High Incidence of Treatment-induced and Vaccine-escape Hepatitis B Virus Mutants among HIV-hepatitis B Infected Patients 

Lacombe K, Boyd A, Lavocat F, Pichoud C, Gozlan J, Miailhes P, Lascoux-Combe C, Vernet G, Girard PM, Zoulim F

Anti-hepatitis B virus (HBV) nucleos(t)ides analogs (NA) exert selective pressures on pol- and S-genes, inducing treatment-resistance and increasing the risk of vaccine-escape mutants. The rate of emergence for these mutations is largely unknown in patients coinfected with human immunodeficiency virus (HIV) and HBV undergoing dual-active therapy. In a three-year, repeat-sampling, prospective cohort study, HBV viral genome sequences of 171 HIV-HBV co-infected patients, presenting with HBV viremia for at least one visit, were analyzed every 12-months via DNA-chip. Logistic and Cox-proportional hazard models were used to determine risk-factors for specifically S-gene mutations at baseline and during follow-up, respectively. HBV-DNA levels>190 IU/mL substantially decreased from 91.8% at inclusion to 40.3% at Month-36 (p<0.001), while lamivudine (LAM) or emtricitabine (FTC)-use remained steady (71.9%) and tenofovir (TDF)-use expanded (Month-0=17.5%, Month-36=66.7%; p<0.001). The largest increase of any mutation class was observed in L-nucleoside-associated pol-gene/antiviral-associated S-gene mutations (cumulative incidence at the end of follow-up=17.5%) followed by alkyl phosphonate-associated pol-gene (7.4%), immune-associated S-gene (specifically any amino acid change at positions s120/s145, 6.4%), and D-Cyclopentane-associated pol-gene mutations (2.4%). Incidence of L-nucleoside-associated pol-gene/antiviral-associated S-gene mutations was significantly associated with concomitant LAM therapy (adjusted-HR=4.61, 95%CI=1.36-15.56), but inversely associated with TDF-use (adjusted-HR/month=0.94, 95%CI=0.89-0.98). Cumulative duration of TDF was significantly associated with a reduction in the occurrence of immune-associated S-gene mutations (HR/month=0.88, 95%CI=0.79-0.98). No major liver-related complications, such as fulminant hepatitis, decompensated liver, and hepatocellular carcinoma (HCC), were observed in patients with incident mutations. Conclusion: Vaccine-escape mutants selected by NA-exposure were frequent and steadily increasing during follow-up. Although the high antiviral potency of TDF can mitigate incident mutations, other antiviral options are limited in this respect. Public health implications of their transmission need to be addressed. (HEPATOLOGY 2013.)