High incidence of treatment-induced and vaccine-escape hepatitis B virus mutants among human immunodeficiency virus/hepatitis B–infected patients


  • Potential conflict of interest: Dr. Zoulim consults for and received grants from Gilead, Bristol-Myers Squibb, and Roche. Dr. Lascoux-Combe consults for and received grants from Janssen. She also consults for Gilead and received grants from Roche.

  • This study was supported by grants from the Agence Nationale de Recherche sur le Sida et les Hépatites (ANRS), SIDACTION, and the European Community (HepBvar project contract QLRT2001-00977 and VIRGIL network contract LSHMCT- 2004-503359). Gilead Sciences, Inc., provided an unrestricted grant for the French HIV-HBV cohort and was not involved in any part of the data collection, analysis, or manuscript writing. A. B. was awarded a postdoctoral fellowship from the ANRS.

Address reprint requests to: Karine Lacombe, M.D., Ph.D., Service de maladies infectieuses, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France. E-mail:; fax: +33 1-49-28-21-49; or Fabien Zoulim, M.D., Ph.D., Centre de recherche en cancérologie de Lyon INSERM U 1052/CNRS UMR 5286, 151 cours Albert Thomas, 69000 Lyon, France. E-mail:; fax: +33 472-68-19-71.


Anti–hepatitis B virus (HBV) nucleos(t)ides analogs (NA) exert selective pressures on polymerase (pol) and surface (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 3-year, repeat-sampling, prospective cohort study, HBV viral genome sequences of 171 HIV-HBV coinfected 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 specifically for 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 hazard ratio [HR], 4.61; 95% confidence interval [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 (e.g., fulminant hepatitis, decompensated liver, and hepatocellular carcinoma) 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. The public health implications of their transmission need to be addressed. (Hepatology 2013;53:912–922)