ACIP Recommends 'Universal' Adult HBV Vaccine—But Not for All

BY MARIE ROSENTHAL, MS

Arisk-based strategy for adult hepatitis B (HepB) vaccination just hasn’t worked, according to Kevin A. Ault, MD, FACOG, FIDSA, the division director of the Department of Obstetrics and Gynecology, University of Kansas Medical Center, in Kansas City.

“The risk-based strategy has been given over a decade to prove itself, and that hasn’t panned out because of the complex list of risk factors,” Dr. Ault told the CDC’s Advisory Committee on Immunization Practices (ACIP).

The list for at-risk adults is indeed complex. There are four risks under those who might be exposed through sexual contact, such as having multiple partners or living with someone who is hepatitis B surface antigen–positive, and six under the category of those at risk from percutaneous or mucosal exposure to blood, such as injection drug users, those with diabetes and hemodialysis patients. In addition, there are “others”: those at risk because of HIV, chronic liver disease, hepatitis C virus (HCV), incarceration or international travel. And finally, there is a catchall—“all other persons seeking protection from HBV infection.”

Determining whether the patient in front of you should be vaccinated is challenging in the time constraints of an office or clinic visit, Dr. Ault said. It’s especially difficult because many patients do not report a risk, added Mark K. Weng, MD, MSc, FAAP, the lead of the ACIP’s Hepatitis Vaccine Work Group.

“It’s important to recall that only one-third of people with reported acute hepatitis B actually recorded any risk factors,” said Dr. Weng, who is a medical epidemiologist in the Hepatitis Branch of the CDC. “The current risk-based vaccination strategy provides no advantages in identifying and vaccinating [those] people.”

It has not been a total wash, he added, because the has been partially successful with initial decreases, but new hepatitis B virus (HBV) infections began to plateau 10 years ago, according to Dr. Weng.

The problem is not insignificant.

An estimated 1.89 million people live with chronic HBV, and up to 25% of them are at risk for premature death from cirrhosis or liver cancer. About 20,700 acute infections occur annually. Each year, the United States spends more than $1 billion on HBV-related hospitalizations, and this figure does not include indirect costs, according to Dr. Weng, who is a medical epidemiologist at the CDC.

“The HepB immunization strategy has evolved over the past four decades,” he said. “Risk-based strategies were first introduced among the adults and perinatally exposed infants in the early 1980s. Then universal infant vaccination was introduced in 1991 with catch-up vaccination recommendations for adolescents in 1999, followed by the introduction of a universal birth dose among all newborns in 2005. All of these steps toward routine HepB vaccination resulted in large declines,” Dr. Weng explained. “However, hepatitis B incidents have plateaued over the past 10 years, with more than 20,000 new infections estimated to occur each year.”

HepB vaccination has had the most success among children, because the recommendation is part of the universal childhood immunization schedule, he said.

Rates are now highest among adults and have increased among adults 40 years of age and older.

The Department of Health and Human Services called for the elimination of viral hepatitis in the United States by 2030,

according to Dr. Ault, and the plan emphasizes the role of vaccination. The Viral Hepatitis Plan focuses on the three most common hepatitis viruses in the United States: hepatitis A, HBV and HCV. According to HHS, “the nation faces unprecedented hepatitis A outbreaks, progress on preventing hepatitis B has stalled, and hepatitis C rates nearly tripled from 2011 to 2018” (https://bit.ly/3EMOvUO-IDSE).

Another problem with the risk-based strategy was health inequity, according to Dr. Weng. Risk-based recommendations favor people with consistent access to preventive health services, who trust their health care provider enough to disclose potentially stigmatizing risk factors, are aware of their risk and enjoy a high degree of health literacy.

“Right now, acute infection rates among Black American adults were up to three times the rates of Asian/Pacific Islanders and Hispanics,” he said, and all minorities have higher rates of disease than whites.

The universal strategy for children and adolescents eliminated most of the racial disparities among children when it came to HepB vaccination. “Rates of HBV infection for children and adolescents of all races/ethnicities converged to a lower rate when a universal vaccination strategy was implemented for children 18 and younger,” Dr. Weng explained.

A universal vaccination strategy has been successful in increasing the uptake of several vaccines: In 2010, almost 27% of adults were vaccinated under a risk-based recommendation, and that increased to 51% of adults during the 2020-2021 flu season under a universal recommendation. The same was seen for pneumococcal vaccination going from 23.3% in 2018 to 69% when the vaccine was universal for those 65 years of age and older.

“The past decade has illustrated that risk-based screening among adults has gotten us as far as it can take us,” Dr. Weng said.

The hepatitis work group recommended a universal strategy for all adults because universal vaccination would: • reduce stigma and barriers; • make the recommendation simpler and easier to implement for providers; • help eliminate HBV both here and abroad; and • advance health equity goals.

But everything has a cost. The Institute for Clinical and Economic Review, which provides independent evaluations about the value of medical interventions, found that universal HepB vaccination would cost $153,000 per quality-adjusted life-year (QALY). However, the QALY estimate would decrease as more people were vaccinated, according to Dr. Weng.

Acute HBV infections should be reduced by 24% and HBVrelated deaths by 23%, he found.

The ACIP agreed with the need for a change in strategy, but disagreed that all older adults needed to be included in a universal recommendation.

“I agree that the risk-based strategy has taken us as far as we can go, and the universal strategy is appropriate. But I have concerns about having a recommendation for adults over the age of 60,” said ACIP Member James Loehr, MD, FAAFP, a family practitioner in Ithaca, N.Y.

“I feel there’s diminishing return,” he said. “If you only give it to people under 59 years old, you’ll be giving 298 million doses. If you give it to all adults, it should be about 352 million doses. That’s an additional 54 million doses, an extra 18%. You are increasing the percentage of people who are protected by 28%, but you’re reducing the acute infections by only 1%,” he said.

Many on the panel had concerns both for and against vaccinating those 60 and older. “I just like to highlight that as a clinician who sees hundreds of patients as they are being evaluated for organ transplant, who have both kidney and liver failure, I am shocked at the number of people who are on dialysis or who have cirrhosis who are not yet vaccinated against hepatitis B,” said Camille Nelson Kotton, MD, FISDA, FAST, the clinical director of transplant and immunocompromised host infectious diseases in the Infectious Diseases Division at Massachusetts General Hospital, in Boston. “So, we have a very large population, some under the age of 16, many over the age of 60, who would benefit from vaccination.”

However, most agreed that the most beneficial group to target would be those younger than 60. “It doesn’t seem to me like a 90-, 95-year-old, an 85-year-old may be the person who really needs to be vaccinated,” said Pablo J. Sanchez, MD, a professor of pediatrics at The Ohio State University Nationwide Children’s Hospital, in Columbus. “And that’s what would happen with this universal recommendation. So, I tend to agree that the age cutoff needs to be relooked at.”

In the end, the committee voted 15-0 to recommend HepB vaccination for all adults 19 to 59 years of age. The committee added caveats for those 60 and older: Those with known risk factors should be vaccinated against HBV; and those who do not know their risk may be vaccinated against HBV.

This recommendation comes with a growing “toolbox,” Dr. Weng said. There are now two single-antigen vaccines given on a three-dose schedule (Engerix, GlaxoSmithKline and Recombivax HB, Merck) and a two-dose vaccine (Heplisav-B, Dynavax). In addition, another vaccine is in the pipeline.

And by late 2022, the CDC is expecting to release recommendations calling for one-time HBV screening for all adults.

Although he supported a universal recommendation that included older adults, Jason M. Goldman, MD, FACP, the liaison representative for the American College of Physicians, said that making the recommendations less complex would help clinicians vaccinate more people. “I try to teach my colleagues nationally on how to implement vaccine programs, and the biggest barrier to implementation is how confusing and detailed these recommendations are, so streamlining it, making it universal and easy to implement as possible is key to success.” ■

The sources reported no relevant financial disclosures.

Hepatitis D Pipeline

continued from page 38

Tobias Böttler, MD, an attending physician at the University Hospital Freiburg, in Germany, commented that bulevirtide has the potential to make a significant difference in managing patients with active HDV infection. “We still need to learn a lot with regard to dosing, treatment duration and possible combination therapies, [because] some data suggest that combination with interferon is even more potent,” he said. “It appears to be well tolerated with little side effects, based on the data we currently have. Going forward, we might even be able to use the drug in hepatitis B–monoinfected patients, but that requires a lot more data from clinical trials.”

Oral Formulation Option

For patients and providers who prefer orally administered therapy, another investigational agent, lonafarnib (Zokinvy, Eiger Biopharmaceuticals), may be an option if it succeeds in its pipeline journey. Lonafarnib is a late-stage, orally active inhibitor of farnesyl transferase, an enzyme involved in the modification of proteins through a process called prenylation. The FDA approved the drug in 2020, to reduce the risk for death from Hutchinson-Gilford progeria syndrome and for the treatment of certain processing-deficient progeroid laminopathies in patients 1 year of age and older.

Lonafarnib has been evaluated in several clinical trials for the treatment of HDV, either as monotherapy or with pegylated interferon alfa-2a (PEG IFN-alfa-2a) or ritonavir. In a proof-ofconcept study that explored optimal treatment regimens, the addition of ritonavir to a twice-daily oral lonafarnib regimen of 100 mg yielded optimal antiviral responses, with significantly fewer gastrointestinal side effects than lonafarnib monotherapy (Hepatology 2018;67[4]:1224-1236). The reduced GI side effects likely are due to ritonavir’s ability to inhibit lonafarnib metabolism, allowing for higher concentrations of the farnesyl transferase inhibitor to build up in the liver and systemic circulation, the researchers noted.

In 2018, the FDA granted lonafarnib breakthrough therapy designation for the treatment of HDV infection. The drug currently is being investigated in D-LIVR, a global phase 3 trial evaluating an all-oral arm of lonafarnib boosted with ritonavir. The trial also so includes a combination arm of ritonavir boosted with ritonavir ir plus PEG IFN-alfa-2a. Each arm is to be compared with a plaacebo arm in HDV-infected patients (ClinicalTrials.gov identifier: r: NCT03719313). The estimated study completion date is April 1, , 2023, according to the ClinicalTrials.gov listing. ■

Dr. Böttler reported that he served on an advisory committee for Gilead Sciences. Dr. Wedemeyer reported financial relationships with Abbott, AbbVie, Altimmune, Biotest, Bristol Myers Squibb, BTG, Dicerna, Gilead, Janssen, Merck/MSD, MYR GmbH, Novartis, Roche, Siemens and Transgene.

Hepatitis D: FAQs

Q: What are some of the key distinguishing features of the hepatitis D virus (HDV) and its associated illness?

A: HDV is known as a “satellite virus,” because it can only infect people who are also infected by the hepatitis B virus (HBV). HDV infection can be acute or lead to chronic, long-term illness. The infection can be acquired either simultaneously with HBV as a coinfection, or as a superinfection in people who are already chronically infected with HBV.

Q: What is the difference between hepatitis B/ HDV coinfection and HDV superinfection?

A: HBV/HDV coinfection occurs when a person simultaneously becomes infected with both HBV and HDV, whereas HDV superinfection occurs when a person who is already chronically infected with HBV acquires HDV. Although acute HBV/HDV coinfections can resolve, HDV superinfection can lead to rapid progression of the already present HBV infection, resulting in liver cirrhosis and liver failure. These outcomes occur within five to 10 years in 70% to 80% of affected people and within one to two years in 15% with chronic HBV/HDV infection.

Q: How common is HDV in the United States?

A: HDV infection is uncommon in the United States; most U.S. cases occur among people who migrate or travel here from countries where HDV is endemic. Because hepatitis D is not a nationally notifiable condition, the actual number of hepatitis D cases in the United States is unknown.

Q: Where is HDV most common?

A: Hepatitis D is most common in Eastern Europe, Southern Europe, the Mediterranean region, the Middle East, West and Central Africa, East Asia, and the Amazon Basin in South America.

Q: Are there different genotypes of HDV, and where do they circulate?

A: Eight different HDV genotypes can be found around the world, all of which share the same transmission routes and risk groups. HDV genotype 1 circulates mainly in North America, Europe, the Middle East, and North Africa. Genotypes 2 and 4 can be found in East Asia. Genotype 3 is found exclusively in the Amazon Basin in South America. Genotypes 5, 6, 7 and 8 are found in West and Central Africa.

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Source: CDC (bit.ly/3jOmrI2).