Hepatitis B virus reactivation during direct‐acting antiviral treatment of chronic hepatitis C: A hidden danger of an otherwise major success story

It has been estimated that 250 million and 170 million people worldwide are infected with hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. Coinfection is relatively common in regions where both viruses are endemic and transmission is facilitated by common routes of exposure. In a recent study of 1,287 New York City residents with hepatitis C, most of whom were born in United States, 62% had resolved HBV infection and 6% were hepatitis B surface antigen (HBsAg)-positive. Dual infection with HBV and HCV leads to accelerated liver disease and a higher risk for cirrhosis and hepatocellular carcinoma. Treatment of coinfected patients is controversial, but it is a common practice to treat the virus that genomic testing reveals to be dominant. The intracellular interactions of the two viruses are unclear. Cross-sectional studies have shown that coinfected individuals often have high levels of HCV RNA, low or undetectable HBV DNA, antibody to hepatitis B e antigen reactivity, and lower levels of HBsAg compared with HBV monoinfection. Thus, HCV is most often the primary target of antiviral therapy. However, longitudinal studies have demonstrated that the levels of HBV DNA and HCV RNA may fluctuate with time, suggesting that competitive interactions between the two viruses are more dynamic than previously thought. The recent development of direct-acting antiviral (DAA) drugs that are highly effective in eradicating hepatitis C virus is a milestone achievement. Registration trials have convincingly shown that DAA treatment is far better tolerated than interferon/ribavirinbased regimens. However, postapproval case series and a compilation of 24 international cases in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) have demonstrated that HBV reactivation (HBVr) occurs during DAA treatment. The recent emergence of this adverse effect of DAAs is explainable by the exclusion of HBVcoinfected individuals from registration trials. As with HBVr during immunosuppressive medications, reactivation with DAA therapy occurs in HBsAgpositive individuals and is less common in persons with resolved infection (HBsAg-negative, antibody to hepatitis B core antigen [anti-HBc]-positive with or without antibody to hepatitis B surface antigen [anti-HBs]). Predictive factors have not been identified, but there is no apparent association of HBVr with the type of DAA therapy or HCV genotype. Frequent biochemical evidence of hepatitis in the reported cases with liver injury severe enough to require liver transplantation in a few instances—as well as rare cases of fatalities—have resulted in an FDA box warning for these agents. Both the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases/ Abbreviations: AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen; DAA, directacting antiviral; FAERS, US Food and Drug Administration Adverse Event Reporting System; FDA, US Food and Drug Administration; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HBVr, HBV reactivation; HCV, hepatitis C virus.