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Hepatitis due to Reactivation of Hepatitis B Virus in Endemic Areas Among Patients With Hepatitis C Treated With Direct-acting Antiviral Agents.
Wang C, et al.
Clinical Gastroenterology and Hepatology 2017;15:132–136

Hepatitis due to reactivation of hepatitis B virus (HBV) has been reported inpatients treated with direct-acting antiviral (DAA) agents for chronic hepatitis C virusinfection.We performed an observational study to determine the incidence of and factorsassociated with hepatitis in 327 patients receiving pan-oral DAA agents for HCVinfections in areas endemic for HBV in China. Ten patients were positive for hepatitis Bsurface antigen (HBsAg), and 124 patients had occult HBV infection. HBV reactivationwas determined by measuring HBV DNA and HBsAg status in serial serum samplescollected every 2 weeks during DAA treatment and then every 4 weeks after treatmentuntil week 12.In the total study population, 10 patients (3.1%) had hepatitis; 3 cases were associatedwith HBV reactivation (1 case not in the icteric phase, 1 case in the icteric phase, and 1case with liver failure) and 7 from other causes.Testing positive for HBsAg before DAA treatment was a strong risk factor for developinghepatitis during treatment (hazard ratio, 15.0; P < .001).

Expert's Commentary (Dr Jordan Feld, senior author)

In October 2016, the FDA put out a black-box warning on all direct-acting antivirals(DAAs) for HCV about the risk of hepatitis B virus (HBV) reactivation. They noted thatcases had been reported of severe and even fatal HBV reactivation in patients treatedwith DAAs and recommended checking HBV DNA in all patients who were HBsAg+ve oranti-HBc +ve prior to starting HCV therapy. Unfortunately the FDA data come frompost-approval surveillance and are missing many details. The study by Wang andcolleagues helps quantify the risks involved. They screened all patients and found thatof 10 who were HBsAg +ve at baseline, 3 experienced HBV-reactivation, including 2 verysevere cases. In contrast, of 317 patients who were HBsAg –ve but anti-HBc +ve,including 124 who had detectable HBV DNA (by a sensitive in-house assay), noneexperienced clinically significant HBV-reactivation. These are extremely helpful data.
These results clearly support the recommendation to screen all patients for HBsAg priorto DAA therapy and make a case for considering HBV antiviral therapy for those who areHBsAg +ve. At the minimum, these patients need close follow-up. However, these dataalso are very reassuring that the risk of reactivation in those who are HBsAg –ve butanti-HBc +ve, the risk of HBV reactivation is extremely low. This is in keeping withanother report by Sulkowski et al (CID 2016; 63:1202-4.) who found no cases ofreactivation of 103 patients who were lone anti-HBc +ve before therapy in sofosbuvirregistration trials in Asia. The presence of anti-HBc antibodies is extremely common inthose with HCV, both in HBV-endemic countries and in patients who acquired HCVthrough injection drug use. The FDA recommendation to test HBV DNA in all thosepatients is not only costly, but may be a significant barrier for new treaters to enter thefield. Although it is still reasonable to screen for anti-HBc prior to treatment, collectivelythese 2 studies give me reassurance that we do not need to check HBV DNA unlesspatients either fail to normalize ALT on therapy or have a rise in ALT during or aftertreatment. Hopefully as the data accumulate, the FDA will reconsider their currentrecommendation.

Jordan Feld MD MPH, University of Toronto, Ontario, Canada