Unmet need in screening for hepatitis D virus: Time to take action

Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countriesJournal of HepatologyVol. 79Issue 2PreviewHepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Full-Text PDF Open Access None declared. Concept and design: Grace Wong and Terry Yip. Data collection: Grace Wong. Data analysis: Jimmy Lai and Terry Yip. Drafting and critical review of the article: All. All authors read and approved the final version of the manuscript. The data that support the findings of this study are available on request from the author, GLHW, subject to approval from the Ethics Committee. The data are not publicly available due to ethical restrictions. We read with interest the article by Razavi et al. recently published in the Journal of Hepatology.[1]Razavi H.A. Buti M. Terrault N.A. Zeuzem S. Yurdaydin C. Tanaka J. 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: 576-580Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Coinfection of hepatitis D virus (HDV) in patients with hepatitis B virus (HBV) infection leads to more severe hepatitis and an increased risk of liver disease progression. Accurate estimation of the prevalence of HDV infection and the disease burden is crucial for developing more targeted and efficient approaches to identifying individuals with coinfections. Moreover, the introduction of bulevirtide is expected to revolutionise the future clinical management of chronic hepatitis D (CHD) after its approval in other parts of the world.[2]Wedemeyer H. Aleman S. Brunetto M.R. Blank A. Andreone P. Bogomolov P. et al.A Phase 3, Randomized Trial of bulevirtide in chronic hepatitis D.N Engl J Med. 2023; 389: 22-32Crossref PubMed Scopus (25) Google Scholar Since bulevirtide was approved for use by the European Medicines Agency in July 2020, real-world data have confirmed its effectiveness and favourable safety in reducing HDV viremia and normalising alanine aminotransferase (ALT) levels in patients with compensated CHD.[3]Degasperi E. Anolli M.P. Uceda Renteria S.C. Sambarino D. Borghi M. Perbellini R. et al.Bulevirtide monotherapy for 48 weeks in patients with HDV-related compensated cirrhosis and clinically significant portal hypertension.J Hepatol. 2022; 77: 1525-1531Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar,[4]Dietz-Fricke C. Tacke F. Zollner C. Demir M. Schmidt H.H. Schramm C. et al.Treating hepatitis D with bulevirtide - real-world experience from 114 patients.JHEP Rep. 2023; 5100686Google Scholar After the availability of antiviral treatment, the crucial next step is to detect and treat individuals infected with HDV. Currently, the American guidelines recommend screening for HDV in at-risk hepatitis B surface antigen (HBsAg)-positive individuals including those with HIV infection, high-risk behaviour, and immigrating from HDV-endemic regions,[5]Terrault N.A. Lok A.S.F. McMahon B.J. Chang K.M. Hwang J.P. Jonas M.M. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (2436) Google Scholar while the European and Asian-Pacific guidelines recommend universal anti-HDV screening in all HBsAg-positive patients.[6]European Association for the Study of the LiverEASL Clinical Practice Guidelines on hepatitis delta virus.J Hepatol. 2023; 79: 433-460Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar,[7]Sarin S.K. Kumar M. Lau G.K. Abbas Z. Chan H.L. Chen C.J. et al.Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.Hepatol Int. 2016; 10: 1-98Crossref PubMed Scopus (1793) Google Scholar Based on the updated prevalence estimates on HDV infection, Razavi et al. suggested that double reflex testing can be recommended in most countries.[1]Razavi H.A. Buti M. Terrault N.A. Zeuzem S. Yurdaydin C. Tanaka J. 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: 576-580Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Nonetheless, in reality, screening for HDV is rarely performed, even among those at-risk HBV carriers. So far, there is limited information regarding the prevalence of HDV in Hong Kong. A study in 1992 reported an HDV prevalence of 93% in 14 parenteral drug abusers with chronic HBV infection and 0.15% in 664 non-drug abusers with chronic HBV infection.[8]Lok A.S. Wong A. Sporton S. Lai C.L. Liu V. Chung H.T. Hepatitis D virus superinfection remains a rare occurrence in non-drug abusers in Hong Kong.J Hepatol. 1992; 14: 332-334Abstract Full Text PDF PubMed Scopus (7) Google Scholar To examine the real-world situation of HDV screening and provide an updated estimate of the HDV prevalence, we collected data on HBsAg and anti-HDV tests performed from 2002-2022 in Hong Kong through the Clinical Data Analysis and Reporting System, an electronic healthcare database managed by the Hospital Authority, Hong Kong, which covers around 80% of the local population.[9]Wong G.L. Hui V.W. Yip T.C. Liang L.Y. Zhang X. Tse Y.K. et al.Universal HBV vaccination dramatically reduces the prevalence of HBV infection and incidence of hepatocellular carcinoma.Aliment Pharmacol Ther. 2022; 56: 869-877Crossref PubMed Scopus (14) Google Scholar The study protocol was approved by the Joint Chinese University of Hong Kong - New Territories East Cluster Clinical Research Ethics Committee. Informed consent was waived due to the retrospective nature of the study. Hong Kong is an HBV-endemic region with a prevalence of 7.2%, which translates to around 540,000 HBV cases. In the past 21 years, there were a total of 5,856 anti-HDV tests performed in 5,166 patients, with an average of 279 tests done and 246 new individuals tested per year. As a reference, the average number of HBsAg tests performed each year during the same period was about 170,000, of which 30,000 tests were positive. These numbers reflect that we have only tested for anti-HDV in around 1% of our HBV-infected patients and the percentage of patients tested mildly decreased over time (Figure 1). Among patients with available anti-HDV test results, the prevalence of positive anti-HDV was 1.2%. It is important to note that this estimated prevalence is likely overstated, as those who have undergone HDV screening are likely to be at risk with a median serum ALT level greater than 100 IU/L regardless of the use of HBV antiviral agents. Formulation and cost-effectiveness evaluation of HDV screening strategies rely on an accurate estimation of the prevalence of HDV infection and the related disease burden. Meanwhile, treatment cannot be successful without identifying the targeted patients. While the HBsAg testing rate is improving and moving toward the goal of hepatitis elimination, the HDV testing rate in daily clinical practice remains suboptimal. Emerging data have shown that anti-HDV reflex testing in HBsAg-positive individuals can be cost-saving and improve detection and linking-to-care.[1]Razavi H.A. Buti M. Terrault N.A. Zeuzem S. Yurdaydin C. Tanaka J. 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: 576-580Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,[10]Palom A. Rando-Segura A. Vico J. Pacin B. Vargas E. Barreira-Diaz A. et al.Implementation of anti-HDV reflex testing among HBsAg-positive individuals increases testing for hepatitis D.JHEP Rep. 2022; 4100547Google Scholar In Hong Kong, an HBV-endemic region, HDV screening has been suboptimal over the last two decades and efforts should be made to improve anti-HDV testing. Despite the possibly low anti-HDV prevalence, the absolute number of patients with positive anti-HDV will likely increase with screening, implying that more patients at risk of liver disease progression will be identified. Given the increased risk of disease progression associated with HDV co-infection and treatment only available for compensated liver disease, it is crucial to increase the HDV screening rate and facilitate timely treatment. Jimmy Lai declares that he has no conflict of interest. Grace Wong has served as an advisory committee member for Gilead Sciences and Janssen, and as a speaker for Abbott, Abbvie, Ascletis, Bristol-Myers Squibb, Echosens, Gilead Sciences, Janssen, and Roche. She has also received a research grant from Gilead Sciences. Vincent Wong served as an advisory board member or consultant for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, and Visirna; and a speaker for Abbott, AbbVie, Gilead Sciences, Novo Nordisk, and Unilab. He has received a grant from Gilead Sciences, and is a co-founder of Illuminatio Medical Technology Limited. Terry Yip has served as an advisory committee member and a speaker for Gilead Sciences.