The FDA recently announced that it will require the labeling of all direct-acting antiviral drugs used for treatment of hepatitis C virus (HCV) infection to include a boxed warning about a risk of hepatitis B virus (HBV) reactivation associated with their use.1

Twenty-four cases of HBV reactivation occurring during treatment with direct-acting antiviral drugs for HCV were identified from the FDA Adverse Event Reporting System and the medical literature.2-5 Before starting direct-acting antiviral treatment for HCV, some of these patients were hepatitis B surface antigen (HbsAG) positive and others showed evidence of resolved HBV infection. HBV reactivation generally occurred within 4-8 weeks of starting treatment. Reactivation of HBV can cause increases in bilirubin and aminotransferase levels, fulminant hepatitis, hepatic failure, and death. Of the 24 patients, two died and one required a liver transplant.

HBV reactivation was not identified before FDA approval of these drugs because the clinical trials used to support their approval excluded patients with HBV co-infection. The mechanism by which HBV reactivation occurs during treatment with direct-acting antiviral drugs for HCV is unknown. Patients should be screened for current or past HBV infection before starting treatment with a direct-acting antiviral and monitored for HBV reactivation during and following treatment with these drugs.

1. FDA Drug Safety Communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. Available at: www.fda.gov. Accessed October 13, 2016.
2. JM Collins et al. Hepatitis B virus reactivation during successful treatment of hepatitis C virus with sofosbuvir and simeprevir. Clin Infect Dis 2015; 61:1304.
3. A De Monte et al. Direct-acting antiviral treatment in adults infected with hepatitis C virus: reactivation of hepatitis B virus coinfection as a further challenge. J Clin Virol 2016; 78:27.
4. AR Ende et al. Fulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report. J Med Case Rep 2015; 9:164.
5. C Wang et al. Hepatitis due to reactivation of hepatitis B virus in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol 2016 July 5 (epub).

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The FDA has approved Epclusa (Gilead), a fixed-dose combination of sofosbuvir (Sovaldi) and velpatasvir, a new direct-acting antiviral agent, for oral treatment of chronic hepatitis C virus (HCV) infection. Epclusa is the first oral combination to be approved for treatment of all six major HCV genotypes.

The FDA has approved Zepatier (Merck), a fixed-dose combination of two direct-acting antiviral agents — elbasvir, an NS5A inhibitor, and grazoprevir, an NS3/4A protease inhibitor — for oral treatment of chronic hepatitis C virus (HCV) genotype 1 or 4 infection.

The FDA has approved daclatasvir (Daklinza – BMS), an oral direct-acting antiviral drug, for use with sofosbuvir (Sovaldi) for treatment of chronic hepatitis C virus (HCV) genotype 3 infection. Daclatasvir is the first drug approved for this indication that does not require the addition of interferon or ribavirin. It is approved in Japan and Europe in combination with other drugs for treatment of HCV genotypes 1-4.