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HBV: An underprioritized public health threat
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Viral hepatitis kills thousands of people each year in the United States and causes more deaths worldwide than HIV, malaria and tuberculosis. Yet when experts traveled to Washington, D.C, last year to brief members of Congress about a national strategy to eliminate hepatitis B and C, they were met with a surprising lack of interest.
Just two people showed up for a briefing at which 30 or 40 lawmakers and staff would normally have been expected to attend, according to Brian L. Strom, MD, MPH, chancellor of Rutgers Biomedical and Health Sciences and chair of the Committee on a National Strategy for the Elimination of Hepatitis B and C.
“There just wasn’t any interest,” Strom told Infectious Disease News. “Here we’re talking about getting rid of the major cause of liver cancer — one of the very few cancers that are increasing — and the major cause of liver transplant, and no one bothered. The people who did show up were focused on the cost of hepatitis C drugs, not hepatitis B.”
Source: Rutgers, The State University of New Jersey
Strom chaired an expert committee that has published two reports through the National Academies of Science, Engineering and Medicine that explore the possibility of eliminating viral hepatitis, including HBV, as a public health problem in the U.S. By focusing on vaccination, testing and treatment, they said it is possible to reduce mortality from HBV by 50% by 2030 and eliminate mother-to-child transmission, a main driver of infection rates globally.
Unlike HCV, there are effective vaccines but no cure for HBV. The national plan to fight HBV has long focused on vaccination, a tool that may be as important as finding a cure for the disease.
“No disease has ever been eradicated without a vaccine, and we have a very effective vaccine for hepatitis B,” Strom said. “We can still get rid of the disease as a public health problem without a cure if we vaccinate more people.”
Infectious Disease News spoke with several experts about the challenges of eradicating HBV in the U.S., the role of vaccination, testing and treatment in our national elimination strategy and the potential for a cure.
‘Not prioritized’
According to Strom, viral hepatitis accounts for less than 1% of the NIH budget. Although experts characterized HBV as an historically underprioritized public health issue, they said it has recently gained more attention.
“The fact that we’re even talking about elimination ... is progress in itself,” Chari Cohen, DrPH, MPH, vice president for public health and programs at the Hepatitis B Foundation and co-chair of the Hep B United coalition, said in an interview.
According to Cohen, as many as 2 million people in the U.S. may have chronic HBV, but only around 25% of them know it.
“So, 1.5 million people in the U.S. have chronic hepatitis B and are at serious risk of dying from cirrhosis or liver cancer, and they have no idea,” she said.
HBV can either be an acute illness or a long-term chronic infection, with the latter occurring more commonly in patients who contract the virus as infants, according to the CDC. The agency lists many ways HBV can be transmitted, including being born to an infected mother — the most common form of transmission in countries where the virus is prevalent — injection drug use and having sex with an infected partner, which accounts for nearly two-thirds of all cases reported in the U.S. HBV is a hardy virus, capable of surviving in an infectious state outside the body for at least 7 days. It is between 50 and 100 times more infectious than HIV.
Symptoms of acute HBV, if they appear at all, usually start months after infection and can persist for up to 6 months, according to the CDC. Most children aged younger than 5 years and newly infected immunosuppressed adults are asymptomatic.
Acute HBV infections are rarely fatal, causing death in fewer than 1% of cases reported to the CDC. But chronic infections, which may not produce symptoms for decades, are a major public health concern. Cirrhosis or liver cancer kills approximately 25% of patients with chronic HBV who are infected in childhood and 15% who are infected after childhood. Chronic infections are far more common in patients who contract HBV at a young age, with approximately 90% of infants and up to half of children aged 1 to 5 years remaining chronically infected compared with around 5% of patients who are infected as adults.
Cohen said it is difficult to tell how many people die each year in the U.S. from HBV, in part because of the way death certificates are filled out. Certificates might list liver cancer or cirrhosis as the cause of death but ignore HBV as the underlying cause. Data indicate that HBV causes around 6,000 deaths per year in the U.S., but Cohen said that is probably an underestimation.
“We don’t talk about it in the U.S., and there’s not a lot of money for it,” Cohen said. “Because it’s not prioritized, we don’t have enough funds to do things like get an accurate picture of the epidemic because we don’t do surveillance for chronic hepatitis B infection.”
Role of vaccination
Experts agree that vaccination is fundamental to eliminating HBV.
“If you vaccinate everyone, the virus has nowhere to go,” William Schaffner, MD,Infectious Disease News Editorial Board member and professor of preventive medicine and medicine at Vanderbilt University, said in an interview.
A vaccine-based strategy to eliminate HBV in the U.S. has been in place since 1991, almost a decade after vaccination was first recommended by the CDC’s Advisory Committee on Immunization Practices (ACIP). The vaccination strategy, which has led to an 82% decrease in acute HBV cases, currently includes four main components:
The vaccine is usually given as three to four shots over 6 months and protects patients for at least 20 years, according to the CDC. An estimated 92.6% of children aged 19 to 35 months have received at least three doses of the vaccine, but coverage is far lower in adults. The vaccine — or a shot called hepatitis B immunoglobin — may prevent infection if given within 24 hours of exposure.
Vaccination is mostly effective, protecting more than 90% of infants, children and healthy adults, according to the CDC. But Schaffner said one of the limitations of the two HBV vaccines currently available in the U.S. — Recombivax HB (Merck) and Engerix (GlaxoSmithKline) — is that they do not optimally protect patients who are older, obese, have diabetes or smoke. In fact, according to the CDC, HBV vaccine effectiveness declines from 90% to 75% between the ages 40 and 60 years.
Heplisav-B (Dynavax), the new two-dose HBV vaccine approved recently by the FDA for use in adults aged 18 years an older, may address some of these gaps in vaccination, making it an attractive addition to the armamentarium, Schaffner said.
“A two-dose series is likely to enhance compliance and provide much more protection quickly,” he said. “And even with two doses, the new vaccine performed better in all of the risk groups. If you add that to enhanced compliance with two doses, it provides us with a new vaccine that might well accelerate its use and effectiveness in adults.”
Schaffner said the FDA’s approval of Heplisav-B, which was based on data from three phase 3 trials, could “speed up” talks by the ACIP to extend its recommendations for HBV vaccination to include all adults, not just those at an increased risk for infection.
“That would be a much more comprehensive recommendation that would accelerate the progress toward interrupting transmission of hepatitis B and protect a lot of people against the effects of chronic infection,” he said. “I know it will be discussed. What is finally determined depends upon the voting members of the committee.”
Testing and treatment
Whereas acute HBV cases may go away on their own, chronic cases are treated with antiviral drugs that suppress the virus, although not every patient needs them and the drugs may cause side effects. In the U.S., there are seven FDA-approved antivirals for HBV infection, compared with dozens of compounds that have been licensed to treat HIV and HCV infection.
There are barriers to getting every infected patient linked to care. According to unpublished CDC surveillance data, around 75% of chronic HBV infections in the U.S. are in patients who were born outside the country in places where routine vaccination may not have been implemented until more recently. About 50% of infections occur in Asians and Pacific Islanders, who are dying at disproportionate rates because of the disease, according to the agency.
Cohen said marginalized communities of immigrants have monetary, lingual, cultural and systemic barriers to accessing health care, including testing for HBV.
“Even when they are tested and diagnosed, they’re not getting into care,” she said. “If you can’t diagnose people who have hepatitis B and you can’t get them into care, you can’t prevent them from getting cirrhosis or liver cancer. You’re also not preventing the spread of the infection.”
In the U.S., rates of new HBV infections are highest among adults aged 30 to 49 years, highlighting low vaccination coverage among adults — just 24.5% for all adults aged older than 18 years, according to a 2016 study — and the burden of infections caused by injection drug use related to the ongoing opioid epidemic, which has hindered progress toward elimination. In 2016, for example, researchers noted a 114% increase in acute HBV infections in the Appalachian states of Kentucky, Tennessee and West Virginia that occurred after 2009 among whites aged 30 to 39 years who reported injection drug use. And a recent CDC progress report on HBV elimination noted that the rate of new infections in adults aged 19 years and older was 1.38 per 100,000 people in 2015 — nearly three times higher than a target set for 2020.
“With the increase in the opioid epidemic, which isn’t going away anytime soon, you’re going to see a lot more acute hep B infections,” Cohen said.
Strom and colleagues focused on the need for better HBV surveillance and expansion of testing and linkage to treatment among infected patients. Among their recommendations, they called for increased screening, vaccination and treatment in correctional facilities, expanded access to needle exchange programs, free HBV vaccination at pharmacies, and the type of state-level support for HBV vaccination that is given to the seasonal influenza vaccine. To link more patients to care, Strom and colleagues recommended that HHS work with states to build a system that could offer primary medical care and support for viral hepatitis patients comparable to the Ryan White HIV/AIDS Program.
They said the number of deaths due to HBV in the U.S. could be cut in half by 2030 by diagnosing 90% of patients with chronic HBV, linking 90% of those patients to care, and treating 80% of patients who require antivirals. Additionally, they said liver cancer and cirrhosis due to HBV could be reduced by 45%.
“The most important thing is for cases to be detected and more people to be vaccinated,” Strom said.
In recent clinical practice guidelines, the American College of Physicians and the CDC recommend screening at-risk adults for HBV, increasing vaccination rates — including among pregnant women — and linking all infected patients to post-test counseling and HBV-directed care.
Path to a cure
Experts believe it will be some time before a cure or functional cure for HBV is available.
“I would say it’s definitely years away,” Jordan J. Feld, MD, MPH, scientist at Toronto General Hospital Research Institute and associate professor of medicine at the University of Toronto, said in an interview.
On top of the time it takes to investigate potential medicines, there are other challenges to developing a cure for HBV.
“It is likely that combination therapy will be required,” Feld said. “And another challenge is there are different phases of HBV infection, and it’s possible that certain approaches may only work in one phase or another, complicating study design and ultimate use of new therapies.”
Using input from dozens of experts, the Hepatitis B Foundation recently published a road map that outlines the most promising avenues of research for an HBV cure and how much it will cost. The document was condensed from two papers, including a manuscript Cohen said will soon be published in Hepatology.
Feld said one of the reasons HBV has gained more attention recently is that HCV drugs have been so successful and lucrative.
“I don’t think anyone would have predicted that hep C treatment would advance the way it has and as quickly as it did,” he said. “To go from 50% cure rates with very difficult-to-tolerate treatment to near 100% cure rates with a pill a day with no side effects is almost hard to imagine, let alone predict. Many people have come into the hep B space who say, ‘Maybe we can do for hep B what we did for hep C’ — that would be fantastic, especially given that there are somewhere between three or four times more people with hep B than hep C globally.”
According to the Hepatitis B Foundation road map, an HBV cure would need to reduce a patient’s risk for liver cancer, cirrhosis and death due to liver disease, ideally to a level comparable to that of a patient who has never been infected. The report outlines several broad areas of research needed to find a cure, including improving the understanding of HBV virology. A separate panel of experts estimated that the steps laid out in the road map would require an additional $232 million in NIH support over 6 years.
Current HBV treatments work by inhibiting the assembly of new viral DNA. Among the experts who took part in the road map, there was a consensus on the need to prioritize research into understanding viral genomic DNA that persists in infected liver cells. According to the report, long-acting covalently closed circular DNA (cccDNA) results in rebounding virus levels in patients who stop antiviral treatment, and understanding that process better might be the fastest route to a cure.
Feld noted cccDNA as the reason that, unlike HCV, HBV is rarely if ever naturally truly curable — that is, there are almost always traces of the virus left in the liver, even after a “resolved” infection. There are other differences. HCV is a steady, progressive disease, whereas HBV is a “dynamic” infection, difficult to predict over time, Feld said.
“It’s much more difficult to develop a curative therapy for hep B but hopefully not impossible,” he said. “The science is very interesting, and there’s been great progress in terms of understanding a lot of aspects of hep B. I am cautiously optimistic that it will lead to curative therapy. The only question is whether it will be a commercially viable thing and whether companies hang around long enough to find a therapy that works.”
Another challenge is that a curative therapy would have to be significantly better than the antivirals that are already used to treat HBV. In this way, Feld said the bar for an HBV cure is much higher than it was for HCV.
“We have very effective suppressive therapies that work very well — the only downsides are that you need to take them for a very long time, if not for life, and they reduce but do not completely eliminate the risk for liver cancer,” he said. “If a curative treatment requires very long-term therapy or it has significant side effects, it’s probably not a major advance over what we already have.”
All four experts agreed that finding a cure for HBV is important for elimination, but not more important than using the currently available tools. Feld said “it’s not a ridiculous proposition” to focus every resource on raising global vaccination rates to 100% and using currently available treatments to manage patients who are already infected.
“In terms of reducing the burden of illness, morbidity and mortality from hep B globally, that might be the most effective strategy,” he said. “But for individuals living with the infection, that doesn’t help them very much.” – by Gerard Gallagher
- References:
- Abara WE, et al. Ann Intern Med. 2017;doi:10.7326/M17-1106.
- CDC. Hepatitis B FAQs for the public. 2016. https://www.cdc.gov/hepatitis/hbv/bfaq.htm/.
- CDC. Viral hepatitis surveillance – United States, 2015. https://www.cdc.gov/hepatitis/statistics/2015surveillance/pdfs/2015HepSurveillanceRpt.pdf. Accessed December 1, 2017.
- Harris AM, et al. MMWR Morb Mortal Wkly Rep. 2016;doi:10.15585/mmwr.mm6503a2.
- Hepatitis B Foundation. An overview of a roadmap for a cure. 2017. http://www.hepb.org/research-and-programs/roadmap-to-a-cure/. Accessed December 1, 2017.
- Naghavi M, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)32152-9.
- National Academies of Sciences, Engineering and Medicine. A national strategy for the elimination of hepatitis B and C: Phase two report. 2017. http://www.nationalacademies.org/hmd/reports/2017/national-strategy-for-the-elimination-of-hepatitis-b-and-c.aspx. Accessed December 1, 2017
- For more information:
- Chari Cohen, DrPH, MPH, can be reached at Chari.Cohen@hepb.org.
- Jordan J. Feld, MD, MPH, can be reached at Jordan.Feld@uhn.ca.
- William Schaffner, MD, can be reached at William.Schaffner@vanderbilt.edu.
- Brian L. Strom, MD, MPH, can be reached at chancellor@rbhs.rutgers.edu.
Disclosures: Cohen and Strom report no relevant financial disclosures. Feld reports receiving research support from AbbVie, Gilead Sciences, Janssen, Merck and Wako and consulting fees from AbbVie, ContraVir, Gilead and Intellia. Schaffner reports serving on a data safety monitoring board for Merck and consulting with Dynavax prior to licensure of Heplisav-B.