INSERM UMR-S707, Paris, France.
Hepatology. 2013 Sep;58(3):912-22. doi: 10.1002/hep.26374. Epub 2013 Jun 25.
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.
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.
研究在接受双重活性治疗的人类免疫缺陷病毒（HIV）和乙型肝炎病毒（HBV）合并感染患者中，核苷（酸）类似物（NA）对聚合酶（pol）和表面（S）基因的选择性压力，导致治疗耐药和增加疫苗逃逸突变的风险。在一项为期 3 年、重复采样、前瞻性队列研究中，对 171 例因至少一次就诊而出现 HBV 病毒血症的 HIV-HBV 合并感染患者的 HBV 病毒基因组序列进行了分析，每 12 个月通过 DNA 芯片进行一次分析。采用逻辑和 Cox 比例风险模型分别确定基线和随访期间 S 基因突变的危险因素。HBV-DNA 水平>190 IU/mL 从纳入时的 91.8%显著下降至 36 个月时的 40.3%（P<0.001），而拉米夫定（LAM）或恩曲他滨（FTC）的使用保持稳定（71.9%），替诺福韦（TDF）的使用则扩大（0 个月时，17.5%；36 个月时，66.7%；P<0.001）。任何突变类别的最大增加都发生在 l-核苷相关的 pol 基因/抗病毒相关的 S 基因突变（随访结束时的累积发生率为 17.5%）之后是膦酸酯相关的 pol 基因（7.4%）、免疫相关的 S 基因（特别是在位置 s120/s145 的任何氨基酸变化，6.4%）和 d-环戊烷相关的 pol 基因突变（2.4%）。l-核苷相关的 pol 基因/抗病毒相关的 S 基因突变的发生率与同时使用 LAM 治疗显著相关（调整后的危险比[HR]，4.61；95%置信区间[CI]，1.36-15.56），但与 TDF 的使用呈负相关（调整后的 HR/月，0.94；95%CI，0.89-0.98）。TDF 的累积持续时间与免疫相关的 S 基因突变的发生减少显著相关（HR/月，0.88；95%CI，0.79-0.98）。在发生突变的患者中未观察到与肝脏相关的重大并发症（如暴发性肝炎、肝功能失代偿和肝细胞癌）。
NA 暴露选择的疫苗逃逸突变在随访期间频繁且持续增加。尽管 TDF 的高抗病毒效力可以减轻新出现的突变，但其他抗病毒选择在这方面受到限制。需要解决它们传播的公共卫生影响。
