‘Uncommon’ but not ‘unimportant’: Screen all patients with hepatitis B for HDV
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Despite being the smallest virus capable of causing human disease, it is estimated that up to 80% of patients with hepatitis delta virus will progress to liver cirrhosis and more than 50% will die of liver disease within 10 years of diagnosis.
“It is the most severe form of viral hepatitis,” Beatrice Zovich, MPH, public health program manager at Hepatitis B Foundation, told Healio Gastroenterology. “When someone is living with hepatitis delta, they have a much more rapid progression to cirrhosis and potentially liver failure or hepatocellular carcinoma.”
Members of The Coalition for Global Hepatitis Elimination who attended the United Nations second annual Group of Friends to Eliminate Hepatitis meeting on Sept. 22, 2023, pictured (L to R) Lindsey Hiebert-Suwondo, Jallure Harrell, Harvey Alter, MD, John W. Ward, MD, Zadia Valdez, Monica Fambrough and Nida Ali, MD.
Source: The Coalition for Global Hepatitis Elimination
Nancy S. Reau, MD, FAASLD, AGAF, Richard B. Capps Chair of Hepatology, section chief and associate director of organ transplantation at Rush University, described HDV as a “deficient virus” because it requires the presence of hepatitis B virus to complete its life cycle and replicate.
It is also considered a “rare disease,” Zovich said, with WHO estimating it affects nearly 5% of the global population with chronic HBV and that co-infection could explain one in five cases of liver disease and liver cancer in HBV.
Despite the downstream effects of HDV, surveillance efforts are largely hindered by a lack of awareness and inconsistent and inaccurate rates of infection. John W. Ward, MD, director of the Coalition for Global Hepatitis Elimination and professor at Emory University, said that only a “better sense of how big the prevalence is” will motivate change in policy, practice and HDV care.
In this exclusive, Healio Gastroenterology spoke with experts across the field to highlight best practices as well as current screening guidelines for HDV and propel forward awareness about this rare disease.
Clinical Features of HDV
Once a patient is infected with HDV, symptoms such as fever, fatigue, loss of appetite, nausea and vomiting appear within 3 to 7 weeks. Calvin Pan, MD, and colleagues reported in Digestive Diseases and Sciences that levels of alanine aminotransferase and aspartate aminotransferase “increase dramatically as replication is at its most active.”
The icteric phase often follows initial symptoms, during which nausea and fatigue persist, and may worsen, but abate during the third phase of acute infection: the convalescent phase.
An individual can contract HDV either through co-infection or superinfection.
“A co-infection refers to a situation in which an individual acquires both HDV and HBV infections simultaneously,” Zovich said. “In 90% of these cases, the individual will clear both viruses from their body within 6 months, but in a small percentage of situations, this can lead to severe or even fatal liver failure. The vast majority of individuals, however, acquire HDV after already having a chronic HBV infection, also known as a superinfection. This has a high likelihood of progressing to severe liver disease very rapidly, especially without proper management.”
According to a meta-analysis in The Journal of Infectious Diseases, 80.96% (95% CI, 48.71-98.91) of coinfected patients spontaneously recover from HDV vs. 30.35% (95% CI, 12.05-52.7) of superinfected patients, while 10.45% (95% CI, 4.49-18.52) vs. 77.38% (95% CI, 55.09-93.54), respectively, progress to chronic disease.
“People who contract delta after they have been infected with hepatitis B are at the greatest risk for faster disease progression because of that second infection,” Ward said. “Someone with hepatitis B infection could be tested once and be negative for delta but then subsequently be infected.”
He added, “It is important to be mindful of an HBV patient’s ongoing risk of becoming infected with delta infection,” he added.
The meta-analysis also showed progression to chronic hepatitis and cirrhosis occurred within 1.5 years and 3 years, respectively, in 39.2% (95% CI, 13.14-69.16) and 30.44% (95% CI, 13.32-50.99) of patients with acute illness and 3 years and 3.1 years in 76.47% (95% CI, 63.98-86.98) and 29.74% (95% CI, 19.43-41.22) of patients with chronic infection. Of those with chronic hepatitis and cirrhosis, 14.04% (95% CI, 9.51-19.3) will progress to HCC within 3.7 years.
These results and more lead to one glaring question: Should every person with HBV be concerned about HDV? According to Ward, the answer is yes.
“Every person who has evidence of hepatitis B surface antigen positivity needs to also be tested for evidence of delta infection,” he said. “That way, we can begin to recognize those people who are at increased risk for disease progression and take steps for them to receive the care they need.”
Current Screening Guidelines
According to Reau, one of the biggest barriers patients face right now is inconsistency in screening guidelines.
“WHO and European guidelines now recommend near universal screening for delta among people who have hepatitis B surface antigen,” she said. “The U.S. guidelines are under revision, and we hope that will be added. If you are not instructed to screen everyone — and current guidelines still concentrate on high-risk screening — you tend to miss a lot of people simply because you may not recognize they are at risk.”
Currently, guidelines from AASLD — as reported in Clinical Liver Disease — recommend screening for:
- all HBsAg-positive individuals born in regions of high or intermediate HBV endemicity, defined as a prevalence of greater than 2%;
- patients born in the U.S. to parents from regions of high HBV endemicity who were not vaccinated as infants;
- persons who have ever injected drugs;
- men who have sex with men; and
- individuals with elevated ALT or AST of unknown etiology.
“We have a real challenge when it comes to screening and diagnosis for delta,” Ward said. “There are no licensed tests for delta in the United States and the quality of testing around the world varies. That’s one of the reasons for the poor data regarding prevalence: We don’t have a sense of how big the [HDV] is.”
Despite the absence of licensed diagnostic tools, Zovich said that testing patients with suspected HDV occurs in two parts.
“You first test for hepatitis delta antibody total, which will indicate if someone has ever been exposed,” she said.
Following a positive result, determination of the presence or viral load of HDV RNA “would confirm an active infection,” Zovich continued. This can be done using HDV RNA-qualitative PCR testing, which detects HDV at lower concentrations, or quantitative PCR testing, which determines viral load.
Data from a two-part retrospective and prospective analysis published in JHEP Reports showed that implementation of the current screening guidelines among 2,236 HBsAg-positive determinations in Barcelona from January 2018 to December 2021 increased the number of HBsAg-positive cases tested for HDV — from 7.6% (114/1,492) to 93% (691/744) — and “quintupled the absolute number of diagnoses” from 11 to 56 cases.
“I’m calling all clinicians to think about hepatitis B and hepatitis D as they take care of their patients and follow the recommendations for their countries,” Ward said. “If they are found to be HBsAg-positive, they should be screened for delta immediately so we can use the treatments available in their country, beginning with pegylated interferon-alfa, for their benefit.”
PEG-IFN-a: The ‘Most Widely Prescribed’ Treatment Available Now
Since the 1980s, early studies positioned type 1 interferons, and later PEG-IFN-a, as off-label treatment for patients with chronic HDV.
“Pegylated interferon is really the only option that is available now globally,” Zovich said. “Even though it has never officially been approved, it is still the most widely prescribed medication for adults around the world.”
Despite its widespread use, Ward noted that “only a minority of patients” exhibit a response to treatment. According to a review published in the Journal of Experimental Pharmacology, only 23% to 48% of patients with HDV across two large prospective clinical trials responded to PEG-IFN-a. Results also demonstrated HDV RNA negativity 24 weeks following the end of therapy among 25%, while 50% experienced a late relapse.
Though PEG-IFN-a is associated with improved long-term outcomes, severe adverse events such as flu-like symptoms, anemia, thrombocytopenia and psychiatric disturbances occur frequently among patients, underscoring the need for new therapeutic options.
“Right now, there is a big emphasis on a functional cure for hepatitis B,” Reau said. “And remember that delta is an obligatory virus — it needs HBV, so anything that is going to get rid of hepatitis B surface antigen will also potentially impact delta.
“I think that excitement in our hepatitis B pipeline also carries overs to excitement for delta, which is really awesome,” she added.
While a couple of drugs such as REP 2139 (Replicor) and JNJ-3989 (GSK) are currently in development, Hepcludex 2 mg (bulevirtide, Gilead Sciences) stands above the rest with approval in the European Union for the treatment of adult patients with chronic HDV and compensated liver disease.
Updates on Bulevirtide
In May 2023, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended bulevirtide 2 mg for full marketing authorization, based on data from the phase 3 MYR301 study that reinforced a greater benefit vs. risk profile.
“The development of bulevirtide has really revolutionized the whole field of hepatitis B care and treatment, because it provides an effective treatment specifically for delta that wasn’t there before and, in so doing, increases the value of screening and diagnosis of delta,” Ward said.
At this year’s EASL Congress, Pietro Lampertico, MD, PhD, and colleagues reported updated data from the MYR301 study, which showed long-term bulevirtide monotherapy 2 mg and 10 mg remained safe and effective for chronic HDV with improved biochemical, fibrosis and virologic markers at 144 weeks. Specifically, 57% of patients in the 2 mg group achieved combined response, with 73% achieving virologic response and 59% attaining ALT normalization, compared with patients who received 10 mg (combined response: 54%; virologic response: 76%; ALT: 60%).
“It’s important to note bulevirtide 2 mg remains the only approved treatment for hepatitis delta in the European Union; it is not approved in the U.S. at this time,” Anu Osinusi, MD, MPH, vice president of virology at Gilead Sciences, previously told Healio Gastroenterology. “The 10 mg dose of bulevirtide is an investigational product that is not approved anywhere in the world at this point in time.”
Analyses from MYR204 — a randomized, open-label, phase 2b study that evaluated the effectiveness of combined PEF-IFN a-2a and bulevirtide — showed combination therapy demonstrated the highest rates of undetectable HDV RNA through 48 weeks.
At 24 and 48 weeks following end of treatment, 17% and 25% of those assigned PEG-IFN a-2a for 48 weeks, respectively, achieved undetectable HDV RNA, as did 32% and 26% assigned bulevirtide 2 mg with PEG-IFN a-2a. In addition, 46% of patients assigned bulevirtide 10 mg with PEG-IFN a-2a for 48 weeks followed by 48 weeks of bulevirtide monotherapy achieved this result at weeks 24 and 48, as did 12% assigned bulevirtide 10 mg for 96 weeks.
“The results suggest that combination bulevirtide 10 mg with pegylated interferon was superior to bulevirtide monotherapy in achieving this undetectable HDV RNA 24 weeks after the end of treatment, with similar results when we followed patients out till 48 weeks after the end of treatment,” Osinusi said. “This shows that the bulevirtide combination with pegylated interferon has potential as a viable finite therapy for patients living with chronic hepatitis delta.”
Overcoming Barriers to Screening, Care
Another barrier affecting patients and the public health system is the gap in knowledge and awareness surrounding HDV. Zovich believes the driving force behind these persisting barriers lies in the fact that a specific and consistent case definition for HDV does not exist.
“Establishing a case definition for hepatitis delta would go a long way toward making it both notifiable for public health departments and reportable to the CDC,” she said. “Having HDV be a notifiable disease, same as with hepatitis B, could help us work toward establishing accurate epidemiology, fill huge gaps in knowledge and demonstrate the need to screen, as well as for insurance companies to cover it.”
She continued: “It can do so much in terms of driving change.”
According to Ward, another avenue health care can focus on to advance patient care is to “scale up” global screening for HBV to prevent the development of HDV.
“When you think about delta screening, you really have to start with hepatitis B screening,” he said. “Only about 10% of people with HBV worldwide are aware of their status and you cannot screen for delta until you are diagnosed with hepatitis B.”
Reau urged providers to remember this one piece of advice: “It is really important to understand that even if something is uncommon, it does not mean it is unimportant. You might think you don’t have viral hepatitis in your practice, but everybody with hepatitis B should be screened. Do not miss something that is going to help your patient stay alive and healthy.”
- References:
- Akiva KL, et al. Clin Liver Dis (Hoboken). 2024;doi:10.1097/CLD.0000000000000138.
- Asselah T, et al. 48-week off-therapy efficacy and safety of bulevirtide in combination with pegylated interferon alfa-2a in patients with chronic hepatitis delta: final results from the phase 2b, open-label, randomized, multicenter study MYR204. Presented at: EASL Congress; June 5-8, 2024; Milan (hybrid).
- CHMP adopts positive opinion recommending Hepcludex (bulevirtide) for full marketing authorization for the treatment of hepatitis delta virus (HDV). https://www.gilead.com/news-and-press/press-room/press-releases/2023/5/chmp-adopts-positive-opinion-recommending-hepcludex-bulevirtide-for-full-marketing-authorization-for-the-treatment-of-hepatitis-delta-virus-hdv. Published May 04, 2023.
- Lampertico P, et al. Efficacy and safety of 144 weeks of bulevirtide 2 mg or 10 mg monotherapy from the ongoing phase 3 study, MYR302. Presented at: EASL Congress; June 5-8, 2024; Milan (hybrid).
- Miao Z, et al. J Infect Dis. 2020;doi:10.1093/infdis/jiz633.
- Palom A, et al. JHEP Rep. 2022;doi:10.1016/j.jhepr.2022.100547.
- Pan C, et al. Dig Dis Sci. 2023;doi:10.1007/s10620-023-07960-y.
- Sandmann L, et al. J Exp Pharmacol. 2021;doi:10.2147/JEP.S235550.
- Voelker R. JAMA. 2024;doi:10.1001/jama.2024.1317.
- For more information:
- Nancy S. Reau, MD, FAASLD, AGAF, is the Richard B. Capps Chair of Hepatology, section chief and associate director of organ transplantation at Rush University; she can be reached at nancy_reau@rush.edu.
- John W. Ward, MD, is the director of the Coalition for Global Hepatitis Elimination and professor at Emory University; he can be reached at jward@taskforce.org.
- Beatrice Zovich, MPH, is the public health program manager at Hepatitis B Foundation; she can be reached at beatrice.zovich@hepb.org.
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