Editor's Note: Hepatitis D virus (HDV) is a defective virus that relies on hepatitis B virus (HBV) to produce infectious particles for transmission. The combined infection of both is considered one of the most severe forms of chronic viral hepatitis, posing a significant threat to human health. At the 9th "Silk Road Hepatitis Forum," Professor Xiaozhong Wang, Director of the Hepatology Department at the Xinjiang Uyghur Autonomous Region Traditional Chinese Medicine Hospital, was invited to present the latest research developments in screening, treatment, and prevention of HBV combined with HDV infection, providing essential insights for clinical management. "International Digest" has invited Professor Xiaozhong Wang and Professor Yunxiao Lui to share the highlights of the report.Hepatitis D virus (HDV) is a defective virus that relies on hepatitis B virus (HBV) to produce infectious particles for transmission. The combined infection of these two viruses is considered one of the most severe forms of chronic viral hepatitis, affecting an estimated 12 to 72 million people globally.
A retrospective study in South Korea [1] found that compared to chronic hepatitis B (CHB) alone, CHB combined with chronic hepatitis D (CHD) significantly increases the risk of compensated cirrhosis, decompensated cirrhosis, liver cell carcinoma (HCC), and liver transplantation. China has the highest number of HDV-infected patients globally, with an estimated prevalence of 0.69% in the general population and 10.16% in hepatitis B surface antigen (HBsAg)-positive individuals [2].
Due to unreliable infection assessment methods and non-standardized infection detection methods, the current prevalence of HDV is still subject to debate, and its actual epidemiology may be significantly underestimated. These hidden HDV infection groups pose a substantial threat to human health. Therefore, there is an urgent need to apply reliable screening tools and robust monitoring methods to study HDV and achieve the goals of the “Healthy China 2030” plan. Thus, the prevention and treatment of HBV combined with HDV infection are of paramount importance.
Screening for Hepatitis D
HDV infection primarily occurs through coinfection, where HBV and HDV infect the host simultaneously, but few infected individuals progress to chronic HDV infection. Overlapping infection, where HDV infection occurs in HBsAg or CHB carriers, often progresses to chronic HDV infection. These different infection pathways also result in significant differences in the incubation period and clinical presentation.
Screening for hepatitis D mainly involves laboratory tests and medical history assessments. According to the “2023 Clinical Practice Guidelines for Hepatitis Delta Virus,” it is recommended that all HBsAg-positive individuals undergo at least one screening for anti-HDV antibodies. Furthermore, individuals who test positive for anti-HDV antibodies should undergo HDV ribonucleic acid (RNA) testing, which is considered the most effective and accurate approach [3].
However, the development of HDV RNA testing faces various challenges, such as viral heterogeneity (different genotypes and subgenotypes), viral diversity within hosts, rapid viral evolution, and unique structural features of HDV RNA [4]. In addition, diverse RNA extraction methods, varying primer or probe designs for nucleic acid detection, and inconsistent testing standards among laboratories lead to significant differences in the performance characteristics of HDV RNA testing, whether in research or commercial settings.
Therefore, it is advocated that laboratories worldwide follow the World Health Organization’s standards for HDV RNA to establish the thresholds for their testing and promote the comparison of RNA levels across research centers. Developing a reliable quantitative assay for HDV RNA for rapid point-of-care diagnosis in serological studies is crucial for HDV screening and diagnosis. However, there is currently no reliable method for quantifying HDV RNA [5].
Recent research has found that HDV RNA detection based on CRISPR-Cas13a technology is a highly sensitive, specific, and convenient diagnostic method and serves as a critical indicator for assessing HDV infection progression and treatment effectiveness [6].
Treatment for Hepatitis D
HDV infection can cause significant liver damage, making it imperative to find antiviral drugs targeting HDV. Pegylated interferon alpha has been a recommended drug for treating CHD for many years, but its efficacy is limited, and it has poor tolerance and safety. To address this challenge, a global wave of new drug development has emerged, aiming to “cure” both CHB and CHD. Achieving a cure for HBV essentially offers an advantage in curing HDV infection [7].
To standardize the treatment endpoints in clinical trials, in June 2022, led by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) [8], a consensus was reached regarding the “Chronic HBV and HDV Treatment Endpoints” for Phase II/III clinical trials. The preferred primary treatment endpoint for CHB Phase II/III trials is “functional” cure or “partial cure.” HBsAg loss will be the primary treatment endpoint for CHD Phase II/III trials, with HDV RNA below the lower limit of quantification (LLOQ) being a major alternative endpoint. For clinical trials assessing maintenance therapy, the primary endpoint is achieving HDV RNA below LLOQ or a ≥2-log reduction in HDV RNA levels along with alanine aminotransferase (ALT) levels within the normal range by week 48.
In recent years, there have been significant advances in seeking potent antiviral therapies that can induce functional cures for HBV and HDV. It has been discovered that Bulevirtide [9] is an inhibitor that blocks HBV and HDV entry into liver cells, hinders intracellular HBV infection, and is involved in inhibiting HBV transcription. It has been shown to be safe and effective, making it a new treatment option for patients with HDV infection and compensated liver disease. After six months of antiviral treatment, virological markers in these patients undergo changes, with significant reductions in hepatitis B core-related antigen (HBcrAg) levels and decreased transcriptional activity of hepatitis B covalently closed circular DNA (HBV cccDNA). Using Bulevirtide for three years has been found to cure HDV infection in patients with cirrhosis [10], although it is not suitable for patients with decompensated liver disease [11].
By isolating and characterizing an effective human antibody, VIR-3434, in a humanized mouse model of HBV infection [12], it has been shown to prevent HBV transmission and the increase of HBV RNA and cccDNA in the liver, as well as reduce HBsAg and HDV RNA levels in the chronic phase of HBV or HDV infection. Currently, this antibody is still in clinical development, aiming to become a new treatment approach for patients with HBV combined with HDV infection.
Prevention of Hepatitis D
Vaccination with protective viral vaccines is a crucial strategy for preventing related morbidity and mortality from HBV combined with HDV infection. Given HDV’s dependence on HBsAg, the cure for HDV may ultimately depend on clearing circulating HBsAg. As HDV relies on HBV envelope proteins for virus assembly and replication, immunization against HBV can also prevent HDV co-infection and transmission. The World Health Organization’s “Global Health Sector Strategy on Viral Hepatitis” sets a goal to achieve 90% HBV vaccine coverage (including birth doses) by 2030. From an economic perspective, HBV vaccination is more cost-effective than testing and treatment strategies.
Research has found [13] that preS1-HDAg immunotherapy mainly induces neutralizing antibodies against HBV in vivo and enhances HBV/HDV-specific T-cell expression, ultimately preventing HBV and HDV infections both in vitro and in vivo. However, immunomodulators rarely achieve functional cures on their own, so research into their combined use to assess the best combinations is ongoing for widespread clinical use.
In conclusion, emphasizing HDV screening and preventive measures for HBV-infected individuals is crucial. Prevention is better than cure, and early prevention is key to averting complications. We hope that achieving clinical cures for HBV combined with HDV infection is on the horizon.
Reference :
1. Cho Y, Park S, Park S, Choi W, Kim B, Han H. Real-World Epidemiology, Treatment Patterns, and Disease Burden of Chronic Hepatitis B and HDV Co-Infection in South Korea. Infect Dis Ther. 2023;12(10):2387-2403. doi:10.1007/s40121-023-00860-8
2. Miao Z, Zhang S, Ou X, et al. Estimating the Global Prevalence, Disease Progression, and Clinical Outcome of Hepatitis Delta Virus Infection. J Infect Dis. 2020;221(10):1677-1687. doi:10.1093/infdis/jiz633
3. Razavi HA, Buti M, Terrault NA, et al. Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries. J Hepatol. 2023;79(2):576-580. doi:10.1016/j.jhep.2023.02.041
4. Wedemeyer H, Leus M, Battersby TR, et al. HDV RNA Assays: Performance characteristics, clinical utility and challenges. Hepatology. Published online August 28, 2023. doi:10.1097/HEP.0000000000000584
5. Mangia A, Squillante MM, Fraticelli F, et al. HDV RNA Levels and Progression of Hepatitis Delta Infection: A 14 Year Follow Up Experience in Italy. Cells. 2023;12(10):1413.doi:10.3390/cells12101413
6. Tian Y, Fan Z, Zhang X, et al. CRISPR/Cas13a-Assisted accurate and portable hepatitis D virus RNA detection. Emerg Microbes Infect. 2023;12(2):2276337. doi:10.1080/22221751.2023.2276337
7. Asselah T, Loureiro D, Boyer N, Mansouri A. Targets and future direct-acting antiviral approaches to achieve hepatitis B virus cure. Lancet Gastroenterol Hepatol. 2019;4(11):883-892. doi:10.1016/S2468-1253(19)30190-6
8. Ghany MG, Buti M, Lampertico P, Lee HM; 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference Faculty. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: Report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference. Hepatology. 2023;78(5):1654-1673. doi:10.1097/HEP.0000000000000431
9. Sandmann L, Deterding K, Bremer B, et al. Kinetics and predictive value of HBcrAg, HBV RNA and anti-HBc during bulevirtide treatment of chronic HDV-infected patients. J Viral Hepat. 2023;30(4):283-286. doi:10.1111/jvh.13804
10. Anolli MP, Degasperi E, Allweiss L, et al. A 3-Year Course Of Bulevirtide Monotherapy May Cure Hdv Infection In Cirrhotics. J Hepatol. Published online January 3, 2023. doi:10.1016/j.jhep.2022.12.023
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13. Burm R, Maravelia P, Ahlen G, et al. Novel prime-boost immune-based therapy inhibiting both hepatitis B and D virus infections. Gut. 2023;72(6):1186-1195. doi:10.1136/gutjnl-2022-327216
Expert Profile
Dr. Xiaozhong Wang
Chief Physician, Professor, Doctoral Supervisor
Director of the Hepatology Department, Xinjiang Uyghur Autonomous Region Traditional Chinese Medicine Hospital
TAG: insights; Hepatitis D virus