Hepatitis B virus reactivation during direct‐acting antiviral treatment of chronic hepatitis C: A hidden danger of an otherwise major success story
Authors: Robert P. Perrillo
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. See Articles on Pages 13 and 27 It has been estimated that 250 million and 170 million people worldwide are infected with hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. Coinfection is relatively common in regions where both viruses are endemic and transmission is facilitated by common routes of exposure. In a recent study of 1,287 New York City residents with hepatitis C, most of whom were born in United States, 62% had resolved HBV infection and 6% were hepatitis B surface antigen (HBsAg)‐positive.1 Dual infection with HBV and HCV leads to accelerated liver disease and a higher risk for cirrhosis and hepatocellular carcinoma. Treatment of coinfected patients is controversial, but it is a common practice to treat the virus that genomic testing reveals to be dominant. The intracellular interactions of the two viruses are unclear. Cross‐sectional studies have shown that coinfected individuals often have high levels of HCV RNA, low or undetectable HBV DNA, antibody to hepatitis B e antigen reactivity, and lower levels of HBsAg compared with HBV monoinfection.2 Thus, HCV is most often the primary target of antiviral therapy. However, longitudinal studies have demonstrated that the levels of HBV DNA and HCV RNA may fluctuate with time, suggesting that competitive interactions between the two viruses are more dynamic than previously thought.3 The recent development of direct‐acting antiviral (DAA) drugs that are highly effective in eradicating hepatitis C virus is a milestone achievement. Registration trials have convincingly shown that DAA treatment is far better tolerated than interferon/ribavirin‐based regimens. However, postapproval case series and a compilation of 24 international cases in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) have demonstrated that HBV reactivation (HBVr) occurs during DAA treatment.4 The recent emergence of this adverse effect of DAAs is explainable by the exclusion of HBV‐coinfected individuals from registration trials. As with HBVr during immunosuppressive medications, reactivation with DAA therapy occurs in HBsAg‐positive individuals and is less common in persons with resolved infection (HBsAg‐negative, antibody to hepatitis B core antigen [anti‐HBc]‐positive with or without antibody to hepatitis B surface antigen [anti‐HBs]).5 Predictive factors have not been identified, but there is no apparent association of HBVr with the type of DAA therapy or HCV genotype. Frequent biochemical evidence of hepatitis in the reported cases with liver injury severe enough to require liver transplantation in a few instances—as well as rare cases of fatalities—have resulted in an FDA box warning for these agents. Both the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA) Guidance Panel have recommended HBV screening with HBsAg, anti‐HBc, and anti‐HBs before initiation of HCV treatment.8 The AASLD/IDSA Guidance Panel recommends that all HBsAg‐positive patients should be tested for HBV DNA and that individuals who meet the criteria for antiviral therapy (>2000 IU) should be given HBV therapy, whereas HBsAg carriers with low or undetectable HBV DNA should be monitored with regular HBV DNA testing during DAA treatment. A paucity of data prevented the AASLD/IDSA Guidance Panel from making specific recommendations for individuals with resolved hepatitis B. These recommendations are likely to change as further information is acquired. Two articles in this issue of Hepatology provide further clarity on the relative risk of HBVr during DAA therapy in patients with active and resolved hepatitis B.10 These studies are important because they allow us to better evaluate the adequacy of the current treatment guidelines. In the first study, Belperio et al.10 used the US Department of Veterans Affairs Corporate Data Warehouse to review data on 62,000 HCV‐infected patients who had undergone treatment with DAA therapy. The study cohort included 377 HBsAg‐positive and 7200 anti‐HBc–positive patients. Of this number, nine cases (eight HBsAg‐positive, one with resolved infection) met the virologic criterion for HBVr of a greater than 3 log increase in HBV DNA. One of the eight HBsAg‐positive reactivations was associated with a severe elevation of alanine aminotransferase (ALT) level (1540 U), and this was the only case in which the pretherapy HBV DNA level exceeded 2000 IU. Twelve additional HBsAg‐positive patients demonstrated a 1.32‐2.95 log increase in HBV DNA during treatment. Peak on treatment ALT levels in these cases were either normal or minimally elevated, and pretherapy HBV DNA was either undetectable or less than 100 IU. Reactivation was rare in the resolved hepatitis B patients, with only one patient meeting the virologic criterion for reactivation and none of the 390 patients tested for HBsAg during treatment becoming positive. Although this timely study gives us an important glimpse at reactivation in a large hepatitis C cohort with active or resolved hepatitis B, the observed frequency of HBVr was likely to be an underestimate. HBV DNA testing was only done in 84 (22%) of the 377 HBsAg‐positive patients, and testing for HBV DNA and HBsAg in the group with resolved infection were available in a small minority of patients (2.4% and 5.3%, respectively). Also, the virologic criterion used to diagnose HBVr was considerably more stringent than the 1 log increase in HBV DNA that is frequently cited in the literature. The second study by Chen et al.11 is a systematic review and meta‐analysis of 29 interferon studies and seven DAA studies with a primary objective of determining the efficacy and safety of interferon and DAA treatment of hepatitis C.11 The authors found that the rate of occurrence of HBVr (12%‐14%) was comparable with interferon and DAA therapy, but as they point out, the level of confidence in the pooled incidence rates of HBVr was reduced by substantial heterogeneity of the virologic and ALT criteria used to define reactivation and associated hepatitis. Severe hepatitis was more frequently reported with DAA treatment, and reactivation was not recorded in interferon‐treated patients with occult infection (HBsAg‐negative, anti‐HBc–positive). As with the study by Belperio et al., baseline HBV DNA level was not associated with reactivation in either HBsAg‐positive or occult‐infected patients. The operative mechanisms behind HBVr during DAA therapy of hepatitis C are currently unclear. However, examination of the contrasting clinical features of the cases reported with interferon and DAA treatment provide clues to possible pathogenetic mechanisms. As emphasized in the article by Chen et al., HBVr occurs earlier during DAA therapy compared with interferon. The slower emergence of HBVr with interferon, often occurring after discontinuation of treatment, can be explained by the drug's anti‐HBV properties and a slower and weaker effect on HCV replication that provides less momentum toward reciprocal dominance by HBV. In contrast, HBVr first emerges during DAA therapy coincident to the disappearance of HCV RNA at weeks 4‐8 of treatment. Investigations in DAA‐treated patients have shown that this is a time when there is a major change in the hepatic immunologic environment with a steep decline in interferon signaling genes and proinflammatory cytokines such as tumor necrosis factor α and interferon γ–induced protein 10, each of which could favor enhanced HBV replication.12 Eradication of HCV would also be anticipated to result in the disappearance of the HCV core protein that has been shown to impede HBV replication in vitro and in vivo.14 In addition, a recent study using peripheral and intrahepatic natural killer T cells has shown a rapid loss of natural killer cell activation markers during DAA treatment of hepatitis C.15 The most pressing clinical issue currently is how to best prevent HBVr during DAA treatment. Prevention requires that all patients who will be placed on DAA treatment should be scrupulously tested for at least HBsAg and anti‐HBc before treatment initiation followed by HBV DNA assessment in individuals who are found to be HBsAg‐positive. Early initiation of treatment with entecavir or tenofovir is indicated in HBsAg carriers who meet the standard criteria for antiviral therapy. However, as noted in the FAERS and the two aforementioned articles in this issue, a baseline finding of undetectable or low‐level HBV DNA in HBsAg‐positive patients does not ensure that HBVr will not occur during DAA therapy. Thus, it is my belief that anti‐HBV prophylaxis also should be given to all HBsAg‐positive patients who fail to meet treatment criteria, as is currently done with immunosuppressive drug therapy. Until more information is available, prophylaxis should probably be continued until a sustained virologic response can be documented at posttreatment week 12. Patients who fail to achieve a sustained virologic response with DAA therapy may be less likely to have a lower risk for HBVr after treatment, but more information is needed. Routine testing for HBV DNA in resolved HBV infection is not recommended currently because of significant costs involved (particularly from a global perspective) and the relative rarity of HBVr in these individuals.5 Instead, these patients should have regular ALT monitoring with reflexive HBV DNA testing for unexplained elevation of ALT levels. Reactivation of hepatitis B is an infrequent but not rare complication of DAA therapy in HBV/HCV‐coinfected patients. The availability of curative treatments for hepatitis C has placed increased emphasis on diagnosing and treating this condition. This is an apt time, however, to be reminded of the importance of screening all HCV‐infected patients for HBV. As with immunosuppressive drug therapy, HBV screening and early treatment are the key elements in preventing HBVr during DAA therapy.