Hepatitis B Reactivation in Hepatitis B and C Coinfected Patients Treated With Antiviral Agents: A Systematic Review and Meta-analysis
Chen G, et al.
Hepatology 2017; 66:13-26.

Abstract: There is an increased awareness of HBV reactivation in chronic hepatitis C (CHC) patients coinfected with HBV treated with pan-oral DAAs. We performed a systematic review and meta-analysis to compare the rate of HBV reactivation in CHC patients coinfected with overt HBV (HBsAg] positive) and occult HBV (HBsAg negative with positive HBV DNA) infection separately, treated with IFN-based therapy to those with pan-oral DAAs. The primary outcome was HBV reactivation, and the secondary outcomes included hepatitis due to HBV reactivation, sustained SVR for CHC, loss of HBV DNA and HBsAg seroclearance. Although the pooled incidence rate of HBV reactivation, among CHC patients with overt HBV (n 5 779), was similar among those treated with IFN-based therapy (14.5%, P <0.001) and DAAs (12.2%, P =0.03; P =0.91 for heterogeneity between subgroups), it was reported to occur much earlier in those treated with DAAs (4-12 weeks during treatment) than in those treated with IFN-based therapies (most at the end of treatment and some during follow-up). Also, studies with DAA-based therapies were more likely to report incidence of hepatitis due to HBV reactivation (12.2% in DAAs vs. 0% in IFN; P =0.009 for heterogeneity between subgroups). HBV reactivation and hepatitis due to HBV reactivation also occurred, though less frequently in CHC patients with occult HBV infection. CHC SVR was not affected by HBV reactivation (P =0.27).

Conclusion: HBV reactivation occurs earlier and is clinically more significant in CHC patients coinfected with overt and occult HBV who are treated with pan-oral DAAs compared with IFN-based therapy. It is therefore important to have all patients screened for evidence of overt or occult HBV infection and managed during pan-oral DAAs therapy.

Evaluation of Hepatitis B Reactivation Among 62,920 Veterans Treated With Oral Hepatitis C Antivirals
Belperio PS.
Hepatology 2017;66:27-36.

Abstract: Reactivation of HBV has been reported in HCV–infected individuals receiving DAA therapy. The overall risk among patients with current or prior HBV infection in the context of DAA treatment is unknown. The aim of this evaluation was to identify and characterize HBV reactivation among veterans treated with oral DAA therapy. This retrospective evaluation included 62,290 HCV–infected veterans completing oral DAA treatment. Baseline HBV infection status for each veteran was identified from HBV laboratory data performed prior to DAA initiation. To assess for HBV reactivation and hepatitis we identified all HBsAg, HBV DNA, and alanine aminotransferase results obtained while on DAA treatment or 7 days after. HBV reactivation was defined as a >1000 IU/mL increase in HBV DNA or HBsAg detection in a person who was previously negative. Prior to DAA treatment 85.5% (53,784/62,920) had HBsAg testing and 0.70% (377/53,784) were positive; 84.6% (53,237/62,920) had a hepatitis B surface antibody test, of which 42.2% (22,479/53,237) were positive. In all, 9 of 62,290 patients treated with DAAs had evidence of HBV reactivation occurring while on DAA treatment. 8 occurred in patients known to be HBsAg-positive, and 1 occurred in a patient known to be isolated HBc Ab–positive. 17 other patients had small increases in HBV DNA levels that did not qualify as HBV reactivation. Only 3 of the 9 patients identified with HBV reactivation in this cohort exhibited peak alanine aminotransferase elevations >2 times the upper limit of normal.

Conclusion: HBV reactivation of varying severity, even in the setting of isolated HBc Ab, with or without accompanying hepatitis can occur—though the occurrence of accompanying severe hepatitis was rare.

Expert's Commentary: DAA-associated HBV reactivation: from the warning to the daily practice - To treat or not to treat

Around 5% of patients have HBV/HCV coinfection which is associated with a risk of more severe liver disease (cirrhosis and/or hepatocellular carcinoma)^(1-4). This could suggest that most of HBV/HCV-coinfected patients require an antiviral therapy against both HCV and HBV infection⁽⁴⁾ with a comparable HCV SVR rates^(5-7). However, a cautious follow-up has to monitor a potential risk of HBV reactivation⁽⁸⁾ associated with HCV clearance during treatment with the DAAs regimens or after, as recently indicated by studies and Drug Agencies^(9-10). Even if there is a risk of severe reactivation as defined by a > 1 log increase of HBV DNA and an ALT flare resulting in death or liver transplantation⁽¹⁰⁾, the real-life experience in Spain or China does not evidence a major risk associated with reactivation which appears to be spontaneously resolutive in most cases^(11-12). Any HBV reactivation must then be treated according to the guidelines with nucleos(t)ides analogues⁽⁴⁾.

A recent evaluation of HBV reactivation among 62,920 veterans treated with DAA, revealed 8 among 377 cases of reactivation in HBsAg-positive and one in a patient with isolated anti-HBc antibodies: only 3 patients had a ALT peak > 2 UNL⁽¹³⁾. A systematic review and meta-analysis in 779 patients with coinfection who were given IFN- or DAA-based therapies⁽¹²⁾ identified a similar rate of so-called HBV reactivation (14.5% and 12.2%, respectively) but the incidence of hepatitis was different (0 vs 12.2%, respectively, P = 0.009) in overt and occult infection.

Even if definitions of HBV reactivation on the one hand and of hepatitis (namely the severity of the reactivation) are heterogeneous across the different studies, they confirm that HBV reactivation is a rare event and ususally without significant clinical impact in the HCV general population. They underline first the need of screening and second to manage overt or occult HBV infection, given the rare risk of severe reactivation in any DAA-treated patient. According to guidelines, all DAA treated patients should be tested for HBsAg and anti-HBc and HBV DNA for HBsAg positive. Beyond recommended HBV treatment, the main issue is to decide to treat all HBsAg and HBV DNA positive patients with nucleos(t)ide analogues⁽¹⁴⁾ or to prefer a regular monitoring of ALT and HBV DNA in HBsAg positive patients according to the French AFEF recommendations. In a such unusual situation, the physician will have to make a decision to treat or not to treat on a case-by-case evaluation.

Pr Stanislas Pol
Université Paris Descartes ; APHP, Unité d'Hépatologie, Hôpital Cochin ;
Centre de Recherche Translationnelle and INSERM U-1223 and UMS20, Institut Pasteur, Paris, France

References

1. Chu CJ, Lee SD. Hepatitis B virus/hepatitis C virus coinfection: Epidemiology, clinical features, viral interactions and treatment. J Gastroenterol Hepatol 2008; 23:512-20.
2. Jamma S, et al. Current Concepts of HBV/HCV Coinfection: Coexistence, but Not Necessarily in Harmony. Curr Hepat Rep 2010; 9:260-9.
3. Donato F, et al. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer 1998; 75:347-54.
4. European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012; 57:167-185.
5. Piroth L, et al. Management and treatment of chronic hepatitis B virus infection in HIV positive and negative patients: the EPIB 2008 study. J Hepatol 2010; 53:1006-1012.
6. Zhou J, et al. Hepatitis B and C virus coinfection in the TREAT asia HIV observational database. J Gastroenterol Hepatol 2007; 22:1510-8.
7. Saitta C, et al. Virological profiles in hepatitis B virus/hepatitis C virus coinfected patients under interferon plus ribavirin therapy. Antivir Ther 2006; 11:931-4.
8. Takayama H, et al. Reactivation of hepatitis B virus during interferon-free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus co- infection. Hepatol Res 2016 Mar; 46:489-491