Hepatitis B Reactivation During Treatment for Hepatitis C

The yellowed eye of a jaundiced patient.

Conquering one foe only to unleash another.

By Martina M. McGrath, MD
January 12, 2017

In October 2016, the FDA published a drug safety communication warning of the risk of Hepatitis B (HBV) reactivation in patients treated with direct-acting antivirals (DAAs) for Hepatitis C (HCV) infection.1 They reported 24 cases of HBV reactivation, including two deaths and one patient who required liver transplantation. Interestingly, the HBV status of affected patients was heterogenous and included those with positive and negative HBV viral loads, as well as positive and negative HBsAg. Reactivation appears to occur early, within four to eight weeks of treatment initiation.

One report published in 2015 described two such patients.2 The first patient had compensated cirrhosis, chronic HBV with a viral load 2,000 IU/mL and HCV with a viral load of 1.3 million IU/mL. After initiation on sofosbuvir and simeprevir, HCV was undetectable at four weeks. At seven weeks, the patient developed jaundice, hepatomegaly, and had grossly deranged LFTs with HCV viral load >22 million copies. DAAs were discontinued and treatment for HBV was initiated with good response. HCV remained undetectable at six-month follow-up.

The second patient had chronic HCV with a positive HBcAb and negative HBsAg and HBsAb. HBV viral load was undetectable. HCV and HBV viral loads were monitored prospectively and at four weeks, HCV was undetectable while HBV viral load was 11,255 IU/mL. DAAs were continued and anti-HBV treatment was added. Both viruses were undetectable at 12 weeks.

Using older, interferon-based regimens, HBV reactivation was noted in up to 30 percent of patients treated for HCV, particularly in those achieving a sustained virologic response.3 The original trials of DAAs excluded patients with co-infection with HBV, and therefore this complication was not recognized.

The mechanism of HBV reactivation is unclear. There are some data that in co-infected patients, HCV suppresses replication of HBV, either through a suppressive effect of the virus, or more likely, through stimulating an innate immune response within the liver which also serves to suppress HBV replication. With resolution of HCV infection, the stimulus to immunity is decreased or altered, possibly allowing HBV reactivation3. Furthermore, previous treatment regimens for HCV included interferon-α, which also has significant anti-HBV activity, and may have limited the impact of clearing HCV infection.

The true incidence is unknown but given the severity of this complication, the FDA now recommend that all patients be screened for HBV prior to initiation of anti-HCV therapy, and those with evidence of HBV infection be monitored for evidence of viral reactivation on a regular basis.


  1. http://www.fda.gov/Drugs/DrugSafety/ucm522932. 2016. (Accessed 4th January 2017)
  2. Collins JM, Raphael KL, Terry C, et al. Hepatitis B Virus Reactivation During Successful Treatment of Hepatitis C Virus With Sofosbuvir and Simeprevir. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2015;61:1304-6.
  3. Balagopal A, Thio CL. Editorial Commentary: Another Call to Cure Hepatitis B. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2015;61:1307-9.

Headshot of Dr. McGrathDr. Martina McGrath is an Instructor in Medicine at Harvard Medical School, and a member of the Renal Division, Department of Medicine, at Brigham and Women’s Hospital, both in Boston. Dr. McGrath is the Medical Editor for the Trends in Medicine blog.

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