Treatment of HCV in the setting of HBV coinfection

All individuals with chronic HCV infection should be tested for HBV infection. Testing should include HBsAg, anti-HBc and anti-HBs serology (all three tests for HBV may be requested if the clinical notes indicate acute or chronic hepatitis). Current hepatitis B infection is defined by HBsAg positivity, with chronic hepatitis B infection defined as presence of infection for more than 6 months (Table 9). All individuals with current HBV infection should be referred for specialist management. Past HBV infection is defined by HBsAg negativity, positive anti-HBc  positive anti-HBs serology (note that anti-HBs titre may wane over time and become undetectable; Table 9). Occult hepatitis B infection is very rare, but is defined by positive HBV DNA in the absence of HBsAg — in most cases, the HBV DNA level is very low; anti-HBc is normally positive.100

In October 2016, the United States Food and Drug Administration (FDA) issued a boxed warning regarding the risk of HBV reactivation in patients undergoing treatment with DAA therapy. The warning was issued on the basis of 24 case reports notified to the FDA and/or published in the literature between November 2013 and July 2016.101 Full details of all 24 cases are not publicly available, although the FDA released a summary of key findings. The cases occurred in patients with differing HBV serological profiles before commencing DAA therapy, including those who were HBsAg-positive, with both detectable HBV DNA (n = 7) and undetectable HBV DNA (n = 4), and in those with serological profiles consistent with past HBV infection (anti-HBc positive, HBsAg-negative and undetectable HBV DNA; n = 3). The two clinically significant cases of HBV reactivation among anti-HBc-positive, HBsAg-negative people were associated with a history of immunosuppression (previous Burkitt lymphoma, HIV coinfection). In 10 cases, baseline HBV status was not available. No patients were receiving HBV antiviral therapy. No pattern was observed with regard to HCV genotype or DAA regimen used. In almost all cases, elevation of HBV DNA level was observed within the initial 4–12 weeks of DAA therapy, as HCV RNA levels fell rapidly to undetectable. In some patients, elevation of HBV DNA level was asymptomatic and settled without further intervention, but hepatic decompensation occurred in three patients, resulting in the death of two patients and liver transplantation in one patient. Twelve patients commenced HBV antiviral therapy (entecavir or tenofovir), with resultant HBV DNA suppression and normalisation of ALT levels. HCV RNA remained undetectable in all cases. 

There is biological plausibility for the development of HBV reactivation during HCV therapy, although the exact mechanism is unknown. When HCV and HBV coexist in the same host, HCV exerts a dominant immunosuppressive effect, resulting in lower HBV DNA and HBV antigen levels and reflecting a state of immune control. Reactivation of HBV DNA during HCV treatment with IFN-containing regimens has been well described and shown to occur in up to 31% of coinfected patients,102 although the anti-HBV effect of IFN meant that this was rarely clinically significant. In the context of DAA therapy, rapid suppression of HCV RNA may trigger complex immunological change, allowing uncontrolled HBV reactivation and replication. This theory is consistent with the timing observed in reported cases. It remains unclear how common significant clinical reactivation is in the context of HCV–HBV coinfected patients undergoing DAA therapy. It is also unclear whether all patients should commence HBV antiviral therapy or whether a period of watchful waiting is appropriate. 

In the absence of further data at this time, the following conclusions have been drawn about risk of HBV reactivation. There is a risk gradient for the occurrence of HBV reactivation, wherein HBsAg-positive individuals have a moderate risk of HBV reactivation. HBsAg-positive people should have HBV DNA levels measured at baseline and should be considered for antiviral therapy according to current guidelines (see below). If antiviral therapy for HBV is not indicated, active monitoring of ALT and HBV DNA levels should be performed during HCV treatment (see below).

Anti-HBc-positive and HBsAg-negative individuals have a low risk of reactivation. Anti-HBc-positive and HBsAg-negative serostatus is common in people who were exposed to HCV through injecting drug use. Anti-HBc-positive, HBsAg-negative people were not excluded from clinical trials, and no cases of acute HBV reactivation have been reported in any clinical trials evaluating DAA combination regimens in patients infected with HCV.103 Emerging data specifically addressing the risk of HBV reactivation in anti-HBc-positive individuals are reassuring.103,104 Of 173 HBsAg-negative people treated for Gt 1 HCV with open-label sofosbuvir–ledipasvir as part of a Phase IIIb study in Korea, 60% were observed to be anti-HBc-positive.103 At 24 weeks after treatment, all 173 remained HBsAg-negative, with HBV DNA levels < 20 IU/mL. In two patient samples, HBV DNA level was < 20 IU/mL but was detectable. No ALT flares were observed through Week 4 after treatment, the last time point at which ALT level was evaluated. There was no difference in laboratory abnormalities, including ALT levels, between patients who were anti-HBc-positive and anti-HBc-negative. A second single-centre study of 327 Chinese patients receiving DAA treatment for HCV included 124 patients with occult HBV infection, defined as HBV DNA-positive, HBsAg-negative.104 Patients were followed every 2 weeks during treatment, and every 4 weeks after treatment until SVR. HBsAg and HBV DNA levels were measured at all time points in the subset with occult HBV infection. No case of acute HBV reactivation was observed in this population. 

Given the low risk of reactivation, we recommend routine monitoring (specifically a measurement of ALT level at Week 4) for anti-HBc-positive and HBsAg-negative people who are treated with HCV DAAs, as recommended for people who are seronegative for all markers of HBV infection (see Section On-treatment monitoring). We do not recommend routine HBV DNA testing in anti-HBc-positive, HBsAg-negative people at baseline. HBV reactivation should be considered in any patient who experiences an ALT flare during or after DAA treatment. A final caution — the risk of occult HBV infection and acute HBV reactivation may be higher in people with a history of immunosuppression, including HIV coinfection. In these populations, it is reasonable to actively monitor HBV DNA levels during treatment.

Table 9. Definitions of hepatitis B virus (HBV) infection, by HBV test result
TestCurrent HBV infectionPast HBV infectionOccult HBV infectionVaccine-induced immunity
HBsAg+---
Anti-HBc+++-
Anti-HBs-+/-+/-+
HBV DNA+/--+ (typically very lowlevel-

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