr. Singal has disclosed no relevant financial relationships.

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

While two new studies reiterate a possible relationship between adenovirus 41 and acute hepatitis of unknown cause in children, whether these infections are significant or merely bystanders remains unclear.

In both studies – one conducted in Alabama and the other conducted in the United Kingdom – researchers found that 90% of children with acute hepatitis of unknown cause tested positive for adenovirus 41. The virus subtype is not an uncommon infection, but it usually causes gastroenteritis in children.

“Across the world, adenovirus continues to be a common signal” in these pediatric hepatitis cases, said Helena Gutierrez, MD, the medical director of the Pediatric Liver Transplant Program at the University of Alabama at Birmingham, in an interview. She led one of the studies. More data are necessary to understand what role this virus may play in these cases, she said.

In November, the Alabama Department of Public Health and the U.S. Centers for Disease Control and Prevention began investigating a cluster of severe pediatric hepatitis cases at the Children’s of Alabama hospital in Birmingham. These children also tested positive for adenovirus. In April, the United Kingdom announced they were investigating similar cases, and the CDC expanded their search nationally. As of July 8, 1,010 cases in 35 countries have been reported to the World Health Organization. There are 263 confirmed cases in the United Kingdom and 332 cases under investigation by the CDC in the United States, according to the most recent counts.

The two studies, both published in the New England Journal of Medicine, provide additional clinical data on a number of these mysterious hepatitis cases. Dr. Gutierrez’s study looked at nine children admitted for hepatitis of unknown origin between October 1 and February 28. Patients had a median age of 2 years 11 months and two required liver transplants, and there were no deaths.

Eight out of nine patients (89%) tested positive for adenovirus, and all five of the samples that were of sufficient quality for gene sequencing tested positive for adenovirus 41. None of the six liver biopsies performed found signs of adenovirus infection, but the liver tissue samples of three patients tested positive for adenovirus via PCR.

The second study involved 44 children referred to a liver transplantation center in the United Kingdom between January 1 and April 11, 2022. The median age for patients was 4 years. Six children required liver transplants, and there were no deaths. Of the 30 patients who underwent molecular adenovirus testing, 27 (90%) were positive for adenovirus 41. Liver samples of nine children (3 from biopsies and 6 from explanted livers) all tested negative for adenovirus antibodies.

In both studies, however, the median adenovirus viral load of patients needing a transplant was much higher than the viral loads in children who did not require liver transplants.

Although most of the clinical features and test results of these cases suggest that adenovirus may be involved, the negative results in histology are “intriguing,” Chayarani Kelgeri, MD, a consultant pediatric hepatologist at the Birmingham Women’s and Children’s Hospital, U.K., said in an email. She is the lead author of the U.K. study. “Whether this is because the liver injury we see is an aftermath of the viral infection, the mechanism of injury is immune mediated, and if other cofactors are involved is being explored,” she added. “Further investigations being undertaken by UK Health Security Agency will add to our understanding of this illness.”

Although there is a high adenovirus positivity rate amongst these cases, there is not enough evidence yet to say adenovirus 41 is a new cause of pediatric hepatitis in previously healthy children, said Saul Karpen, MD, PhD, the division chief of pediatric gastroenterology, hepatology, and nutrition at Emory University School of Medicine, Atlanta. He wrote an editorial accompanying the two NEJM studies.

The CDC has not yet found an increase in pediatric hepatitis cases, according to a recent analysis, though the United Kingdom has found an uptick in cases this year, he told this news organization. Also, the cases highlighted in both articles showed no histological evidence of adenovirus in liver biopsies. “That’s completely opposite of what we generally see in adenoviral hepatitis that can be quite severe,” he said, adding that in general, there are detectable viral particles and antigens in affected livers.

“These two important reports indicate to those inside and outside the field of pediatric hepatology that registries and clinical studies of acute hepatitis in children are sorely needed,” Dr. Karpen writes in the editorial; “It is likely that with greater attention to collecting data on cases and biospecimens from children with acute hepatitis, we will be able to determine whether this one virus, human adenovirus 41, is of relevance to this important and serious condition in children.”

Dr. Gutierrez, Dr. Kelgeri, and Dr. Karpen report no relevant financial relationships.

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

While two new studies reiterate a possible relationship between adenovirus 41 and acute hepatitis of unknown cause in children, whether these infections are significant or merely bystanders remains unclear.

In both studies – one conducted in Alabama and the other conducted in the United Kingdom – researchers found that 90% of children with acute hepatitis of unknown cause tested positive for adenovirus 41. The virus subtype is not an uncommon infection, but it usually causes gastroenteritis in children.

“Across the world, adenovirus continues to be a common signal” in these pediatric hepatitis cases, said Helena Gutierrez, MD, the medical director of the Pediatric Liver Transplant Program at the University of Alabama at Birmingham, in an interview. She led one of the studies. More data are necessary to understand what role this virus may play in these cases, she said.

In November, the Alabama Department of Public Health and the U.S. Centers for Disease Control and Prevention began investigating a cluster of severe pediatric hepatitis cases at the Children’s of Alabama hospital in Birmingham. These children also tested positive for adenovirus. In April, the United Kingdom announced they were investigating similar cases, and the CDC expanded their search nationally. As of July 8, 1,010 cases in 35 countries have been reported to the World Health Organization. There are 263 confirmed cases in the United Kingdom and 332 cases under investigation by the CDC in the United States, according to the most recent counts.

The two studies, both published in the New England Journal of Medicine, provide additional clinical data on a number of these mysterious hepatitis cases. Dr. Gutierrez’s study looked at nine children admitted for hepatitis of unknown origin between October 1 and February 28. Patients had a median age of 2 years 11 months and two required liver transplants, and there were no deaths.

Eight out of nine patients (89%) tested positive for adenovirus, and all five of the samples that were of sufficient quality for gene sequencing tested positive for adenovirus 41. None of the six liver biopsies performed found signs of adenovirus infection, but the liver tissue samples of three patients tested positive for adenovirus via PCR.

The second study involved 44 children referred to a liver transplantation center in the United Kingdom between January 1 and April 11, 2022. The median age for patients was 4 years. Six children required liver transplants, and there were no deaths. Of the 30 patients who underwent molecular adenovirus testing, 27 (90%) were positive for adenovirus 41. Liver samples of nine children (3 from biopsies and 6 from explanted livers) all tested negative for adenovirus antibodies.

In both studies, however, the median adenovirus viral load of patients needing a transplant was much higher than the viral loads in children who did not require liver transplants.

Although most of the clinical features and test results of these cases suggest that adenovirus may be involved, the negative results in histology are “intriguing,” Chayarani Kelgeri, MD, a consultant pediatric hepatologist at the Birmingham Women’s and Children’s Hospital, U.K., said in an email. She is the lead author of the U.K. study. “Whether this is because the liver injury we see is an aftermath of the viral infection, the mechanism of injury is immune mediated, and if other cofactors are involved is being explored,” she added. “Further investigations being undertaken by UK Health Security Agency will add to our understanding of this illness.”

Although there is a high adenovirus positivity rate amongst these cases, there is not enough evidence yet to say adenovirus 41 is a new cause of pediatric hepatitis in previously healthy children, said Saul Karpen, MD, PhD, the division chief of pediatric gastroenterology, hepatology, and nutrition at Emory University School of Medicine, Atlanta. He wrote an editorial accompanying the two NEJM studies.

The CDC has not yet found an increase in pediatric hepatitis cases, according to a recent analysis, though the United Kingdom has found an uptick in cases this year, he told this news organization. Also, the cases highlighted in both articles showed no histological evidence of adenovirus in liver biopsies. “That’s completely opposite of what we generally see in adenoviral hepatitis that can be quite severe,” he said, adding that in general, there are detectable viral particles and antigens in affected livers.

“These two important reports indicate to those inside and outside the field of pediatric hepatology that registries and clinical studies of acute hepatitis in children are sorely needed,” Dr. Karpen writes in the editorial; “It is likely that with greater attention to collecting data on cases and biospecimens from children with acute hepatitis, we will be able to determine whether this one virus, human adenovirus 41, is of relevance to this important and serious condition in children.”

Dr. Gutierrez, Dr. Kelgeri, and Dr. Karpen report no relevant financial relationships.

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

While two new studies reiterate a possible relationship between adenovirus 41 and acute hepatitis of unknown cause in children, whether these infections are significant or merely bystanders remains unclear.

In both studies – one conducted in Alabama and the other conducted in the United Kingdom – researchers found that 90% of children with acute hepatitis of unknown cause tested positive for adenovirus 41. The virus subtype is not an uncommon infection, but it usually causes gastroenteritis in children.

“Across the world, adenovirus continues to be a common signal” in these pediatric hepatitis cases, said Helena Gutierrez, MD, the medical director of the Pediatric Liver Transplant Program at the University of Alabama at Birmingham, in an interview. She led one of the studies. More data are necessary to understand what role this virus may play in these cases, she said.

In November, the Alabama Department of Public Health and the U.S. Centers for Disease Control and Prevention began investigating a cluster of severe pediatric hepatitis cases at the Children’s of Alabama hospital in Birmingham. These children also tested positive for adenovirus. In April, the United Kingdom announced they were investigating similar cases, and the CDC expanded their search nationally. As of July 8, 1,010 cases in 35 countries have been reported to the World Health Organization. There are 263 confirmed cases in the United Kingdom and 332 cases under investigation by the CDC in the United States, according to the most recent counts.

The two studies, both published in the New England Journal of Medicine, provide additional clinical data on a number of these mysterious hepatitis cases. Dr. Gutierrez’s study looked at nine children admitted for hepatitis of unknown origin between October 1 and February 28. Patients had a median age of 2 years 11 months and two required liver transplants, and there were no deaths.

Eight out of nine patients (89%) tested positive for adenovirus, and all five of the samples that were of sufficient quality for gene sequencing tested positive for adenovirus 41. None of the six liver biopsies performed found signs of adenovirus infection, but the liver tissue samples of three patients tested positive for adenovirus via PCR.

The second study involved 44 children referred to a liver transplantation center in the United Kingdom between January 1 and April 11, 2022. The median age for patients was 4 years. Six children required liver transplants, and there were no deaths. Of the 30 patients who underwent molecular adenovirus testing, 27 (90%) were positive for adenovirus 41. Liver samples of nine children (3 from biopsies and 6 from explanted livers) all tested negative for adenovirus antibodies.

In both studies, however, the median adenovirus viral load of patients needing a transplant was much higher than the viral loads in children who did not require liver transplants.

Although most of the clinical features and test results of these cases suggest that adenovirus may be involved, the negative results in histology are “intriguing,” Chayarani Kelgeri, MD, a consultant pediatric hepatologist at the Birmingham Women’s and Children’s Hospital, U.K., said in an email. She is the lead author of the U.K. study. “Whether this is because the liver injury we see is an aftermath of the viral infection, the mechanism of injury is immune mediated, and if other cofactors are involved is being explored,” she added. “Further investigations being undertaken by UK Health Security Agency will add to our understanding of this illness.”

Although there is a high adenovirus positivity rate amongst these cases, there is not enough evidence yet to say adenovirus 41 is a new cause of pediatric hepatitis in previously healthy children, said Saul Karpen, MD, PhD, the division chief of pediatric gastroenterology, hepatology, and nutrition at Emory University School of Medicine, Atlanta. He wrote an editorial accompanying the two NEJM studies.

The CDC has not yet found an increase in pediatric hepatitis cases, according to a recent analysis, though the United Kingdom has found an uptick in cases this year, he told this news organization. Also, the cases highlighted in both articles showed no histological evidence of adenovirus in liver biopsies. “That’s completely opposite of what we generally see in adenoviral hepatitis that can be quite severe,” he said, adding that in general, there are detectable viral particles and antigens in affected livers.

“These two important reports indicate to those inside and outside the field of pediatric hepatology that registries and clinical studies of acute hepatitis in children are sorely needed,” Dr. Karpen writes in the editorial; “It is likely that with greater attention to collecting data on cases and biospecimens from children with acute hepatitis, we will be able to determine whether this one virus, human adenovirus 41, is of relevance to this important and serious condition in children.”

Dr. Gutierrez, Dr. Kelgeri, and Dr. Karpen report no relevant financial relationships.

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

A new study confirms the very high risk of hepatocellular carcinoma faced by patients with cirrhosis who have been cured of hepatitis C, a finding the researchers hope will encourage clinicians to communicate risk information to patients and encourage regular HCC screening.

On average, the predicted probability of HCC in cirrhosis patients was 410 times greater than the equivalent probability in the general population, the study team found.

“As the prospect of HCV elimination approaches, a key challenge to the clinical community is the management of those who are cured of HCV but have a residual risk of HCC,” Hamish Innes, PhD, with Public Health Scotland, Glasgow, and colleagues wrote.

“Central to this is ensuring that cured cirrhosis patients understand the risk of HCC and are provided with appropriate surveillance,” they added. 

“Most patients with cirrhosis do not adhere to HCC screening guidelines,” Nina Beri, MD, medical oncologist with New York University Perlmutter Cancer Center, who wasn’t involved in the study, said in an interview.

The “important” finding in this study “should be conveyed to patients, as this may help improve screening adherence rates,” Dr. Beri said.

The study was published online in the American Journal of Gastroenterology.
 

Findings may help promote screening uptake

Dr. Innes and colleagues compared the predicted probability of HCC in 1,803 Scottish adults (mean age, 50 years; 74% male) with cirrhosis and cured hepatitis C to the background risk in the general population of Scotland.

The mean predicted 3-year probability of HCC at the time of sustained viral response (SVR), determined using the aMAP prognostic model, was 3.64% (range, 0.012%-36.12%).

This contrasts with a 3-year HCC probability in the general population ranging from less than 0.0001% to 0.25% depending on demographics.

All patients with cirrhosis – even those at lowest risk – had a higher probability of HCC than the general population, but there was considerable heterogeneity from one patient to the next.

For example, the mean 3-year predicted probability was 18 times higher in the top quintile (9.8%) versus the lowest quintile (0.5%) of risk, the researchers found.

They could not identify a patient subgroup who exhibited a similar HCC risk profile to the general population, as was their hope going into the study.

Dr. Innes and colleagues have developed an online tool that allows clinicians to frame a patient›s 3-year HCC probability against the equivalent probability in the general population.

In the future, they said the scope of the tool could be extended by incorporating general population data from countries beyond Scotland.

“Our hope is that this tool will springboard patient-clinician discussions about HCC risk, and could mitigate low screening uptake,” Dr. Innes and colleagues wrote.
 

Curing HCV doesn’t eliminate risk

Commenting on the study, Nancy Reau, MD, section chief of hepatology at Rush University Medical Center, Chicago, said curing HCV is “very important and significantly reduces risk for complications, but it doesn’t return you to the normal population.”

Dr. Reau’s advice to cirrhosis patients: “Get screened twice a year.”

Dr. Beri said, in addition to conveying this risk to patients, “it is also important to disseminate this information to the community and to primary care practices, particularly as some patients may not currently follow in a specialized liver disease clinic.”

Also weighing in, Amit Singal, MD, chief of hepatology at the University of Texas Southwestern Medical Center, Dallas, said this study highlights that underlying cirrhosis is “the strongest risk factor for the development of HCC.”

In contrast to other cancers, such as breast and colorectal cancer, in which high risk populations can be identified by readily available information such as age and sex, implementation of HCC screening programs requires identification of patients with cirrhosis, Dr. Singal noted.

“Underuse of HCC screening in clinical practice is often related to providers having difficulty at this step in the process and contributes to the high proportion of HCC detected at late stages,” he told this news organization.

“Availability of accurate noninvasive markers of fibrosis will hopefully help with better identification of patients with cirrhosis moving forward,” Dr. Singal said, “although we as hepatologists need to work closely with our primary care colleagues to ensure these tools are used routinely in at-risk patients, such as those with nonalcoholic fatty liver disease, alcohol-associated liver disease, or history of cured (post-SVR) hepatitis C infection.”

The study was supported by the Medical Research Foundation and Public Health Scotland. Dr. Innes, Dr. Beri, Dr. Reau, and Dr. Singal reported no relevant financial relationships.

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

A new study confirms the very high risk of hepatocellular carcinoma faced by patients with cirrhosis who have been cured of hepatitis C, a finding the researchers hope will encourage clinicians to communicate risk information to patients and encourage regular HCC screening.

On average, the predicted probability of HCC in cirrhosis patients was 410 times greater than the equivalent probability in the general population, the study team found.

“As the prospect of HCV elimination approaches, a key challenge to the clinical community is the management of those who are cured of HCV but have a residual risk of HCC,” Hamish Innes, PhD, with Public Health Scotland, Glasgow, and colleagues wrote.

“Central to this is ensuring that cured cirrhosis patients understand the risk of HCC and are provided with appropriate surveillance,” they added. 

“Most patients with cirrhosis do not adhere to HCC screening guidelines,” Nina Beri, MD, medical oncologist with New York University Perlmutter Cancer Center, who wasn’t involved in the study, said in an interview.

The “important” finding in this study “should be conveyed to patients, as this may help improve screening adherence rates,” Dr. Beri said.

The study was published online in the American Journal of Gastroenterology.
 

Findings may help promote screening uptake

Dr. Innes and colleagues compared the predicted probability of HCC in 1,803 Scottish adults (mean age, 50 years; 74% male) with cirrhosis and cured hepatitis C to the background risk in the general population of Scotland.

The mean predicted 3-year probability of HCC at the time of sustained viral response (SVR), determined using the aMAP prognostic model, was 3.64% (range, 0.012%-36.12%).

This contrasts with a 3-year HCC probability in the general population ranging from less than 0.0001% to 0.25% depending on demographics.

All patients with cirrhosis – even those at lowest risk – had a higher probability of HCC than the general population, but there was considerable heterogeneity from one patient to the next.

For example, the mean 3-year predicted probability was 18 times higher in the top quintile (9.8%) versus the lowest quintile (0.5%) of risk, the researchers found.

They could not identify a patient subgroup who exhibited a similar HCC risk profile to the general population, as was their hope going into the study.

Dr. Innes and colleagues have developed an online tool that allows clinicians to frame a patient›s 3-year HCC probability against the equivalent probability in the general population.

In the future, they said the scope of the tool could be extended by incorporating general population data from countries beyond Scotland.

“Our hope is that this tool will springboard patient-clinician discussions about HCC risk, and could mitigate low screening uptake,” Dr. Innes and colleagues wrote.
 

Curing HCV doesn’t eliminate risk

Commenting on the study, Nancy Reau, MD, section chief of hepatology at Rush University Medical Center, Chicago, said curing HCV is “very important and significantly reduces risk for complications, but it doesn’t return you to the normal population.”

Dr. Reau’s advice to cirrhosis patients: “Get screened twice a year.”

Dr. Beri said, in addition to conveying this risk to patients, “it is also important to disseminate this information to the community and to primary care practices, particularly as some patients may not currently follow in a specialized liver disease clinic.”

Also weighing in, Amit Singal, MD, chief of hepatology at the University of Texas Southwestern Medical Center, Dallas, said this study highlights that underlying cirrhosis is “the strongest risk factor for the development of HCC.”

In contrast to other cancers, such as breast and colorectal cancer, in which high risk populations can be identified by readily available information such as age and sex, implementation of HCC screening programs requires identification of patients with cirrhosis, Dr. Singal noted.

“Underuse of HCC screening in clinical practice is often related to providers having difficulty at this step in the process and contributes to the high proportion of HCC detected at late stages,” he told this news organization.

“Availability of accurate noninvasive markers of fibrosis will hopefully help with better identification of patients with cirrhosis moving forward,” Dr. Singal said, “although we as hepatologists need to work closely with our primary care colleagues to ensure these tools are used routinely in at-risk patients, such as those with nonalcoholic fatty liver disease, alcohol-associated liver disease, or history of cured (post-SVR) hepatitis C infection.”

The study was supported by the Medical Research Foundation and Public Health Scotland. Dr. Innes, Dr. Beri, Dr. Reau, and Dr. Singal reported no relevant financial relationships.

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

A new study confirms the very high risk of hepatocellular carcinoma faced by patients with cirrhosis who have been cured of hepatitis C, a finding the researchers hope will encourage clinicians to communicate risk information to patients and encourage regular HCC screening.

On average, the predicted probability of HCC in cirrhosis patients was 410 times greater than the equivalent probability in the general population, the study team found.

“As the prospect of HCV elimination approaches, a key challenge to the clinical community is the management of those who are cured of HCV but have a residual risk of HCC,” Hamish Innes, PhD, with Public Health Scotland, Glasgow, and colleagues wrote.

“Central to this is ensuring that cured cirrhosis patients understand the risk of HCC and are provided with appropriate surveillance,” they added. 

“Most patients with cirrhosis do not adhere to HCC screening guidelines,” Nina Beri, MD, medical oncologist with New York University Perlmutter Cancer Center, who wasn’t involved in the study, said in an interview.

The “important” finding in this study “should be conveyed to patients, as this may help improve screening adherence rates,” Dr. Beri said.

The study was published online in the American Journal of Gastroenterology.
 

Findings may help promote screening uptake

Dr. Innes and colleagues compared the predicted probability of HCC in 1,803 Scottish adults (mean age, 50 years; 74% male) with cirrhosis and cured hepatitis C to the background risk in the general population of Scotland.

The mean predicted 3-year probability of HCC at the time of sustained viral response (SVR), determined using the aMAP prognostic model, was 3.64% (range, 0.012%-36.12%).

This contrasts with a 3-year HCC probability in the general population ranging from less than 0.0001% to 0.25% depending on demographics.

All patients with cirrhosis – even those at lowest risk – had a higher probability of HCC than the general population, but there was considerable heterogeneity from one patient to the next.

For example, the mean 3-year predicted probability was 18 times higher in the top quintile (9.8%) versus the lowest quintile (0.5%) of risk, the researchers found.

They could not identify a patient subgroup who exhibited a similar HCC risk profile to the general population, as was their hope going into the study.

Dr. Innes and colleagues have developed an online tool that allows clinicians to frame a patient›s 3-year HCC probability against the equivalent probability in the general population.

In the future, they said the scope of the tool could be extended by incorporating general population data from countries beyond Scotland.

“Our hope is that this tool will springboard patient-clinician discussions about HCC risk, and could mitigate low screening uptake,” Dr. Innes and colleagues wrote.
 

Curing HCV doesn’t eliminate risk

Commenting on the study, Nancy Reau, MD, section chief of hepatology at Rush University Medical Center, Chicago, said curing HCV is “very important and significantly reduces risk for complications, but it doesn’t return you to the normal population.”

Dr. Reau’s advice to cirrhosis patients: “Get screened twice a year.”

Dr. Beri said, in addition to conveying this risk to patients, “it is also important to disseminate this information to the community and to primary care practices, particularly as some patients may not currently follow in a specialized liver disease clinic.”

Also weighing in, Amit Singal, MD, chief of hepatology at the University of Texas Southwestern Medical Center, Dallas, said this study highlights that underlying cirrhosis is “the strongest risk factor for the development of HCC.”

In contrast to other cancers, such as breast and colorectal cancer, in which high risk populations can be identified by readily available information such as age and sex, implementation of HCC screening programs requires identification of patients with cirrhosis, Dr. Singal noted.

“Underuse of HCC screening in clinical practice is often related to providers having difficulty at this step in the process and contributes to the high proportion of HCC detected at late stages,” he told this news organization.

“Availability of accurate noninvasive markers of fibrosis will hopefully help with better identification of patients with cirrhosis moving forward,” Dr. Singal said, “although we as hepatologists need to work closely with our primary care colleagues to ensure these tools are used routinely in at-risk patients, such as those with nonalcoholic fatty liver disease, alcohol-associated liver disease, or history of cured (post-SVR) hepatitis C infection.”

The study was supported by the Medical Research Foundation and Public Health Scotland. Dr. Innes, Dr. Beri, Dr. Reau, and Dr. Singal reported no relevant financial relationships.

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

As obstacles to hepatitis C treatment uptake were removed, rates of hepatitis-related liver disease in marginalized groups plummeted, according to a new study in Baltimore, published in Annals of Internal Medicine.

A community-based cohort study that follows current and former people who inject drugs (PWID) with hepatitis C documented drastic reductions in liver disease and death as effective oral antivirals became more readily accessible there between 2015 and 2019.

The researchers concluded that hepatitis C elimination targets are achievable. But, they warned, uptake is uneven, and more needs to be done to facilitate treatment.

“[The study] gives us a real-world perspective on what’s happening on the ground, in terms of people getting treated,” said first author Javier Cepeda, PhD, MPH, an assistant professor at the Johns Hopkins Bloomberg School of Public Health, Baltimore, in an interview. “Changing policy, reducing barriers, [and] getting them access to treatment really does have this really important public health benefit.”

“It’s compelling to see these improved outcomes amongst a cohort of people who inject drugs with baseline hep C,” said Maria Corcorran, MD, MPH. Dr. Corcorran, an acting assistant professor for the department of medicine at the University of Washington, was not involved with the study. “It’s just further evidence that we need to really be linking people to care and getting people treated and cured.”

The World Health Organization has called for the disease’s global elimination by 2030. Cure rates top 95%. But, there are so many new cases and so many barriers to detection and treatment that how to develop and roll out a public health response is the most important question in the field, wrote study co-author David L. Thomas, MD, MPH, in a review article in The New England Journal of Medicine.

“Folks who inject drugs ... do well on hep C treatment and have similar rates of sustained virologic response or cure,” said Dr. Corcorran, who runs a low-barrier clinic for people experiencing homelessness.

But, she added, “there are barriers that are still put up to treatment in terms of who can treat and what insurance is going to cover.”
 

A look at a vulnerable population

The authors studied adults enrolled in ALIVE (AIDS Linked to the Intravenous Experience), a cohort study that has recruited current and former PWID in the Baltimore area since 1988.

Participants visit the clinic twice a year for health-related interviews and blood testing, including HIV serology, hepatitis C virus (HCV) antibody and RNA testing, and liver function tests. They are counseled about HCV testing and treatment but do not receive treatment through the study.

Beginning in 2006, researchers added liver stiffness measures (LSMs), a noninvasive measure conducted with transient elastography.

From 2006 to 2019, the authors followed 1,323 ALIVE participants with chronic HCV infection. The primary outcome was LSMs.
 

Less liver disease, fewer deaths

At baseline, participants’ median age was 49 years; 82% of participants were Black individuals, 71% percent were male, and two-thirds were HIV-negative.

Three percent reported receiving hepatitis C treatment in 2014, which increased to 39% in 2019.

Among 10,350 LSMs, 15% showed cirrhosis at baseline in 2006. In 2015, that rose to 19%, but by 2019, it had fallen to 8%.

By definition, 100% had detectable HCV RNA at baseline. In 2015, 91% still did. By 2019, that rate had fallen to 48%.

Undetectable HCV RNA correlated with lower log LSM in adjusted models (P < .001). It also correlated strongly with lower odds of liver cirrhosis, with an adjusted odds ratio of 0.28 (95% confidence interval, 0.17-0.45; P < .001). In addition, it correlated with lower risk for all-cause mortality, with an adjusted hazard ratio of 0.54 (95% CI, 0.38-0.77; P < .001).

Limitations include the fact that, although transient elastography is considered the most valid way to detect cirrhosis in people with hepatitis C, liver stiffness has not been validated as a measure of fibrosis among people with a sustained virologic response.

In addition, ALIVE participants are older and more likely to be African American individuals, compared with the general population of PWID in Baltimore, wrote co-author Shruti H. Mehta, PhD, a professor of epidemiology at Johns Hopkins University, Baltimore, in an email exchange with this news organization. That could affect generalizability.
 

Treatment is crucial

The first direct-acting antiviral (DAA) for hepatitis C was approved in 2011, and an oral fixed-dose combination antiviral was approved in 2014, ushering in treatments with cure rates far exceeding those with interferon-based therapy.

But until recently, Medicaid patients in Maryland seeking DAA therapy for hepatitis C required prior authorization, with initial restrictions related to disease stage, substance use, and provider type, according to Dr. Mehta.

Gradually, those restrictions were lifted, Dr. Mehta added, and all were eliminated by 2019.

Dr. Cepeda urges clinicians to treat patients infected with hepatitis C immediately.

“There are really important implications on both reducing liver disease progression and all-cause mortality,” he said.

“Hep C is just one part of a whole constellation of health care delivery [and] of treating all of the other potential problems that might need to be addressed – especially with people who inject drugs,” Dr. Cepeda added. “Getting them into care is really, really important.”

The study was funded by the National Institutes of Health. Dr. Cepeda and Dr. Corcorran report no relevant financial relationships. Dr. Mehta reports receiving payments or honoraria and travel support from Gilead Sciences, the makers of the oral hepatitis C medication ledipasvir/sofosbuvir (Harvoni), as well as equipment, materials, drugs, medical writing, gifts, or other services from Abbott, which sells hepatitis C diagnostics. Dr. Thomas reports ties to Excision Bio and to Merck DSMB.

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

As obstacles to hepatitis C treatment uptake were removed, rates of hepatitis-related liver disease in marginalized groups plummeted, according to a new study in Baltimore, published in Annals of Internal Medicine.

A community-based cohort study that follows current and former people who inject drugs (PWID) with hepatitis C documented drastic reductions in liver disease and death as effective oral antivirals became more readily accessible there between 2015 and 2019.

The researchers concluded that hepatitis C elimination targets are achievable. But, they warned, uptake is uneven, and more needs to be done to facilitate treatment.

“[The study] gives us a real-world perspective on what’s happening on the ground, in terms of people getting treated,” said first author Javier Cepeda, PhD, MPH, an assistant professor at the Johns Hopkins Bloomberg School of Public Health, Baltimore, in an interview. “Changing policy, reducing barriers, [and] getting them access to treatment really does have this really important public health benefit.”

“It’s compelling to see these improved outcomes amongst a cohort of people who inject drugs with baseline hep C,” said Maria Corcorran, MD, MPH. Dr. Corcorran, an acting assistant professor for the department of medicine at the University of Washington, was not involved with the study. “It’s just further evidence that we need to really be linking people to care and getting people treated and cured.”

The World Health Organization has called for the disease’s global elimination by 2030. Cure rates top 95%. But, there are so many new cases and so many barriers to detection and treatment that how to develop and roll out a public health response is the most important question in the field, wrote study co-author David L. Thomas, MD, MPH, in a review article in The New England Journal of Medicine.

“Folks who inject drugs ... do well on hep C treatment and have similar rates of sustained virologic response or cure,” said Dr. Corcorran, who runs a low-barrier clinic for people experiencing homelessness.

But, she added, “there are barriers that are still put up to treatment in terms of who can treat and what insurance is going to cover.”
 

A look at a vulnerable population

The authors studied adults enrolled in ALIVE (AIDS Linked to the Intravenous Experience), a cohort study that has recruited current and former PWID in the Baltimore area since 1988.

Participants visit the clinic twice a year for health-related interviews and blood testing, including HIV serology, hepatitis C virus (HCV) antibody and RNA testing, and liver function tests. They are counseled about HCV testing and treatment but do not receive treatment through the study.

Beginning in 2006, researchers added liver stiffness measures (LSMs), a noninvasive measure conducted with transient elastography.

From 2006 to 2019, the authors followed 1,323 ALIVE participants with chronic HCV infection. The primary outcome was LSMs.
 

Less liver disease, fewer deaths

At baseline, participants’ median age was 49 years; 82% of participants were Black individuals, 71% percent were male, and two-thirds were HIV-negative.

Three percent reported receiving hepatitis C treatment in 2014, which increased to 39% in 2019.

Among 10,350 LSMs, 15% showed cirrhosis at baseline in 2006. In 2015, that rose to 19%, but by 2019, it had fallen to 8%.

By definition, 100% had detectable HCV RNA at baseline. In 2015, 91% still did. By 2019, that rate had fallen to 48%.

Undetectable HCV RNA correlated with lower log LSM in adjusted models (P < .001). It also correlated strongly with lower odds of liver cirrhosis, with an adjusted odds ratio of 0.28 (95% confidence interval, 0.17-0.45; P < .001). In addition, it correlated with lower risk for all-cause mortality, with an adjusted hazard ratio of 0.54 (95% CI, 0.38-0.77; P < .001).

Limitations include the fact that, although transient elastography is considered the most valid way to detect cirrhosis in people with hepatitis C, liver stiffness has not been validated as a measure of fibrosis among people with a sustained virologic response.

In addition, ALIVE participants are older and more likely to be African American individuals, compared with the general population of PWID in Baltimore, wrote co-author Shruti H. Mehta, PhD, a professor of epidemiology at Johns Hopkins University, Baltimore, in an email exchange with this news organization. That could affect generalizability.
 

Treatment is crucial

The first direct-acting antiviral (DAA) for hepatitis C was approved in 2011, and an oral fixed-dose combination antiviral was approved in 2014, ushering in treatments with cure rates far exceeding those with interferon-based therapy.

But until recently, Medicaid patients in Maryland seeking DAA therapy for hepatitis C required prior authorization, with initial restrictions related to disease stage, substance use, and provider type, according to Dr. Mehta.

Gradually, those restrictions were lifted, Dr. Mehta added, and all were eliminated by 2019.

Dr. Cepeda urges clinicians to treat patients infected with hepatitis C immediately.

“There are really important implications on both reducing liver disease progression and all-cause mortality,” he said.

“Hep C is just one part of a whole constellation of health care delivery [and] of treating all of the other potential problems that might need to be addressed – especially with people who inject drugs,” Dr. Cepeda added. “Getting them into care is really, really important.”

The study was funded by the National Institutes of Health. Dr. Cepeda and Dr. Corcorran report no relevant financial relationships. Dr. Mehta reports receiving payments or honoraria and travel support from Gilead Sciences, the makers of the oral hepatitis C medication ledipasvir/sofosbuvir (Harvoni), as well as equipment, materials, drugs, medical writing, gifts, or other services from Abbott, which sells hepatitis C diagnostics. Dr. Thomas reports ties to Excision Bio and to Merck DSMB.

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

As obstacles to hepatitis C treatment uptake were removed, rates of hepatitis-related liver disease in marginalized groups plummeted, according to a new study in Baltimore, published in Annals of Internal Medicine.

A community-based cohort study that follows current and former people who inject drugs (PWID) with hepatitis C documented drastic reductions in liver disease and death as effective oral antivirals became more readily accessible there between 2015 and 2019.

The researchers concluded that hepatitis C elimination targets are achievable. But, they warned, uptake is uneven, and more needs to be done to facilitate treatment.

“[The study] gives us a real-world perspective on what’s happening on the ground, in terms of people getting treated,” said first author Javier Cepeda, PhD, MPH, an assistant professor at the Johns Hopkins Bloomberg School of Public Health, Baltimore, in an interview. “Changing policy, reducing barriers, [and] getting them access to treatment really does have this really important public health benefit.”

“It’s compelling to see these improved outcomes amongst a cohort of people who inject drugs with baseline hep C,” said Maria Corcorran, MD, MPH. Dr. Corcorran, an acting assistant professor for the department of medicine at the University of Washington, was not involved with the study. “It’s just further evidence that we need to really be linking people to care and getting people treated and cured.”

The World Health Organization has called for the disease’s global elimination by 2030. Cure rates top 95%. But, there are so many new cases and so many barriers to detection and treatment that how to develop and roll out a public health response is the most important question in the field, wrote study co-author David L. Thomas, MD, MPH, in a review article in The New England Journal of Medicine.

“Folks who inject drugs ... do well on hep C treatment and have similar rates of sustained virologic response or cure,” said Dr. Corcorran, who runs a low-barrier clinic for people experiencing homelessness.

But, she added, “there are barriers that are still put up to treatment in terms of who can treat and what insurance is going to cover.”
 

A look at a vulnerable population

The authors studied adults enrolled in ALIVE (AIDS Linked to the Intravenous Experience), a cohort study that has recruited current and former PWID in the Baltimore area since 1988.

Participants visit the clinic twice a year for health-related interviews and blood testing, including HIV serology, hepatitis C virus (HCV) antibody and RNA testing, and liver function tests. They are counseled about HCV testing and treatment but do not receive treatment through the study.

Beginning in 2006, researchers added liver stiffness measures (LSMs), a noninvasive measure conducted with transient elastography.

From 2006 to 2019, the authors followed 1,323 ALIVE participants with chronic HCV infection. The primary outcome was LSMs.
 

Less liver disease, fewer deaths

At baseline, participants’ median age was 49 years; 82% of participants were Black individuals, 71% percent were male, and two-thirds were HIV-negative.

Three percent reported receiving hepatitis C treatment in 2014, which increased to 39% in 2019.

Among 10,350 LSMs, 15% showed cirrhosis at baseline in 2006. In 2015, that rose to 19%, but by 2019, it had fallen to 8%.

By definition, 100% had detectable HCV RNA at baseline. In 2015, 91% still did. By 2019, that rate had fallen to 48%.

Undetectable HCV RNA correlated with lower log LSM in adjusted models (P < .001). It also correlated strongly with lower odds of liver cirrhosis, with an adjusted odds ratio of 0.28 (95% confidence interval, 0.17-0.45; P < .001). In addition, it correlated with lower risk for all-cause mortality, with an adjusted hazard ratio of 0.54 (95% CI, 0.38-0.77; P < .001).

Limitations include the fact that, although transient elastography is considered the most valid way to detect cirrhosis in people with hepatitis C, liver stiffness has not been validated as a measure of fibrosis among people with a sustained virologic response.

In addition, ALIVE participants are older and more likely to be African American individuals, compared with the general population of PWID in Baltimore, wrote co-author Shruti H. Mehta, PhD, a professor of epidemiology at Johns Hopkins University, Baltimore, in an email exchange with this news organization. That could affect generalizability.
 

Treatment is crucial

The first direct-acting antiviral (DAA) for hepatitis C was approved in 2011, and an oral fixed-dose combination antiviral was approved in 2014, ushering in treatments with cure rates far exceeding those with interferon-based therapy.

But until recently, Medicaid patients in Maryland seeking DAA therapy for hepatitis C required prior authorization, with initial restrictions related to disease stage, substance use, and provider type, according to Dr. Mehta.

Gradually, those restrictions were lifted, Dr. Mehta added, and all were eliminated by 2019.

Dr. Cepeda urges clinicians to treat patients infected with hepatitis C immediately.

“There are really important implications on both reducing liver disease progression and all-cause mortality,” he said.

“Hep C is just one part of a whole constellation of health care delivery [and] of treating all of the other potential problems that might need to be addressed – especially with people who inject drugs,” Dr. Cepeda added. “Getting them into care is really, really important.”

The study was funded by the National Institutes of Health. Dr. Cepeda and Dr. Corcorran report no relevant financial relationships. Dr. Mehta reports receiving payments or honoraria and travel support from Gilead Sciences, the makers of the oral hepatitis C medication ledipasvir/sofosbuvir (Harvoni), as well as equipment, materials, drugs, medical writing, gifts, or other services from Abbott, which sells hepatitis C diagnostics. Dr. Thomas reports ties to Excision Bio and to Merck DSMB.

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

Bulevirtide (Hepcludex) monotherapy significantly reduces the load of hepatitis delta virus (HDV) and is safe in difficult-to-treat patients with compensated cirrhosis and clinically significant portal hypertension, according to the results of an ongoing 1-year study.

In presenting a poster with these findings at the annual International Liver Congress, sponsored by the European Association for the Study of the Liver, lead author Elisabetta Degasperi, MD, from the Grand Hospital Maggiore Policlinico in Milan, said that they were important “because they confirm the safety of this drug in real life.”

Dr. Degasperi and colleagues showed that bulevirtide leads to a significant viral response in 78% of patients by week 48, which was measured using the outcome of greater than 2 log decline in HDV RNA from baseline.

Dr. Degasperi added that the research still needed to assess the longer-term benefits, but “so far the 1-year results clearly show an initial benefit that is not only a good viral response but also one of disease control and a slight improvement in liver function.”
 

Addressing an immense, unmet therapeutic need

HDV requires the presence of hepatitis B virus to replicate. Bulevirtide blocks the entry of HDV and hepatitis B virus into hepatocytes.

In July 2020, it was conditionally approved in the European Economic Area for use to treat chronic HDV infection in adults with compensated liver disease upon confirmation of HDV RNA in the blood. It currently remains an investigational agent in the United States, as well as outside of the EEA.

The ongoing trial led by Dr. Degasperi is specifically conducted in patients with compensated cirrhosis who also have clinically significant portal hypertension, where safety and efficacy are unknown.

Dr. Degasperi said in an interview that, although HDV was rare, there is nonetheless an “immense” need for effective therapies against it, especially in young patients with advanced liver disease.

“We have a lot of patients with hepatitis D who have not responded to other antiviral treatment. Right now, the only other available treatment is pegylated interferon,” she said. “Unfortunately, rates of sustained viral response to pegylated interferon are extremely low at around 30% of patients.”

Chronic HDV is the most severe form of viral hepatitis and can have mortality rates as high as 50% within 5 years in patients with cirrhosis.

The management of hepatitis D is also complicated by the fact that patients with advanced cirrhosis and clinically significant portal hypertension cannot be treated with pegylated interferon owing to lack of efficacy and safety reasons, including a high risk for decompensation and liver-related complications. Pegylated interferon is contraindicated in these patients.
 

Bulevirtide at 48 weeks: A closer look at the findings

Eighteen patients with HDV, compensated cirrhosis, and clinically significant portal hypertension were consecutively enrolled in this single-center, longitudinal study.

All received bulevirtide monotherapy at 2 mg/day and underwent monitoring every 2 months. They were also treated with nucleotide analogs for their hepatitis B virus, which was suppressed when they began bulevirtide.

Clinical and virologic characteristics were collected at baseline, at weeks 4 and 8, and then every 8 weeks thereafter.

Bulevirtide led to a significant viral response such that by week 48, HDV RNA declined by 3.1 log IU/mL (range, 0.2-4.6 log IU/mL), was undetectable in six patients (33%), and was less than 100 IU/L in 50% of patients. Two patients were nonresponders. In addition, 78% of patients achieved at least an HDV RNA 2 log decline from baseline.

There was also a normalization of biochemical response in the majority of patients.

Alanine aminotransferase normalization was seen in 89% of patients and declined by a median of 34 U/L (range, 15-76 U/L) over 48 weeks. Aspartate aminotransferase declined to 39 U/L (range, 21-92 U/L). A combined response was seen in 72% of patients, reported Dr. Degasperi.

“Previously, we only had results from a phase 2 study, so we had no idea of the results over such a long treatment period,” said Dr. Degasperi. “It is also the first time we have been able to treat these patients with such advanced disease that is so difficult to manage.”

“Real-world results are typically inferior to those from clinical trials, but the viral decline is comparable to phase 2 trials, and the first report of the phase 3 trial,” said Dr. Degasperi.

Gamma-glutamyltransferase, alpha-fetoprotein, immunoglobulin G, and gamma-globulin levels also improved, whereas hepatitis B surface antigen, hepatitis B virus RNA, hepatitis B core-related antigen, platelet, and bilirubin values did not significantly change.

“All patients were Child-Pugh score A, so well-compensated [disease]. However, they increased a little bit in liver function by week 48,” Dr. Degasperi said. “This was important for this very advanced disease population.”

She added that the safety profile was very favorable, with no adverse events, including no injection-site reactions.

There was an asymptomatic increase in serum bile acids. “No patients complained about itching or pruritus,” Dr. Degasperi said.
 

What’s ahead for bulevirtide?

In a comment, Marc Bourlière, MD, from Saint Joseph Hospital in Marseilles, France, welcomed the decrease in viral load.

“This is known to be beneficial in terms of reducing morbidity and mortality in hepatitis D,” he said. “Remember that this disease is very difficult to treat, and until now, we have had no drug available. Pegylated interferon achieves cure in only 30% of patients, and half of these relapse, so actually only 15% have a meaningful response from pegylated interferon.”

“The main issue is its use as a daily subcutaneous injection. In clinical practice, it is a little bit complicated to set up, but once done, it is quite well accepted,” he said.

“I’m impressed with these results to date because there are no other compounds that have, as yet, achieved such results. This is impressive,” he added. “But whether it translates into a long-term response we don’t yet know.”

Dr. Bourlière also noted the meaningful 2-point log decline, noting that “HDV RNA negativity where treatment can be stopped would be really meaningful, but this endpoint is hard to obtain.”

Dr. Bourlière is awaiting results of the current ongoing phase 2/3 study, which would help determine a possible final treatment duration. He is also curious to settle the ongoing debate about whether bulevirtide should be used alone or in combination.

“We need to combine bulevirtide with pegylated interferon in less-advanced patients, because we know it is more potent and active against the HDV RNA,” he said.

Dr. Degasperi has previously declared she was on the advisory board for AbbVie and has spoken and taught for Gilead, MSD, and AbbVie. Dr. Bourlière declared interests with all companies involved in the R&D of liver therapies.

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

Bulevirtide (Hepcludex) monotherapy significantly reduces the load of hepatitis delta virus (HDV) and is safe in difficult-to-treat patients with compensated cirrhosis and clinically significant portal hypertension, according to the results of an ongoing 1-year study.

In presenting a poster with these findings at the annual International Liver Congress, sponsored by the European Association for the Study of the Liver, lead author Elisabetta Degasperi, MD, from the Grand Hospital Maggiore Policlinico in Milan, said that they were important “because they confirm the safety of this drug in real life.”

Dr. Degasperi and colleagues showed that bulevirtide leads to a significant viral response in 78% of patients by week 48, which was measured using the outcome of greater than 2 log decline in HDV RNA from baseline.

Dr. Degasperi added that the research still needed to assess the longer-term benefits, but “so far the 1-year results clearly show an initial benefit that is not only a good viral response but also one of disease control and a slight improvement in liver function.”
 

Addressing an immense, unmet therapeutic need

HDV requires the presence of hepatitis B virus to replicate. Bulevirtide blocks the entry of HDV and hepatitis B virus into hepatocytes.

In July 2020, it was conditionally approved in the European Economic Area for use to treat chronic HDV infection in adults with compensated liver disease upon confirmation of HDV RNA in the blood. It currently remains an investigational agent in the United States, as well as outside of the EEA.

The ongoing trial led by Dr. Degasperi is specifically conducted in patients with compensated cirrhosis who also have clinically significant portal hypertension, where safety and efficacy are unknown.

Dr. Degasperi said in an interview that, although HDV was rare, there is nonetheless an “immense” need for effective therapies against it, especially in young patients with advanced liver disease.

“We have a lot of patients with hepatitis D who have not responded to other antiviral treatment. Right now, the only other available treatment is pegylated interferon,” she said. “Unfortunately, rates of sustained viral response to pegylated interferon are extremely low at around 30% of patients.”

Chronic HDV is the most severe form of viral hepatitis and can have mortality rates as high as 50% within 5 years in patients with cirrhosis.

The management of hepatitis D is also complicated by the fact that patients with advanced cirrhosis and clinically significant portal hypertension cannot be treated with pegylated interferon owing to lack of efficacy and safety reasons, including a high risk for decompensation and liver-related complications. Pegylated interferon is contraindicated in these patients.
 

Bulevirtide at 48 weeks: A closer look at the findings

Eighteen patients with HDV, compensated cirrhosis, and clinically significant portal hypertension were consecutively enrolled in this single-center, longitudinal study.

All received bulevirtide monotherapy at 2 mg/day and underwent monitoring every 2 months. They were also treated with nucleotide analogs for their hepatitis B virus, which was suppressed when they began bulevirtide.

Clinical and virologic characteristics were collected at baseline, at weeks 4 and 8, and then every 8 weeks thereafter.

Bulevirtide led to a significant viral response such that by week 48, HDV RNA declined by 3.1 log IU/mL (range, 0.2-4.6 log IU/mL), was undetectable in six patients (33%), and was less than 100 IU/L in 50% of patients. Two patients were nonresponders. In addition, 78% of patients achieved at least an HDV RNA 2 log decline from baseline.

There was also a normalization of biochemical response in the majority of patients.

Alanine aminotransferase normalization was seen in 89% of patients and declined by a median of 34 U/L (range, 15-76 U/L) over 48 weeks. Aspartate aminotransferase declined to 39 U/L (range, 21-92 U/L). A combined response was seen in 72% of patients, reported Dr. Degasperi.

“Previously, we only had results from a phase 2 study, so we had no idea of the results over such a long treatment period,” said Dr. Degasperi. “It is also the first time we have been able to treat these patients with such advanced disease that is so difficult to manage.”

“Real-world results are typically inferior to those from clinical trials, but the viral decline is comparable to phase 2 trials, and the first report of the phase 3 trial,” said Dr. Degasperi.

Gamma-glutamyltransferase, alpha-fetoprotein, immunoglobulin G, and gamma-globulin levels also improved, whereas hepatitis B surface antigen, hepatitis B virus RNA, hepatitis B core-related antigen, platelet, and bilirubin values did not significantly change.

“All patients were Child-Pugh score A, so well-compensated [disease]. However, they increased a little bit in liver function by week 48,” Dr. Degasperi said. “This was important for this very advanced disease population.”

She added that the safety profile was very favorable, with no adverse events, including no injection-site reactions.

There was an asymptomatic increase in serum bile acids. “No patients complained about itching or pruritus,” Dr. Degasperi said.
 

What’s ahead for bulevirtide?

In a comment, Marc Bourlière, MD, from Saint Joseph Hospital in Marseilles, France, welcomed the decrease in viral load.

“This is known to be beneficial in terms of reducing morbidity and mortality in hepatitis D,” he said. “Remember that this disease is very difficult to treat, and until now, we have had no drug available. Pegylated interferon achieves cure in only 30% of patients, and half of these relapse, so actually only 15% have a meaningful response from pegylated interferon.”

“The main issue is its use as a daily subcutaneous injection. In clinical practice, it is a little bit complicated to set up, but once done, it is quite well accepted,” he said.

“I’m impressed with these results to date because there are no other compounds that have, as yet, achieved such results. This is impressive,” he added. “But whether it translates into a long-term response we don’t yet know.”

Dr. Bourlière also noted the meaningful 2-point log decline, noting that “HDV RNA negativity where treatment can be stopped would be really meaningful, but this endpoint is hard to obtain.”

Dr. Bourlière is awaiting results of the current ongoing phase 2/3 study, which would help determine a possible final treatment duration. He is also curious to settle the ongoing debate about whether bulevirtide should be used alone or in combination.

“We need to combine bulevirtide with pegylated interferon in less-advanced patients, because we know it is more potent and active against the HDV RNA,” he said.

Dr. Degasperi has previously declared she was on the advisory board for AbbVie and has spoken and taught for Gilead, MSD, and AbbVie. Dr. Bourlière declared interests with all companies involved in the R&D of liver therapies.

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

Bulevirtide (Hepcludex) monotherapy significantly reduces the load of hepatitis delta virus (HDV) and is safe in difficult-to-treat patients with compensated cirrhosis and clinically significant portal hypertension, according to the results of an ongoing 1-year study.

In presenting a poster with these findings at the annual International Liver Congress, sponsored by the European Association for the Study of the Liver, lead author Elisabetta Degasperi, MD, from the Grand Hospital Maggiore Policlinico in Milan, said that they were important “because they confirm the safety of this drug in real life.”

Dr. Degasperi and colleagues showed that bulevirtide leads to a significant viral response in 78% of patients by week 48, which was measured using the outcome of greater than 2 log decline in HDV RNA from baseline.

Dr. Degasperi added that the research still needed to assess the longer-term benefits, but “so far the 1-year results clearly show an initial benefit that is not only a good viral response but also one of disease control and a slight improvement in liver function.”
 

Addressing an immense, unmet therapeutic need

HDV requires the presence of hepatitis B virus to replicate. Bulevirtide blocks the entry of HDV and hepatitis B virus into hepatocytes.

In July 2020, it was conditionally approved in the European Economic Area for use to treat chronic HDV infection in adults with compensated liver disease upon confirmation of HDV RNA in the blood. It currently remains an investigational agent in the United States, as well as outside of the EEA.

The ongoing trial led by Dr. Degasperi is specifically conducted in patients with compensated cirrhosis who also have clinically significant portal hypertension, where safety and efficacy are unknown.

Dr. Degasperi said in an interview that, although HDV was rare, there is nonetheless an “immense” need for effective therapies against it, especially in young patients with advanced liver disease.

“We have a lot of patients with hepatitis D who have not responded to other antiviral treatment. Right now, the only other available treatment is pegylated interferon,” she said. “Unfortunately, rates of sustained viral response to pegylated interferon are extremely low at around 30% of patients.”

Chronic HDV is the most severe form of viral hepatitis and can have mortality rates as high as 50% within 5 years in patients with cirrhosis.

The management of hepatitis D is also complicated by the fact that patients with advanced cirrhosis and clinically significant portal hypertension cannot be treated with pegylated interferon owing to lack of efficacy and safety reasons, including a high risk for decompensation and liver-related complications. Pegylated interferon is contraindicated in these patients.
 

Bulevirtide at 48 weeks: A closer look at the findings

Eighteen patients with HDV, compensated cirrhosis, and clinically significant portal hypertension were consecutively enrolled in this single-center, longitudinal study.

All received bulevirtide monotherapy at 2 mg/day and underwent monitoring every 2 months. They were also treated with nucleotide analogs for their hepatitis B virus, which was suppressed when they began bulevirtide.

Clinical and virologic characteristics were collected at baseline, at weeks 4 and 8, and then every 8 weeks thereafter.

Bulevirtide led to a significant viral response such that by week 48, HDV RNA declined by 3.1 log IU/mL (range, 0.2-4.6 log IU/mL), was undetectable in six patients (33%), and was less than 100 IU/L in 50% of patients. Two patients were nonresponders. In addition, 78% of patients achieved at least an HDV RNA 2 log decline from baseline.

There was also a normalization of biochemical response in the majority of patients.

Alanine aminotransferase normalization was seen in 89% of patients and declined by a median of 34 U/L (range, 15-76 U/L) over 48 weeks. Aspartate aminotransferase declined to 39 U/L (range, 21-92 U/L). A combined response was seen in 72% of patients, reported Dr. Degasperi.

“Previously, we only had results from a phase 2 study, so we had no idea of the results over such a long treatment period,” said Dr. Degasperi. “It is also the first time we have been able to treat these patients with such advanced disease that is so difficult to manage.”

“Real-world results are typically inferior to those from clinical trials, but the viral decline is comparable to phase 2 trials, and the first report of the phase 3 trial,” said Dr. Degasperi.

Gamma-glutamyltransferase, alpha-fetoprotein, immunoglobulin G, and gamma-globulin levels also improved, whereas hepatitis B surface antigen, hepatitis B virus RNA, hepatitis B core-related antigen, platelet, and bilirubin values did not significantly change.

“All patients were Child-Pugh score A, so well-compensated [disease]. However, they increased a little bit in liver function by week 48,” Dr. Degasperi said. “This was important for this very advanced disease population.”

She added that the safety profile was very favorable, with no adverse events, including no injection-site reactions.

There was an asymptomatic increase in serum bile acids. “No patients complained about itching or pruritus,” Dr. Degasperi said.
 

What’s ahead for bulevirtide?

In a comment, Marc Bourlière, MD, from Saint Joseph Hospital in Marseilles, France, welcomed the decrease in viral load.

“This is known to be beneficial in terms of reducing morbidity and mortality in hepatitis D,” he said. “Remember that this disease is very difficult to treat, and until now, we have had no drug available. Pegylated interferon achieves cure in only 30% of patients, and half of these relapse, so actually only 15% have a meaningful response from pegylated interferon.”

“The main issue is its use as a daily subcutaneous injection. In clinical practice, it is a little bit complicated to set up, but once done, it is quite well accepted,” he said.

“I’m impressed with these results to date because there are no other compounds that have, as yet, achieved such results. This is impressive,” he added. “But whether it translates into a long-term response we don’t yet know.”

Dr. Bourlière also noted the meaningful 2-point log decline, noting that “HDV RNA negativity where treatment can be stopped would be really meaningful, but this endpoint is hard to obtain.”

Dr. Bourlière is awaiting results of the current ongoing phase 2/3 study, which would help determine a possible final treatment duration. He is also curious to settle the ongoing debate about whether bulevirtide should be used alone or in combination.

“We need to combine bulevirtide with pegylated interferon in less-advanced patients, because we know it is more potent and active against the HDV RNA,” he said.

Dr. Degasperi has previously declared she was on the advisory board for AbbVie and has spoken and taught for Gilead, MSD, and AbbVie. Dr. Bourlière declared interests with all companies involved in the R&D of liver therapies.

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 &amp; 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 &amp; 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 &amp; 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 – 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.