El Bouzidi Kate, White Ellen, Mbisa Jean L, Phillips Andrew, Mackie Nicola, Pozniak Anton, Dunn David
Department of Virology, University College London, London, UK.
MRC Clinical Trials Unit, Medical Research Council, London, UK.
J Int AIDS Soc. 2014 Nov 2;17(4 Suppl 3):19739. doi: 10.7448/IAS.17.4.19739. eCollection 2014.
Darunavir (DRV) is a preferred agent in treatment guidelines for ART-naïve and experienced patients [1]. It is considered to have a high genetic barrier to resistance and 11 resistance-associated mutations (RAMs) are recognized by IAS-USA [2]. These have largely been identified by analyses examining the correlation between baseline genotype and virological response [3]. However, there is little information on RAMs that are directly selected by DRV, outside of short-term clinical trials. We aimed to identify emerging mutations by comparing the genotypes of individuals before and after DRV exposure.
The UK HIV Drug Resistance Database was used to identify patients aged over 16 who had received at least 30 days of a DRV-containing regimen. Patients were included if they had a "baseline" resistance test, prior to DRV exposure, and a "repeat" test, either on DRV or within 30 days of stopping this agent. To avoid attributing the effects of other PIs on emerging RAMs to DRV, patients were excluded if they had received another PI for greater than 90 days between the baseline genotype and the start of DRV. The baseline and repeat tests were compared to determine the nature of mutations stratified by PI history.
A total of 5623 patients had DRV, of whom 306 met the inclusion criteria. A total of 228 (74.5%) were male, median age at the start of DRV was 42 years (IQR 37-47), and half had subtype B infection. The mode of transmission was homosexual contact for 50%, heterosexual for 38%, and 3% were injection drug users. The median CD4 count at the start of DRV was 257 cells/mm(3) (IQR 94-453). A total of 149 patients (49%) had a history of PI use prior to DRV, and 157 (51%) were PI-naïve. The most common previous PIs were lopinavir, atazanavir, and saquinavir. Baseline DRV RAMs were present in 1 (0.6%) PI-naïve and 20 (13.4%) PI-experienced patients. Mutations emerged under DRV pressure in a further 3 (1.9%) PI-naïve patients, and in 7 (4.7%) PI-experienced patients, 5 of whom had other DRV RAMs present at baseline (Table 1). The median time from the start of DRV to the repeat test was 196 days for PI-naïve patients and 296 days for PI-experienced.
PI-experienced patients had a greater prevalence of DRV RAMs at baseline than PI-naïve individuals, probably due to the fact that some DRV RAMs can be selected by other PIs. This group also accumulated more RAMs during DRV exposure, possibly because previous PIs had caused minority variants which then emerged on DRV therapy. Overall, only 10 patients accumulated 16 RAMs, which supports the perception that DRV has a high genetic barrier to resistance. Repeat genotyping in the case of virological failure on DRV may still be warranted to detect emerging resistance and guide management decisions.
达芦那韦（DRV）是初治和经治患者抗逆转录病毒治疗指南中的首选药物[1]。它被认为对耐药具有较高的基因屏障，美国国际抗病毒学会（IAS-USA）识别出11种与耐药相关的突变（RAMs）[2]。这些突变大多是通过分析基线基因型与病毒学反应之间的相关性确定的[3]。然而，除了短期临床试验外，关于直接由DRV选择的RAMs的信息很少。我们旨在通过比较DRV暴露前后个体的基因型来识别新出现的突变。
使用英国HIV耐药数据库识别年龄在16岁以上、接受含DRV方案至少30天的患者。如果患者在DRV暴露前进行了“基线”耐药检测，并且在DRV治疗期间或停药后30天内进行了“重复”检测，则纳入研究。为避免将其他蛋白酶抑制剂（PIs）对新出现的RAMs的影响归因于DRV，如果患者在基线基因型与DRV开始使用之间接受了另一种PI超过90天，则将其排除。比较基线和重复检测结果，以确定按PI用药史分层的突变性质。
共有5623例患者接受了DRV治疗，其中306例符合纳入标准。共有228例（74.5%）为男性，开始使用DRV时的中位年龄为42岁（四分位间距37 - 47岁），一半患者感染的是B亚型。传播方式为同性接触占50%，异性接触占38%，3%为注射吸毒者。开始使用DRV时的中位CD4细胞计数为257个/立方毫米（四分位间距94 - 453）。共有149例患者（49%）在使用DRV之前有PI用药史，157例（51%）为初治患者。之前最常用的PIs是洛匹那韦、阿扎那韦和沙奎那韦。基线时，1例（0.6%）初治患者和20例（13.4%）经治患者存在DRV RAMs。在DRV压力下，又有3例（1.9%）初治患者和7例（4.7%）经治患者出现了突变，其中5例在基线时就存在其他DRV RAMs（表1）。初治患者从开始使用DRV到重复检测的中位时间为196天，经治患者为296天。
经治患者基线时DRV RAMs的患病率高于初治患者，这可能是因为一些DRV RAMs可由其他PIs选择。该组患者在DRV暴露期间也积累了更多的RAMs，可能是因为之前的PIs导致了少数变异，这些变异在DRV治疗时出现。总体而言，只有10例患者积累了16种RAMs，这支持了DRV对耐药具有较高基因屏障的观点。对于DRV治疗出现病毒学失败的情况，重复进行基因分型可能仍有必要，以检测新出现的耐药并指导管理决策。
