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Hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C: a systematic review and meta-analysis Marcus M Mücke, Lisa I Backus, Victoria T Mücke, Nicola Coppola, Carmen M Preda, Ming-Lun Yeh, Lydia S Y Tang, Pamela S Belperio, Eleanor M Wilson, Ming-Lung Yu, Stefan Zeuzem, Eva Herrmann, Johannes Vermehren
Summary
Background Direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection might pose a risk for hepatitis B virus (HBV) reactivation in patients coinfected with chronic or resolved HBV infection. The need for HBV antiviral prophylaxis during DAA treatment remains controversial. We aimed to analyse the absolute risk of HBV reactivation in patients with active or resolved HBV infection treated with DAAs for HCV infection. Methods For this systematic review and meta-analysis, we searched PubMed, Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and Web of Science from Oct 1, 2010, to Sept 30, 2017, to identify studies of patients with chronic or resolved HBV infection at baseline treated with DAAs for chronic HCV infection. Conference proceedings, abstract books, and references from relevant reviews were also examined for potential studies. Two independent researchers extracted data and assessed quality and risk of bias. Data were pooled by use of random-effects models. The primary outcome was HBV reactivation defined by standardised nomenclature. This study is registered with PROSPERO, number CRD42017065882. Findings We identified 17 observational studies involving 1621 patients with chronic (n=242) or resolved (n=1379) HBV infection treated with different DAAs. The pooled proportion of patients who had HBV reactivation was 24% (95% CI 19–30) in patients with chronic HBV infection and 1·4% (0·8–2·4) in those with resolved HBV infection. In patients with chronic HBV infection, the pooled proportion of patients with HBV-reactivation-related hepatitis was 9% (95% CI 5–16) and the relative risk (RR) of HBV-reactivation-related hepatitis was significantly lower in patients with HBV DNA below the lower limit of quantification at baseline than in those with quantifiable HBV DNA (RR 0·17, 95% CI 0·06–0·50; p=0·0011). Three major clinical events related to HBV reactivation in patients with chronic HBV infection were reported (one patient had liver decompensation and two had liver failure, one of whom required liver transplantation). In patients with resolved HBV infection, no HBV-reactivation-related hepatitis was reported. Interpretation HBV reactivation occurs frequently in patients with chronic HBV and HCV coinfection receiving DAA therapy but is rare among patients with resolved HBV infection. Use of antiviral prophylaxis might be warranted in patients who test positive for hepatitis B surface antigen (HBsAg), particularly those with quantifiable HBV DNA. Funding None.
Introduction Chronic infection with either hepatitis B virus (HBV) or hepatitis C virus (HCV) is associated with substantial morbidity and mortality worldwide.1–3 HBV and HCV coinfection is common in HBV-endemic areas but rare in most developed countries.4 However, hepatitis B core antibody (HBcAb) prevalence is reported to be up to 35% in HCV-infected populations in those regions.5–7 Patients with chronic (hepatitis B surface antigen [HBsAg]-positive) or resolved (HBsAg-negative but HBcAb-positive) HBV infection are at risk of HBV reactivation (increased HBV replication) when undergoing immunosuppressive therapy. Reactivation can be associated with severe hepatitis and liver failure.8,9 Although HBV replication is usually suppressed in the presence of HCV coinfection, an overall HBV reactivation rate of 14·5% was recently reported from patients following interferon-induced HCV eradication.10
With the introduction of direct-acting antivirals (DAAs) for treatment of HCV infection, viral eradication can now be achieved in the majority of patients with chronic HCV infection.11 Although patients with HBV and HCV coinfection were excluded from most DAA approval studies, post-marketing reports suggest that HBV reactivation might also occur following DAA-induced HCV clearance. HBV reactivation was reported in patients with both chronic and resolved infection treated with DAAs.12 This observation is particularly noteworthy since HBV reactivation in patients with resolved infection has primarily been associated with B-cell-depleting agents (eg, rituximab).8 The increasing number of reported cases of HBV reactivation has prompted both the US Food and Drug Administration (FDA) and the European Medicine Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) to issue warnings about the possible
www.thelancet.com/gastrohep Published online January 19, 2018 http://dx.doi.org/10.1016/S2468-1253(18)30002-5
Lancet Gastroenterol Hepatol 2018 Published Online January 19, 2018 http://dx.doi.org/10.1016/ S2468-1253(18)30002-5 See Online/Comment http://dx.doi.org/10.1016/ S2468-1253(18)30004-9 Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany (M M Mücke MD, V T Mücke MD, Prof S Zeuzem MD, J Vermehren MD); Department of Veterans Affairs, Population Health Services, Palo Alto Health Care System, Palo Alto, CA, USA (L I Backus MD, P S Belperio PharmD); Department of Mental Health and Public Medicine, University of Campania, Naples, Italy (N Coppola MD); Gastroenterology and Hepatology Department, Fundeni Clinical Institute, Bucharest, Romania (C M Preda MD); Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan (M-L Yeh MD, Prof M-L Yu MD); Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA (L S Y Tang MBChB, E M Wilson MD); Division of Infectious Diseases, Department of Medicine, VA Maryland Health Care System, Baltimore, MD, USA (E M Wilson); and Institute of Biostatistics and Mathematical Modeling, Goethe University Frankfurt, Frankfurt am Main, Germany (Prof E Herrmann PhD) Correspondence to: Dr Johannes Vermehren, Department of Internal Medicine 1, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany
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Research in context Evidence before this study We searched PubMed, Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and Web of Science using the following search algorithm: (((hepatitis B virus AND hepatitis C virus) OR HBV AND HCV OR (hepatitis B virus and C virus) OR (HBV/HCV)) AND ((coinfect* OR co-infect* OR dual infect* OR dual* infect*)) OR ((hepatitis B OR HBV OR hepatitis B virus) AND (hepatitis C OR HCV OR hepatitis C virus))) AND (react* OR direct acting OR DAA). The first publication on sofosbuvir (the first direct-acting antiviral [DAA] that was used in interferon-free regimens) was in October, 2010. We therefore searched for studies published between Oct 1, 2010, and Sept 30, 2017. All studies of patients with chronic hepatitis C virus (HCV) infection treated with interferon-free DAA regimens and reported to have active (hepatitis B surface antigen [HBsAg]-positive) or resolved (HBsAg-negative but hepatitis B core antibody [HBcAb]-positive) hepatitis B virus (HBV) infection at baseline were eligible for inclusion. All study types were eligible for inclusion. Conference proceedings, abstract books, and references from relevant reviews and original research articles were also examined for other potential studies. We found only one meta-analysis evaluating the risk of HBV reactivation in patients treated for HCV infection. However, the meta-analysis focused on HBV reactivation in patients with HBV and HCV coinfection receiving interferon-based treatments, and only
risk of HBV reactivation in patients with active and resolved HBV infection who are treated with DAAs.13,14 National and international guidelines have incorporated recommendations for testing and treatment of patients with HBV and HCV coinfection. However, there is disagreement about which patients require HBV DNA monitoring or even pre-emptive antiviral prophylaxis.15,16 We aimed to analyse the absolute risk of HBV reactivation in patients with active or resolved HBV infection treated with DAAs for HCV infection using a standardised nomenclature.17
Methods
Search strategy and selection criteria
See Online for appendix
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We did a systematic review and meta-analysis using standard methods according to the PRISMA guidelines (appendix pp 1, 2).18 The study and its protocol are registered with the PROSPERO register for systematic reviews (number CRD42017065882). All searches, title and abstract screening, study selection, data extraction, and quality assessment were done independently by two researchers (MMM and JV). Discrepancies were resolved by consensus or by contacting the corresponding authors of the studies. We searched PubMed, Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and Web of Science from Oct 1, 2010—the date of the first publication on
two interferon-free studies comprising 18 HBsAg-positive patients were included. To our knowledge, no systematic review or meta-analysis exists evaluating the risk of HBV reactivation in patients with resolved HBV infection. Added value of this study Our study is, to the best of our knowledge, the first comprehensive meta-analysis of studies assessing the risk of HBV reactivation in patients with HCV infection treated with DAAs. Our findings suggest that, in patients with chronic HBV and HCV coinfection receiving DAA therapy, the risk of HBV reactivation is greater than that previously reported for patients treated with interferon, especially in patients with quantifiable (≥20 IU/mL) HBV DNA at baseline. The risk of HBV reactivation in patients with resolved HBV infection is low and no major clinical events were reported in this group. Implications of all the available evidence The risk of HBV reactivation in patients with HBV and HCV coinfection is similar to that seen in patients undergoing immunosuppression, in whom antiviral prophylaxis is recommended. The risk of HBV reactivation in patients with resolved HBV infection is low. Thus, our results support the use of antiviral prophylaxis in patients with chronic HBV infection, particularly in those with quantifiable HBV DNA, and repeated alanine aminotransferase and/or HBV DNA monitoring in those with resolved HBV infection.
sofosbuvir, the first DAA available that was used in interferon-free regimens—to Sept 30, 2017, using the following search algorithm: (((hepatitis B virus AND hepatitis C virus) OR HBV AND HCV OR (hepatitis B virus and C virus) OR (HBV/HCV)) AND ((coinfect* OR co-infect* OR dual infect* OR dual* infect*)) OR ((hepatitis B OR HBV OR hepatitis B virus) AND (hepatitis C OR HCV OR hepatitis C virus))) AND (react* OR direct acting OR DAA). The OVID MEDLINE search strategy can be found in the appendix (p 3). All study types were eligible for inclusion. Conference proceedings and abstract books about the topic were also reviewed. References from relevant reviews and original research articles were examined for other potential studies. All studies of patients with chronic HCV infection treated with interferon-free DAA regimens and reported to have active (HBsAg-positive) or resolved (HBsAg-negative but HBcAb-positive) HBV infection at baseline were eligible for inclusion. Data for patients were included if the serological HBV status was known or assessed at baseline and if repeated HBV DNA and alanine aminotransferase (ALT) monitoring was done during DAA therapy for patients with chronic HBV infection, or repeated ALT monitoring with additional HBV DNA monitoring was done at the end of treatment or during follow-up in patients with resolved HBV infection. Results obtained from commercial HBV DNA
www.thelancet.com/gastrohep Published online January 19, 2018 http://dx.doi.org/10.1016/S2468-1253(18)30002-5
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assays were used for analysis. Corresponding authors of relevant conference abstracts were contacted and patients were included if all the data could be provided. In cases of insufficient data in full publications, corresponding authors were also contacted to request all relevant data. We required a minimum follow-up period of 12 weeks after DAA therapy for outcome assessment. We excluded studies involving paediatric patients (aged
