Diphoko Thabo, Gaseitsiwe Simani, Kasvosve Ishmael, Moyo Sikhulile, Okatch Harriet, Musonda Rosemary, Wainberg Mark, Makhema Joseph, Marlink Richard, Novitsky Vladimir, Essex Max
1 Botswana Harvard AIDS Institute Partnership , Gaborone, Botswana .
2 Department of Medical Laboratory Sciences, Faculty of Health Sciences, University of Botswana , Gaborone, Botswana .
AIDS Res Hum Retroviruses. 2018 Aug;34(8):667-671. doi: 10.1089/AID.2017.0135. Epub 2018 Jun 12.
Rilpivirine (RPV) and Etravirine (ETR) are approved second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV treatment. There is a cross-resistance HIV mutation profile between first- and second-generation NNRTI drugs. We determined the prevalence of HIV-1 drug resistance mutations (DRMs) to RPV and ETR in Botswana. A total of 168 HIV-1 polymerase gene sequences from participants failing nevirapine (NVP)- or efavirenz (EFV)-containing regimens were analyzed for DRMs using the Stanford University HIV drug resistance database. Forty-one sequences were from an adult antiretroviral therapy (ART) study, the Tshepo study, and 127 from a prevention of mother-to-child transmission (PMTCT) study, the Mashi study, all conducted in Botswana. Prevalence of RPV and ETR highest DRM in the adult ART study (n = 41) were K101E (26.2%), E138A (23.8%), and Y181C (26.2%). The PMTCT cohort's (n = 127) high prevalence mutations were Y181C (15.7%), E138A (15%), and K101E (11%). A total of 42.9% and 3.2% of patients in the adult ART study and PMTCT study, respectively, had three or more NNRTI mutations at virologic failure. We identified HIV-1 mutations conferring resistance to RPV and ETR even though they have not been used in Botswana. Of concern was the high proportion of sequences from the adult ART study that displayed multiple DRMs; as the number of NNRTI mutations increases, the level of cross-resistance increases. It is plausible that patients displaying such profiles maybe at increased risk of failing second-generation NNRTI drugs, hence, calls for genotyping in patients with prior NVP or efavirenz exposure before prescription of RPV- or ETR-containing cART.
利匹韦林（RPV）和依曲韦林（ETR）是已获批用于治疗HIV的第二代非核苷类逆转录酶抑制剂（NNRTIs）。第一代和第二代NNRTI药物之间存在交叉耐药的HIV突变谱。我们确定了博茨瓦纳HIV-1对RPV和ETR的耐药突变（DRMs）流行情况。使用斯坦福大学HIV耐药数据库，对168例含奈韦拉平（NVP）或依非韦伦（EFV）治疗方案失败的参与者的HIV-1聚合酶基因序列进行了DRMs分析。其中41个序列来自一项成人抗逆转录病毒治疗（ART）研究——茨波研究，127个序列来自一项预防母婴传播（PMTCT）研究——马希研究，这两项研究均在博茨瓦纳开展。在成人ART研究（n = 41）中，RPV和ETR的最高DRM流行率分别为K101E（26.2%）、E138A（23.8%）和Y181C（26.2%）。PMTCT队列（n = 127）中的高流行突变分别为Y181C（15.7%）、E138A（15%）和K101E（11%）。在成人ART研究和PMTCT研究中，分别有42.9%和3.2%的患者在病毒学失败时出现了三种或更多的NNRTI突变。我们发现了即使在博茨瓦纳未使用过的情况下仍对RPV和ETR产生耐药的HIV-1突变。令人担忧的是，成人ART研究中有很大比例的序列显示出多重DRMs；随着NNRTI突变数量的增加，交叉耐药水平也会增加。出现此类情况的患者使用第二代NNRTI药物治疗失败的风险可能会增加，因此，在开具含RPV或ETR的联合抗逆转录病毒治疗（cART）处方前，需要对曾暴露于NVP或依非韦伦的患者进行基因分型。
