Nuffield Department of Medicine, University of Oxford, Medawar Building, South Parks Road, Oxford OX1 3SY, UK.
Division of Medical Virology, Stellenbosch University / National Health Laboratory Service Tygerberg, Cape Town, South Africa.
J Clin Virol. 2020 Aug;129:104548. doi: 10.1016/j.jcv.2020.104548. Epub 2020 Jul 8.
Tenofovir disoproxil fumarate (TDF) is widely recommended for treatment of chronic hepatitis B virus (HBV) infection because it is safe, affordable and has a high genetic barrier to resistance. TDF resistance associated mutations (RAMs) have been reported, but data are limited, particularly for Africa. We set out to identify potential RAMs in individuals with detectable HBV viraemia on TDF treatment.
We recruited adults with chronic HBV infection from Cape Town, South Africa, identifying individuals with a TDF resistance phenotype, defined as persistent HBV vireamia despite >12 months of TDF treatment. We sequenced HBV DNA using MiSeq Illumina with whole genome target enrichment, and sought potential TDF RAMs, based on a pre-defined list of polymorphisms.
Among 66 individuals with chronic HBV (genotypes A and D), three met our clinical definition for TDF resistance, of whom two were coinfected with HIV. In one participant, the consensus HBV sequence contained nine polymorphisms that have been described in association with TDF resistance. Significant treatment non-adherence in this individual was unlikely, as HIV RNA was suppressed. TDF RAMs were also present in HBV sequences from the other two participants, but other factors including treatment non-adherence may also have had a role in failure of HBV DNA suppression in these cases.
Our findings add to the evidence that RAMs in HBV reverse transcriptase may underpin a TDF resistant phenotype. This is the first time these RAMs have been reported from Africa in association with clinical evidence of TDF resistance.
富马酸替诺福韦二吡呋酯（TDF）因安全、经济实惠且具有较高的耐药基因屏障，被广泛推荐用于治疗慢性乙型肝炎病毒（HBV）感染。已有报道称存在替诺福韦耐药相关突变（RAMs），但数据有限，尤其是在非洲。我们旨在确定接受替诺福韦治疗时存在可检测到 HBV 病毒血症的个体中的潜在 RAMs。
我们从南非开普敦招募了慢性 HBV 感染的成年人，确定了具有替诺福韦耐药表型的个体，该表型定义为尽管接受替诺福韦治疗>12 个月但仍持续存在 HBV 病毒血症。我们使用靶向全基因组的 MiSeq Illumina 进行 HBV DNA 测序，并根据预先定义的多态性列表寻找潜在的 TDF RAMs。
在 66 名患有慢性 HBV（基因型 A 和 D）的个体中，有 3 名符合我们对替诺福韦耐药的临床定义，其中 2 名合并感染 HIV。在一名参与者中，HBV 序列的共识序列包含了 9 个已与替诺福韦耐药相关的多态性。由于 HIV RNA 得到抑制，该个体不太可能存在明显的治疗不依从，TDF RAMs 也存在于另外 2 名参与者的 HBV 序列中，但其他因素，包括治疗不依从，也可能在这些病例中导致 HBV DNA 抑制失败。
我们的研究结果进一步证明了 HBV 逆转录酶中的 RAMs 可能是 TDF 耐药表型的基础。这是首次在非洲报告这些 RAMs 与 TDF 耐药的临床证据相关。
