Over 240 million people in the world are chronically infected with hepatitis B virus (HBV). In many infected individuals, initial infection leads to clearance (defined as the loss of surface antigen [HBsAg]). Some HBsAg negative individuals remain HBV DNA positive (i.e., occult HBV) and others have HBV DNA in the liver but are serologically cleared. No standard definition of HBV reactivation exists, but various experts include de novo detection of HBV DNA in individuals with no previously detected HBV DNA, a 1-2 log IU/mL rise in HBV DNA, and/or HBsAg seroreversion in HBsAg-negative patients who are positive for anti-HBc. HBV reactivation may occur at any time during the disease course. However, it is most common during previously undiagnosed chronic HBV infection upon initiation of immunosuppressive agents. Despite this risk, HBV screening remains low in patients receiving immunosuppressive therapies in the U.S., and is largely absent from low and middle-income countries. Among individuals with “resolved” HBV infection, there remains a risk of HBV reactivation if receiving immunosuppressive therapies and/or chemotherapy. Similarly, HBV reactivation may occur in individuals treated for autoimmune disorders or undergoing transplantation. Among HBsAg-negative patients, a risk of HBV reactivation remains. HBV reactivation in HIV-positive individuals that initiate or terminate antiretroviral therapy has also been reported. Current guidelines address the need for appropriate patient identification and management.1
Recently, HBV reactivation in patients effectively treated for hepatitis C virus (HCV) infection with HCV-active direct-acting agents has emerged as an area of clinical concern. HCV often inhibits HBV replication in those with dual infections; thus, direct-acting agents (DAAs) that eradicate HCV may inadvertently lead to increased HBV replication. Increasingly, cases of HBV reactivation in HCV-positive individuals treated with various DAAs are reported. Through July 2016, 24 cases of HBV reactivation were reported to the U.S. FDA among patients receiving DAAs, and a black box warning regarding the risk of reactivation was issued in October 2016.2 Subsequently, several studies have tried to characterize the true risk by evaluating HCV treatment cohorts that had undergone curative therapy with DAAs. Risk appears to be highest among those who have detectable HBsAg in their blood and could exceed 50 percent. In contrast, those with isolated anti-core antibody (anti-HBc) appear to have minimal risk for reactivation. In some instances, reactivation results in serious liver injury. Sulkowski et al. evaluated 173 patients — 103 (60 percent) of whom had been infected with HBV previously — in a clinical trial of ledipasvir and sofosbuvir conducted in Taiwan and Korea.3 No cases of HBV reactivation were found. In the largest study performed to date, of 327 patients receiving DAAs in China, 10 individuals were HBsAg positive and 124 patients had occult HBV. Three cases of HBV reactivation were identified.4 A recent meta-analysis compared reactivation rates in patients with chronic versus occult infection and among patients treated with interferon (IFN)-based therapy to those treated with DAAs.5 Among individuals with chronic HBV, the incidence of HBV reaction was similar among those treated with IFN-based therapies or DAAs, although reactivation occurred earlier in the DAA treatment group. Hepatitis due to reactivation was more common when treated with DAAs compared to IFN-based treatment (12.2 percent versus 0 percent). HBV reactivation and hepatitis were less common among individuals with occult HBV infection. In a large “real world” cohort of 848 HCV infected patients treated with DAAs, no HBV reactivation was observed among HBsAg negative/anti-core positive patients. In contrast, five of nine HBsAg positive patients did reactivate HBV, and three required HBV active therapy.6
HCV often inhibits HBV replication in those with dual infections; thus, DAAs that eradicate HCV may inadvertently lead to increased HBV replication.
Prevention of HBV reactivation has focused on prophylactic antiviral therapy. Unfortunately, no consensus exists as to the optimum therapy or duration of therapy to prevent HBV reactivation. In the HBV/HCV coinfected patient in whom HCV therapy is contemplated, it is very important to check for evidence of active (HBsAg positive) or occult (HBV DNA positive but HBsAg negative) HBV infection. It is important to note that HB anti-core IgG is a relatively poor surrogate marker for those with occult HBV. Based upon current data from multiple cohorts, all patients with HBsAg are at risk and should be treated during/after HCV therapy with an HBV suppressive regimen. Tenofovir or entecavir are good choices, though short-term use of lamivudine or telbivudine is likely to be effective as well. The duration of HBV therapy after HCV clearance remains unclear, and current HBV treatment guidelines may or may not be applicable. In lower risk patients, including those with either isolated anti-core IgG or those with occult HBV, close monitoring is recommended at intervals of four or more weeks. Evidence of increased replication or ALT increase will inform the decision to start nucleoside/nucleotide therapy for HBV. Though new HCV treatments have revolutionized care for HCV infected patients, thoughtful pre-treatment evaluation and management of HBV coinfections will improve patient safety and yield optimal treatment results.
Acknowledgments: This work was funded in part by the National Institute of General Medical Sciences (award GM105414 to JTB).
• In HCV-infected patients, pre-treatment testing should include HBsAg, anti-HBs and anti-HBc.
• Patients with HBsAg are at risk and should be treated during/after HCV therapy with an HBV suppressive regimen.
• In lower risk patients (prior infection or occult HBV), close monitoring is recommended at intervals of four or more weeks. Some experts would treat occult HBV with antivirals.
• Thoughtful pre-treatment evaluation and management of HBV coinfections will improve patient safety and yield optimal treatment results.
Dr. Blackard has no conflicts to disclose.
Dr. Sherman has received grants/contracts (paid to institution) from AbbVie, BMS, Gilead, Merck, Innovio and MedImmune and has served on
advisory boards for Gilead, Merck and MedImmune.
1. Reddy K.R., Beavers K.L., Hammond S.P., Lim J.K., Falck-Ytter Y.T. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015;148(1):215-9.
2. US 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. March 2017. https://www.fda.gov/Drugs/DrugSafety/ucm522932.htm.
3. Sulkowski M.S., Chuang W.L., Kao J.H. et al, No evidence of reactivation of hepatitis B virus among patients treated with ledipasvir-sofosbuvir for hepatitis C virus infection. Clin Infect Dis. 2016;63(9):1202-4.
4. Wang C., Ji D., Chen J. 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. 2017;15:132-6.4.
5. Chen G., Wang C., Chen J. et al, Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents: A systematic review and metaanalysis. Hepatology. 2017;Epub ahead of print.
6. Mücke V.T., Mücke M.M., Peiffer K.H. et al, No evidence of hepatitis B virus reactivation in patients with resolved infection treated with direct-acting antivirals for hepatitis C in a large real-world cohort. Aliment Pharmacol Ther. 2017;46(4):432-9.