TY - JOUR
T1 - High incidence of treatment-induced and vaccine-escape hepatitis B virus mutants among human immunodeficiency virus/hepatitis B-infected patients
AU - Lacombe, Karine
AU - Boyd, Anders
AU - Lavocat, Fabien
AU - Pichoud, Christian
AU - Gozlan, Joel
AU - Miailhes, Patrick
AU - Lascoux-Combe, Caroline
AU - Vernet, Guy
AU - Girard, Pierre-Marie
AU - Zoulim, Fabien
N1 - Copyright © 2013 by the American Association for the Study of Liver Diseases.
PY - 2013/9
Y1 - 2013/9
N2 - 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). © 2013 by the American Association for the Study of Liver Diseases.
AB - 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). © 2013 by the American Association for the Study of Liver Diseases.
KW - Adult
KW - Antiviral Agents/pharmacology
KW - Cohort Studies
KW - Comorbidity
KW - DNA, Viral/genetics
KW - Female
KW - Follow-Up Studies
KW - Genes, pol/genetics
KW - HIV Infections/epidemiology
KW - Hepatitis B Vaccines/pharmacology
KW - Hepatitis B virus/drug effects
KW - Hepatitis B/epidemiology
KW - Humans
KW - Incidence
KW - Male
KW - Middle Aged
KW - Mutation/drug effects
KW - Prevalence
KW - Prospective Studies
KW - Retrospective Studies
KW - Risk Factors
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84883250802&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/23468093
U2 - https://doi.org/10.1002/hep.26374
DO - https://doi.org/10.1002/hep.26374
M3 - Article
C2 - 23468093
SN - 0270-9139
VL - 58
SP - 912
EP - 922
JO - Hepatology (Baltimore, Md.)
JF - Hepatology (Baltimore, Md.)
IS - 3
ER -