Delivery, manufacturing concerns hinder green light from US Agency, but European Medicines Agency approves treatment.
Hepatitis D virus (HDV) can cause acute or chronic infection and only affects those with a positive hepatitis B surface antigen (HBsAg).1 HDV is a significant contributor to hepatitis B virus (HBV)-associated liver disease and has been estimated to cause 1 in 6 cases of cirrhosis and 1 in 5 cases of hepatocellular carcinoma in individuals with HBV.2 The global prevalence of HDV among individuals who are HBsAg positive has been estimated to be approximately 4.5% and varies based on geographical region, with the highest prevalence in Mongolia (36.9%).2
Transmission occurs through exposure to infected blood or bodily fluids.3 Individuals at risk of acquiring HDV include those with chronic HBV, household contacts and sexual partners of individuals with HDV, men who have sex with men, and individuals who inject drugs.
There is currently no vaccine for HDV; however, HBV vaccination does provide protection and is the only method of prevention.3,4 Vaccination does not prevent HDV infection in patients already infected with HBV.
Currently, there is no FDA-approved regimen for the treatment of HDV. For more than 30 years, off-label use of pegylated interferon-α (PEG-IFN-α) for a minimum of 48 weeks has been the mainstay of treatment for chronic HDV in individuals with elevated HDV RNA and active liver disease.5 However, treatment with PEG-IFN-α has been associated with limited sustained clinical response and high virologic relapses.6,7 PEG-IFN-α therapy also carries risks of significant toxicities, such as musculoskeletal pain, skin toxicity, fatigue, neutropenia, gastrointestinal symptoms, and flu-like symptoms, which often lead to discontinuation of therapy. Because chronic HDV infection is considered serious and life-threatening with limited treatment options, there is a dire need for more effective and safer therapies.
Bulevirtide (Hepcludex; Gilead Sciences, Inc) is a first-in-class investigational entry inhibitor for the treatment of chronic HBV/HDV.8 It is a daily subcutaneous injection. Common adverse effects include headache, eosinophilia, dizziness, nausea, increased total bile salts, pruritus, arthralgia, fatigue, influenza-like illness, and injection site reactions.
In phase 2 trials, bulevirtide (BLV) was studied in combination with tenofovir disoproxil fumarate (TDF) in MYR202 (NCT03546621) and in combination with PEG-IFN-α in MYR203 (NCT02888106) and MYR204 (NCT03852433).9-13
Combination therapy with BLV (2, 5, or 10 mg) and TDF for 24 weeks resulted in virologic response (VR), defined as a 2-log decline or undetectable HDV RNA by week 24, in 54%, 50%, and 77% of subjects, respectively, compared withonly 4% with TDF monotherapy.9-11 Relapse occurred in 87%, 94%, and87% of responders on BLV 2, 5, and10 mg, respectively.
In the MYR203 and MYR204 trials, VR was highest in patients treated with BLV and PEG-IFN-α.9,11,13 VR at week 72 was achieved in 53.3% of patients assigned to BLV 2 mg with PEG-IFN-α and 26.7% of patients on BLV 5 mg with PEG-IFN-α, all of whom were treated for 48 weeks in the MYR203 trial. A decline of more than 1 log HBsAg was observed in 47% of the BLV 2-mg group and 13% of the BLV 5-mg group.
VR in the MYR204 trial was achieved in 88% and 92% of patients taking BLV 2 and 10 mg, respectively, with PEG-IFN-α compared with 72% of patients taking BLV 10-mg monotherapy at week 24.13 Combined response of VR and alanine aminotransferase normalization at week 24 was achieved in 50% of theBLV 10-mg monotherapy arm, which was higherthan the combination arms. Final results have not yet been published.
Despite VR, the above studies suggest durable response is only achieved in patients who lose HBsAg.9-13 MYR301 (NCT03852719),a phase 3 study investigating BLV monotherapy at 2 or 10 mg, is currently underway.13 At the 24-week interim analysis, combined response was numerically higher in the 2-mg group (37%) than the 10-mg group (28%).13
Based on results from MYR202 and MYR203, BLV was conditionally approved by the European Medicines Agency in 2020 for the treatment of chronic HDV with compensated liver disease.14 BLV was not as well received by the FDA and was not approved due to concerns with manufacturing and delivery of the medication, which is similar to other recent rejections turned approvals. The manufacturer released a statement regarding their plans to continue working toward approval with the FDA.14
Although there is low prevalence of HDV in the United States, it is considered to be the most severe type of viral hepatitis. Existing treatment options are poorly tolerated, necessitating the development of novel agents.
BLV has promising safety and efficacy data from phase 2 and 3 trials, and additional data from ongoing studies will be helpful in determining its optimal use. Although news of BLV’s rejection by the FDA is a barrier to treatment of this severe infection, recent successes with other medications on the same trajectory suggest a potential positive outcome for BLV inthe future.
1. Urban S, Neumann-Haefelin C, Lampertico P. Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease. Gut.2021;70(9):1782-1794. doi:10.1136/gutjnl-2020-323888
2. Stockdale AJ, Kreuels B, Henrion MYR, et al. The global prevalence of hepatitis D virus infection: systematic review and meta-analysis. J Hepatol. 2020;73(3):523-532. doi:10.1016/j.jhep.2020.04.008
3. Hepatitis D. World Health Organization. June 24, 2022. Accessed January 26, 2023. https://www.who.int/news-room/fact-sheets/detail/hepatitis-d
4. Hepatitis D questions and answers for health professionals. CDC. Reviewed March 9, 2020. Accessed January 26, 2023. https://www.cdc.gov/hepatitis/hdv/hdvfaq.htm#section2
5. Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 9th Edition. Elsevier; 2019.
6. Wedemeyer H, Yurdaydin C, Hardtke S, et al. Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial. Lancet Infect Dis. 2019;19(3):275-286. doi:10.1016/S1473-3099(18)30663-7
7. Heidrich B, Yurdaydin C, Kabaçam G, et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology. 2014;60(1):87-97. doi:10.1002/hep.27102
8. HEPCLUDEX 2 mg powder for solution for injection. Electronic Medicines Compendium. Updated September 7, 2022. Accessed January 27, 2023. https://www.medicines.org.uk/emc/product/13482/smpc#gref
9. 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(5):1422-1430. doi:10.1016/j.jhep.2022.06.010
10. Wedemeyer H, Schöneweis K, Bogomolov P, 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, randomised, parallel-group, open-label, phase 2 trial. Lancet Infect Dis. 2023;23(1):117-129. doi:10.1016/S1473-3099(22)00318-8
11. Wedemeyer H, Schöneweis K, Bogomolov PO, 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:S19-S57. doi:10.1016/S0168-8278(20)30651-6
12. Asselah A, Arama SS, Bogomolov P, et al. Safety and efficacy of bulevirtide monotherapy and in combination with peginterferon alfa-2a in patients with chronic hepatitis delta: 24 weeks interim data of MYR204 phase 2b study. J Hepatol. 2021;75:S291.
13. Wedemeyer H, Aleman S, Andreone P, et al. Bulevirtide monotherapy at low and high doses in patients with chronic hepatitis delta: 24-week interim data of phase 2 MYR301 study. J Hepatol. 2021;75:S294.
14. Gilead receives complete response letter from U.S. FDA for bulevirtide for the treatment of adults with hepatitis Delta virus. News release. Gilead Sciences, Inc. October 27, 2022. Accessed January 26, 2023. https://www.gilead.com/news-and-press/company-statements/gilead-receives-complete-response-letter-from-us-fda-for-bulevirtide-for-the-treatment-of-adults-with-hepatitis-delta-virus
About the Authors
Jenna Januszka, PharmD, BCPS, AAHIVP, is a PGY2 HIV/infectious diseases resident at the University of Illinois Chicago.
Cara Slaton, PharmD, BCIDP, is an infectious diseases clinical pharmacist at Orlando Health Orlando Regional Medical Center in Florida.