Belyhun Yeshambel, Liebert Uwe Gerd, Maier Melanie
Institute of Virology, Medical Faculty, Leipzig University, Leipzig, Germany.
School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia.
PLoS One. 2018 Feb 6;13(2):e0191970. doi: 10.1371/journal.pone.0191970. eCollection 2018.
We recently reported complex hepatitis B virus (HBV) drug resistant and concomitant vaccine escape hepatitis B surface antigen (HBsAg) variants during human immunodeficiency virus (HIV) co-infection and antiretroviral therapy (ART) exposure in Ethiopia. As a continuation of this report using the HBV positive sera from the same study participants, the current study further analyzed the HBV basal core promoter (BCP)/precore (PC) genes variability in patients with HBV drug resistance (at tyrosine-methionine-aspartate-aspartate (YMDD) reverse transcriptase (RT) motifs) and HIV co-infection in comparison with HBV mono-infected counterparts with no HBV drug resistant gene variants.
A total of 143 participants of HBV-HIV co-infected (n = 48), HBV mono-infected blood donors (n = 43) and chronic liver disease (CLD) patients (n = 52) were included in the study. The BCP/PC genome regions responsible for HBeAg expression from the EcoRI site (nucleotides 1653-1959) were sequenced and analyzed for the BCP/PC mutant variants.
Among the major mutant variants detected, double BCP mutations (A1762T/G1764A) (25.9%), Kozak sequences mutations (nt1809-1812) (51.7%) and the classical PC mutations such as A1814C/C1816T (15.4%), G1896A (25.2%) and G1862T (44.8%) were predominant mutant variants. The prevalence of the double BCP mutations was significantly lower in HIV co-infected patients (8.3%) compared with HBV mono-infected blood donors (32.6%) and CLD patients (36.5%). However, the Kozak sequences BCP mutations and the majority of PC mutations showed no significant differences among the study groups. Moreover, except for the overall BCP/PC mutant variants, co-prevalence rates of each major BCP/PC mutations and YMDDRT motif associated lamivudine (3TC)/entecavir (ETV) resistance mutations showed no significant differences when compared with the rates of BCP/PC mutations without YMDD RT motif drug resistance gene mutations. Unlike HIV co-infected group, no similar comparison made among HBV mono-infected blood donors and CLD patients since none of them developed the YMDD RT motif associated 3TC/ETV resistance mutations. However, HBV mono-infected blood donors and CLD patients who had no any drug resistance gene variants developed comparable G1862T (60.6% vs. 65.1%) and G1896A (24.2% vs. 11.6%) PC gene mutations.
No correlation observed between the BCP/PC genome variability and the YMDD RT motif associated HBV drug resistance gene variants during HIV co-infection. Nevertheless, irrespective of HIV co-infection status, the higher records of the BCP/PC gene variability in this study setting indicate a high risk of potential HBeAg negative chronic HBV infection in Northwest Ethiopia.
我们最近报告了在埃塞俄比亚人类免疫缺陷病毒（HIV）合并感染及接受抗逆转录病毒治疗（ART）期间，出现了复杂的乙型肝炎病毒（HBV）耐药及伴随的疫苗逃逸乙型肝炎表面抗原（HBsAg）变异株。作为该报告的延续，本研究使用同一研究参与者的HBV阳性血清，进一步分析了与无HBV耐药基因变异的HBV单一感染患者相比，HBV耐药（在酪氨酸-甲硫氨酸-天冬氨酸-天冬氨酸（YMDD）逆转录酶（RT）基序处）且合并HIV感染患者的HBV基础核心启动子（BCP）/前核心（PC）基因变异性。
本研究共纳入143名参与者，包括HBV-HIV合并感染患者（n = 48）、HBV单一感染献血者（n = 43）和慢性肝病（CLD）患者（n = 52）。对负责从EcoRI位点（核苷酸1653 - 1959）表达HBeAg的BCP/PC基因组区域进行测序，并分析BCP/PC突变变异株。
在检测到的主要突变变异株中，双BCP突变（A1762T/G1764A）（25.9%）、科扎克序列突变（nt1809 - 1812）（51.7%）以及经典的PC突变如A1814C/C1816T（15.4%）、G1896A（25.2%）和G1862T（44.8%）是主要的突变变异株。与HBV单一感染献血者（32.6%）和CLD患者（36.5%）相比，HIV合并感染患者中双BCP突变的患病率显著较低（8.3%）。然而，科扎克序列BCP突变和大多数PC突变在各研究组之间无显著差异。此外，除了总体BCP/PC突变变异株外，与无YMDD RT基序耐药基因突变的BCP/PC突变率相比，各主要BCP/PC突变与YMDD RT基序相关的拉米夫定（3TC）/恩替卡韦（ETV）耐药突变的共患病率无显著差异。与HIV合并感染组不同，由于HBV单一感染献血者和CLD患者均未出现与YMDD RT基序相关的3TC/ETV耐药突变，因此未在他们之间进行类似比较。然而，无任何耐药基因变异的HBV单一感染献血者和CLD患者出现了相当的G1862T（60.6%对65.1%）和G1896A（24.2%对11.6%）PC基因突变。
HIV合并感染期间，未观察到BCP/PC基因组变异性与YMDD RT基序相关的HBV耐药基因变异之间存在相关性。然而，无论HIV合并感染状态如何，本研究中BCP/PC基因变异性的较高记录表明埃塞俄比亚西北部存在潜在HBeAg阴性慢性HBV感染的高风险。
