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Hepatitis B

FDA Warns of HBV Reactivation Risk After Starting Hepatitis C Medications


The U.S. Food and Drug Administration (FDA) this week issued a new safety warning about the risk of hepatitis B virus (HBV) reactivation in people treated with direct-acting antivirals (DAAs) for hepatitis C. In a few cases HBV reactivation has led to serious liver problems or death. The FDA will now require a boxed warning on package labels for all DAAs. The caution applies to people who currently have chronic hepatitis B and those who previously cleared HBV spontaneously or with treatment.

In people with HBV and HCV coinfection, the 2 viruses seem to interact and keep each other in check. HBV DNA viral load is often low or undetectable and HCV is typically the main driver of active liver disease. But when hepatitis C is cured with DAA therapy, this allows HBV to reactivate, often indicated by a rapid increase in HBV DNA and ALT liver enzyme levels and sometimes jaundice (yellowing of the skin and eyes due to elevated bilirubin). In severe cases it can lead to fulminant hepatitis, liver failure, and death. This phenomenon may not have been apparent in the interferon era because interferon alfa is active against both viruses.

American and European hepatitis C treatment guidelines were recently revised to recommend that people considering hepatitis C treatment should first be tested for hepatitis B and monitored during and after therapy, and those with active HBV should receive hepatitis B antiviral therapy.

Earlier this year the European Medicines Agency announced that its Pharmacovigilance Risk Assessment Committee had started a review of approved DAAs following reports of HBV reactivation in people treated for hepatitis C. Japan’s Pharmaceuticals and Medical Devices Agency said it would conduct a similar review.

According to a Drug Safety Communication issued on October 4, the FDA identified 24 confirmed cases of HBV reactivation -- either reported to the agency or described in published literature -- in HBV/HCV coinfected people treated with DAAs between November 2013 and July 2016. Additional cases were likely never reported. HBV reactivation usually occurred within 4 to 8 weeks (average 52 days), and occurred in people with both detectable and undetectable HBV DNA at baseline.

Some cases resulted in fulminant hepatitis or liver failure. Among the reported cases, 3 patients experienced hepatic decompensation, 1 required a liver transplant, and 2 died. Half the patients received hepatitis B treatment, most of whom then experienced decreases in HBV DNA and improvement of symptoms. In several cases liver enzyme elevations were initially mistakenly attributed to DAA toxicity and hepatitis C treatment was stopped unnecessarily.

"The mechanism through which HBV reactivation occurs with DAAs is currently unknown," according to the FDA's data summary. "These medicines are not known to cause immunosuppression, but HBV reactivation may result from a complex interplay of host immunologic responses in the setting of infection with 2 hepatitis viruses."

The agency noted that HBV reactivation was not reported as an adverse event in the clinical trials supporting DAA approvals because people with hepatitis B were excluded from these Phase 3 studies.

The FDA will now require a Boxed Warning (commonly called a "black box") -- the most prominent type of warning available -- for all DAAs. The warning will also be included in the products' patient information leaflets or medication guides.

The warning applies to the following DAAs and DAA coformulations used in interferon-free regimens:

  • Daklinza (daclatasvir)
  • Olysio (simeprevir)
  • Sovaldi (sofosbuvir)
  • Epclusa (sofosbuvir/velpatasvir)
  • Harvoni (sofosbuvir/ledipasvir)
  • Technivie or Viekirax (paritaprevir/ritonavir/ombitasvir)
  • Viekira Pak or Viekira XR (paritaprevir/ritonavir/ombitasvir/dasabuvir)
  • Zepatier (grazoprevir/elbasvir)

The EMA review also includes Exviera, or dasabuvir alone, which is not sold separately in the U.S. The FDA warning does not include the older DAAs boceprevir (Victrelis) and telaprevir (Incivek or Incivo), which are used with pegylated interferon and ribavirin.

According to the FDA advisory, health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with DAAs, and monitor patients using blood tests for HBV flare-ups or reactivation during treatment and post-treatment follow-up.

Revised AASLD guidelines state that patients who test positive for hepatitis B antigens or antibodies should receive an HBV DNA test to see if the virus is actively replicating. People who meet criteria for treatment of active HBV infection should start hepatitis B antivirals -- such as entecavir (Baraclude) or tenofovir (Viread) -- at the same time, or before, hepatitis C DAA therapy is started. People with low or undetectable HBV DNA should undergo regular monitoring during and after hepatitis C treatment to check for reactivation. People who remain susceptible to hepatitis B should receive an HBV vaccine.

The FDA advises patients considering DAA therapy to tell their providers if they have a known history of hepatitis B or other liver problems before being treated for hepatitis C. Patients should contact their provider immediately if they develop symptoms of liver problems including fatigue, weakness, loss of appetite, nausea and vomiting, yellow skin or eyes, or light-colored stools. However, people already taking DAAs should not stop without first consulting their provider, as stopping treatment early could lead to HCV becoming drug resistant and affecting future treatment options.

Providers and patients are urged to report side effects involving DAAs and other medicines to the FDA MedWatch program at 1-888-INFO-FDA or using the MedWatch Online Voluntary Reporting Form.



Food and Drug Administration. FDA Drug Safety Communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. Drug Safety Communication. October 4, 2016.

AASLD/ISDA. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Updated September 16, 2016.

JM Pawlotsky et al (European Association for the Study of the Liver). EASL Recommendations on Treatment of Hepatitis C 2016. Journal of Hepatology, 2016 (in press).

European Medicines Agency. EMA reviews direct-acting antivirals for hepatitis C. EMA advisory. March 18, 2016.