title: High incidence of treatment-induced and vaccine-escape hepatitis B virus mutants among human immunodeficiency virus/hepatitis B-infected patients.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: INSERM UMR-S707, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Lacombe
authors.forename: Anders
authors.initials: A
authors.lastname: Boyd
authors.forename: Fabien
authors.initials: F
authors.lastname: Lavocat
authors.forename: Christian
authors.initials: C
authors.lastname: Pichoud
authors.forename: Joel
authors.initials: J
authors.lastname: Gozlan
authors.forename: Patrick
authors.initials: P
authors.lastname: Miailhes
authors.forename: Caroline
authors.initials: C
authors.lastname: Lascoux-Combe
authors.forename: Guy
authors.initials: G
authors.lastname: Vernet
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Girard
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D015331:Cohort Studies; D015897:Comorbidity; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015751:Genes, pol / Q000235:genetics; D015658:HIV Infections / Q000453:epidemiology / Q000235:genetics*; D006509:Hepatitis B / Q000453:epidemiology / Q000235:genetics*; D017325:Hepatitis B Vaccines / Q000494:pharmacology*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects* / Q000235:genetics*; D015995:Prevalence; D011446:Prospective Studies; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D017325:Hepatitis B Vaccines