Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
Clin Infect Dis. 2010 Sep 1;51(5):620-8. doi: 10.1086/655764.
Factors promoting the emergence of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) connection domain mutations and their effect on antiretroviral therapy (ART) are still largely undetermined. We investigated this matter by analyzing genotypic resistance tests covering 400 amino acid positions in the RT of HIV-1 subtype B viruses and corresponding treatment histories and laboratory measurements.
The emergence of connection domain mutations was studied in 334 patients receiving monotherapy or dual therapy with thymidine analogues at the time of the genotypic resistance test. Response to subsequent combination ART (cART) was analyzed using Cox regression for 291 patients receiving unboosted protease inhibitors. Response was defined by ever reaching an HIV RNA level <50 copies/mL during the first cART.
The connection domain mutations N348I, R356K, R358K, A360V, and A371V were more frequently observed in ART-exposed than ART-naive patients, of which only N348I and A360V were nonpolymorphic (with a prevalence of <1.5% in untreated patients). N348I correlated with M184V and predominantly occurred in patients receiving lamivudine and zidovudine concomitantly. A360V was not associated with specific drug combinations and was found to emerge later than M184V or thymidine analogue mutations. Nonpolymorphic connection domain mutations were rarely detected in the absence of established drug resistance mutations in ART-exposed individuals (prevalence, <1%). None of the 5 connection domain mutations associated with treatment showed a statistically significant effect on response to cART.
Despite their frequent emergence, connection domain mutations did not show large detrimental effects on response to cART. Currently, routine implementation of connection domain sequencing seems unnecessary for developed health care settings.
促进人类免疫缺陷病毒 1 型（HIV-1）逆转录酶（RT）连接域突变出现的因素及其对抗逆转录病毒治疗（ART）的影响在很大程度上仍未确定。我们通过分析涵盖 HIV-1 亚型 B 病毒 RT 中 400 个氨基酸位置的基因型耐药性测试以及相应的治疗史和实验室测量结果来研究这个问题。
在进行基因型耐药性测试时，对 334 名接受胸苷类似物单药或联合治疗的患者的连接域突变出现情况进行了研究。对 291 名接受未增强蛋白酶抑制剂的联合 ART（cART）的患者使用 Cox 回归分析了对随后的 cART 的反应。定义反应是指在首次 cART 期间，HIV RNA 水平是否曾经达到<50 拷贝/mL。
在接受 ART 治疗的患者中，连接域突变 N348I、R356K、R358K、A360V 和 A371V 比未接受 ART 治疗的患者更频繁地观察到，其中只有 N348I 和 A360V 是非多态性的（在未治疗的患者中，其发生率<1.5%）。N348I 与 M184V 相关，主要发生在同时接受拉米夫定和齐多夫定治疗的患者中。A360V 与特定的药物组合无关，并且比 M184V 或胸苷类似物突变出现得更晚。在接受 ART 治疗的个体中，在没有明确的耐药性突变的情况下，很少检测到非多态性连接域突变（发生率<1%）。与治疗相关的 5 个连接域突变中，没有一个对 cART 的反应有统计学显著影响。
尽管经常出现，但连接域突变对 cART 的反应没有产生较大的不利影响。目前，在发达的医疗保健环境中，似乎没有必要常规进行连接域测序。
