Hepatitis D makes the treatment of hepatitis B more difficult. The risk of liver cirrhosis is greatly increased with simultaneous HDV infection. Due to the risk of a fulminant course, monitoring of transaminases and liver synthesis performance is of particular importance in acute HDV infection. In addition to pegylated interferon-alpha, bulevirtide is also available for treatment. Phase III data on this entry inhibitor were published in the New England Journal of Medicine 2023.
If there is a concomitant hepatitis D infection in addition to the hepatitis B infection, this must be treated separately, as the nucleoside and nucleotide analogs are not effective against hepatitis D. In addition, the hepatitis D virus (“delta”) usually dominates in a so-called co-infection with a significantly higher viral load [1]. In these cases, the administration of pegylated interferon-alpha (PegIFNα) or the entry inhibitor bulevirtide is recommended for adults. Bulevirtide inhibits the uptake of the virus particles into the liver cells [2].
Fulminant and chronic progressive courses possible
Co-infection with HDV (Box) usually follows the same course as acute hepatitis B, with a typically biphasic increase in transaminases. Around one third of all fulminant hepatitis B infections have a concomitant delta infection [3–5]. In patients with pre-existing chronic hepatitis B and a pronounced increase in transaminases, the possible presence of an HDV superinfection should be clarified [3–5]. Fulminant and chronic progressive courses with accelerated development to cirrhosis are common. If anti-HDV-IgM (over 5-6 or up to 12 weeks, then anti-HDV-IgG) and a high titer of anti-HBc-IgM are detected at the same time, a co-infection can be assumed. In the case of a superinfection, anti-HDV-IgM is found without detection of anti-HBc-IgM (or only low anti-HBc-IgM titres). Determination of HDV RNA to detect HDV replication is necessary.
| Coinfection or superinfection The hepatitis D virus (HDV; delta virus) is a virusoid that contains RNA and the HDV antigen (Ag). The incomplete virus requires the envelope antigen of HBV for HDV replication. The interaction between the two viruses also influences the extent of virus replication. Infection with HDV can occur simultaneously with HBV infection (co-infection) or in chronic HBs-Ag carriers (superinfection). Risk groups for HDV infection largely correspond to those for HBV infection. An accumulation is found in intravenous drug abuse (20-53%) and hemophilia patients (48-80%). Sexual transmission is possible, but less frequent than with HBV, and perinatal transmission is extremely rare. In Switzerland, infection with hepatitis D is rare; infections are most common in Mediterranean countries, Eastern Europe, some parts of South America and the Pacific Islands. In the 1980s, around 8-20% of HBs-Ag carriers in Mediterranean countries were HDV-positive, but the incidence of infection has fallen significantly in recent years. |
| according to [3] |
In a chronic course, anti-HDV IgM and IgG are simultaneously detectable [3–5]. Persistently high anti-HDV-IgG titers (>1:1000) correlate with continued viral replication. HDV-Ag is often only detectable in the serum for a short time during the incubation period. HDV RNA can be detected in serum and liver tissue in anti-HDV IgM-positive patients with acute or chronic infection. It is recommended that patients with chronic HBV infection undergo HDV diagnostics at least once. Vaccination against hepatitis B also protects against delta infection
Therapy with pegylated interferon-alpha and/or bulevirtide
Bulevirtide and PegIFNα can be used either as monotherapy or in combination [4]. Clinical studies in which PegIFNα was used showed virological response rates of around 17-47%. HDV late recurrences after the end of therapy occurred in more than 50% of responder patients [4]. Bulevirtide (s.c.) has been approved in Europe for adult patients with chronic hepatitis D and compensated liver disease since 2020 [4]. The active substance blocks viral entry into hepatocytes [4]. Bulevirtide showed good efficacy in terms of virological response (virological response rate of around 50%) and clinical response, even in patients with advanced cirrhosis and portal hypertension, both in clinical trials and in practice [6].
Current study data on bulevirtide
In Phase II clinical trials, bulevirtide was investigated both as monotherapy (MYR-202, MYR-203, MYR 204) and in combination with PegIFNα (MYR-203, MYR-204) for different doses (2 mg vs. 5 mg vs. 10 mg) and treatment periods (24 weeks, 48 weeks, 96 weeks) [6–9]. Overall, bulevirtide led to a decrease in HDV RNA both as monotherapy and in combination with PegIFNα ; in combination treatment, the antiviral effect was synergistic and led to a more pronounced decrease in HDV RNA [10].
The Phase III MYR-301 study evaluated the safety and efficacy of bulevirtide monotherapy: 2 mg vs. 10 mg for 144 weeks vs. 10 mg for 96 weeks (48-week delayed treatment arm) in a total of 150 patients**. A combined response, defined as virological response (undetectable HDV RNA or ≥2 log decrease from baseline) plus biochemical response (ALT normalization) at week 48, was achieved by 45% (2 mg arm) and 48% (10 mg arm) of patients treated with bulevirtide. The virological response rates were 71% and 76% respectively, while ALT normalization occurred in 51% and 56% of patients [11].
** 43% with compensated cirrhosis
Literature:
- “Hepatitis B”, www.ukw.de/behandlungszentren/leberzentrum/schwerpunkte/chronische-lebererkrankungen/hepatitis-b,(last accessed 08.01.2024)
- Sandmann L, et al: Addendum “Antiviral therapy of chronic hepatitis D virus infection” to the S3 guideline “Prophylaxis, diagnosis and therapy of hepatitis B virus infection” of the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS). May 2023 – AWMF register number: 021-11, consultation version.
- “Liver”, Practical Gastroenterology 2011: 281-366.
- “Hepatitis D”, https://flexikon.doccheck.com/de/Hepatitis_D,(last accessed 08.01.2024)
- “Hepatitis Delta”, https://www.hepatitisandmore.de/hepatitis_delta,(last accessed 08.01.2024)
- Lampertico P, et al; Delta Cure 2022 Working Group. Hepatitis D virus infection: Pathophysiology, epidemiology and treatment. Report from the first international delta cure meeting 2022 JHEP Rep 2023 Jun 28; 5(9): 100818.
- Wedemeyer H, et al: Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR202): a multicentre, randomized, parallel-group, open-label, phase 2 trial. Lancet Infect Dis 2023; 23: 117-129.
- Wedemeyer H, et al: 48 weeks of high dose (10 mg) bulevirtide as monotherapy or with peginterferon alfa-2a in patients with chronic HBV/HDV coinfection. J Hepatol 2020; 73: S52.
- Asselah A, et al: Safety and efficacy of bulevirtide monotherapy and in combination with peginterferon alfa-2a in patients with chronic hepatitis delta: 24-week interim data of MYR204 Phase 2b study. J Hepatol 2021; 75 (OS-2717): S291.
- Lampertico P, Roulot D, Wedemeyer H: Bulevirtide with or without pegIFNα for patients with compensated chronic hepatitis delta: from clinical trials to real-world studies.J Hepatol. 2022; 77: 1422-1430.
- Wedemeyer H, et al; MYR 301 Study Group. A Phase 3, Randomized Trial of Bulevirtide in Chronic Hepatitis D. N Engl J Med 2023 Jul 6; 389(1): 22-32.
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