Hep B reactivation common during direct-acting antiviral therapy for hep C

Last Updated: 2018-02-02

By Will Boggs MD

NEW YORK (Reuters Health) - Hepatitis B virus (HBV) reactivation is common in patients with chronic HBV and hepatitis C virus (HCV) coinfection receiving direct-acting antiviral (DAA) therapy, according to a systematic review and meta-analysis.

"It is important to identify patients at risk of HBV reactivation," said Dr. Johannes Vermehren from University Hospital Frankfurt, in Frankfurt am Main, Germany.

"HBsAg-positive patients who also have detectable HBV DNA should be closely monitored when treated for hepatitis C with direct antivirals. Alternatively, (nucleoside/nucleotide) prophylaxis may be justified in these patients," he told Reuters Health by email.

HBV replication is usually suppressed in the presence of HCV coinfection, but HBV reactivation rates of 14.5% have been reported following interferon-induced HCV eradication.

An increasing number of reported cases of HBV reactivation during DAA therapy for HCV prompted both the U.S. Food and Drug Administration (FDA) and the European Medicine Agency's Pharmacovigilance Risk Assessment Committee (PRAC) to issue warnings about the risk of HBV reactivation in patients treated with DAAs.

Dr. Vermehren and colleagues used data from 17 observational studies involving 1,621 patients with chronic or resolved HBV infection to analyze the absolute risk of HBV reactivation in patients treated with DAAs for HCV infection.

HBV reactivation occurred in 24% and HBV-reactivation-related hepatitis occurred in 9% of patients with chronic (HBsAg-positive) HBV infection receiving DAA therapy for HCV infection, the researchers report in The Lancet Gastroenterology & Hepatology, online January 19.

The risk of HBV reactivation was similar between patients with HBV DNA below the lower limit of quantification (LLOQ) and those with quantifiable HBV DNA at baseline, whereas the risk of HBV-reactivation-related hepatitis was 83% lower in patients with HBV DNA below the LLOQ than in those with quantifiable HBV DNA.

In contrast, only 1.4% of patients with resolved (HBsAg-negative and HBcAb-positive) HBV infection developed HBV reactivation during DAA therapy for HCV infection. None of these patients developed HBV-reactivation-related hepatitis.

"Patients with chronic hepatitis C should always be tested for HBV prior to starting direct antiviral therapy," Dr. Vermehren said. "Knowing the serologic HBV status gives us enough time to adequately manage each individual patient."

"Further studies are needed to prospectively evaluate the use and cost-effectiveness of antiviral prophylaxis in these populations," the researchers note.

"The authors of this study provide a strong rationale for assessment of the HBV serological status (HBsAg, HBsAb, and HBcAb) of all patients with HCV infection; prophylactic HBV treatment of HBsAg-positive patients at least until a sustained virological response is documented; and monitoring of HBcAb-positive patients, particularly those with advanced liver disease," writes Dr. Vincent Thibault from the University of Rennes, France, in a linked editorial.

"Recent improvements in HBV and HCV cell-culture systems should help to better dissect the mechanisms behind this clinical event," he notes.

Dr. Akihiro Tamori from Osaka City University Graduate School of Medicine, in Japan, who has reported a low incidence of HBV reactivation in a similar study, told Reuters Health by email, "I find it interesting and surprising that HBV reactivation rate was 24% in patients coinfected with HBV and HCV treated with interferon-free DAA therapy. Compared to the rate of such patients with interferon-based therapy, the rate was twice as high."

His recommendations: "First, prophylactic treatment should be considered for coinfected patients at the initiation of interferon-free anti-HCV therapy. Second, regular monitoring of HBV DNA is not necessary for HBV-resolved patients during DAA therapy."

Dr. Marina Serper from VA Medical Center and Hospital of the University of Pennsylvania, in Philadelphia, recently reported that clinically significant hepatic events are rare even with HBV reactivation.

"It is also important to note that using a less stringent definition of HBV reactivation (e.g., 1 log increase in HBV DNA), the risk could be as high as 45%," Dr. Serper, who was not involved in the new work, told Reuters Health by email.

"These findings should prompt clinicians to be mindful to check hepatitis B status on all patients starting DAA therapy for HCV," she said. "Baseline serologies should include HBsAg, anti-HBc antibody, anti-HBs antibody. Patients with HBsAg, and especially those with a detectable HBV DNA, should receive HBV prophylaxis prior to starting DAA therapy. Patients who are anti-HBc+ and HBsAg- (resolved HBV infection) should be monitored closely with ALT measurements every 4 weeks. ALT elevations should prompt repeat HBV DNA and HBsAg testing."

"Ongoing unanswered questions include mechanisms of HBV reactivation, cost-effectiveness of universal HBV prophylaxis among patients with chronic HBV, and duration of monitoring for possible HBV flare after HCV therapy is complete," Dr. Serper said.

"Among the 5 cases of HBV reactivation in HBsAg+ patients in our study, half of cases were noted to have reactivation after completion of HCV DAA therapy, underscoring the importance of close follow-up past SVR12 (sustained virological remission 12 weeks after cessation of treatment)," she said.

Eight of the 13 authors of the new report disclosed relationships with pharmaceutical companies that produce DAAs.

SOURCES: http://bit.ly/2GENAbw and http://bit.ly/2GBYIWl

Lancet Gastroenterol Hepatol 2018.