Audsley Jennifer, Bent Stephen J, Littlejohn Margaret, Avihingsanon Anchalee, Matthews Gail, Bowden Scott, Bayliss Julianne, Luciani Fabio, Yuen Lilly, Fairley Christopher K, Locarnini Stephen, Lewin Sharon R, Sasadeusz Joe
aDepartment of Infectious Diseases, Monash University, MelbournebDepartment of Infectious Diseases, The Alfred Hospital, PrahrancDoherty Institute for Infection and Immunity, University of Melbourne, ParkvilledRobinson Research Institute, University of Adelaide, Adelaide, AustraliaeHIV-NAT Research Collaboration, Bangkok, ThailandfThe Kirby Institute, SydneygVictorian Infectious Diseases Reference Laboratory, North MelbournehSystems Medicine, School of Medical Sciences, University of NSW, SydneyiCentral Clinical School, Monash University, MelbournejMelbourne Sexual Health Centre, Carlton, Australia.
AIDS. 2016 Jun 19;30(10):1597-606. doi: 10.1097/QAD.0000000000001080.
Hepatitis B virus (HBV) can persist in some HIV-HBV coinfected individuals on tenofovir disoproxil fumarate (TDF)-containing combination antiretroviral therapy (cART) but HBV resistance to TDF has not been reported and the source of persistent HBV DNA on TDF is poorly understood. The aims of this study were to assess long-term HBV suppression in HIV-HBV coinfected individuals receiving TDF and investigate quasispecies variation using ultradeep pyrosequencing (UDPS).
Ninety-two HIV-HBV coinfected participants on, or about to commence, TDF-containing cART were enrolled [Australia (n = 40), Thailand (n = 52)] and followed for 2 years with study visits every 6 months. HBV reverse transcriptase sequencing was performed on samples with HBV DNA more than 400 IU/ml by population-based methods and UDPS. Quasispecies diversity was assessed using Shannon entropy.
Over 24 months, viremia was detected at least once in 17% (n = 16) of the cohort. Novel mutations were not identified in on TDF samples tested by population-based sequencing (n = 19). Using UDPS, the median Shannon entropy value in samples prior to TDF in patients aviremic on TDF was not statistically different from those who were viremic on TDF (n = 50; 8.4 and 9.1, respectively, P = 0.9). Longitudinal Shannon entropy analysis of on TDF samples from five participants showed three individuals with significant changes in viral diversity over time.
Persistent viremia on TDF-containing cART is common but TDF-resistance was not detected. In some individuals, changes in viral diversity over time were observed on TDF which could potentially be active viral replication. Further follow-up will be needed to determine the clinical significance of detectable HBV DNA on TDF-containing cART.
乙型肝炎病毒（HBV）可在一些接受含替诺福韦酯（TDF）的联合抗逆转录病毒疗法（cART）的HIV-HBV合并感染个体中持续存在，但尚未有HBV对TDF耐药的报道，且对TDF治疗期间持续存在的HBV DNA来源了解甚少。本研究旨在评估接受TDF治疗的HIV-HBV合并感染个体的长期HBV抑制情况，并使用超深度焦磷酸测序（UDPS）研究准种变异。
招募了92名正在接受或即将开始含TDF的cART治疗的HIV-HBV合并感染参与者[澳大利亚（n = 40），泰国（n = 52）]，并随访2年，每6个月进行一次研究访视。通过基于群体的方法和UDPS对HBV DNA超过400 IU/ml的样本进行HBV逆转录酶测序。使用香农熵评估准种多样性。
在24个月期间，17%（n = 16）的队列中至少有一次检测到病毒血症。在基于群体测序检测的TDF样本中未发现新的突变（n = 19）。使用UDPS，TDF治疗时病毒血症阴性患者TDF治疗前样本的香农熵中值与TDF治疗时病毒血症阳性患者的样本无统计学差异（n = 50；分别为8.4和9.1，P = 0.9）。对5名参与者的TDF样本进行纵向香农熵分析显示，3名个体的病毒多样性随时间有显著变化。
含TDF的cART治疗中持续存在病毒血症很常见，但未检测到TDF耐药。在一些个体中，观察到TDF治疗期间病毒多样性随时间的变化，这可能是活跃的病毒复制。需要进一步随访以确定含TDF的cART治疗中可检测到的HBV DNA的临床意义。
