Division of Infectious Diseases, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC.
Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC.
J Chin Med Assoc. 2024 Nov 1;87(11):1002-1010. doi: 10.1097/JCMA.0000000000001152. Epub 2024 Aug 13.
This study aims to delineate the resistance profiles of integrase strand transfer inhibitors (INSTIs) among patients in southern Taiwan who had experienced antiretroviral therapy (ART) failure. We focused on individuals previously treated with highly active ART (HAART) regimens, providing insights into the implications of INSTI resistance in a broader treatment-experienced population.
Data were collected from patients failing an INSTI-containing regimen in a medical center in southern Taiwan between 2009 and 2022. Virological failure was defined as a plasma viral load >1000 copies/mL. Reverse transcriptase, protease, and integrase coding regions were sequenced at failure. Resistance-associated mutations included in the 2022 International Antiviral Society (IAS)-USA list were used. Drug resistance was analyzed using the HIV Stanford HIVDB 9.4 edition algorithm. Logistic regression analysis was used to analyze the risk factors associated with INSTI failure.
A total of 184 patients were enrolled for genotypic drug resistance testing due to virological failure, of whom 104 failed on nonnucleoside reverse transcriptase inhibitors, 58 on protease inhibitors (PIs), and 21 on INSTIs. Among 21 patients who failed INSTI therapy, 6 failed raltegravir-based treatment, 3 elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF), 2 bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), and 10 abacavir/dolutegravir/lamivudine (ABC/DTG/3TC). Only 10 patients had INSTI drug resistance testing results available, and 40% (4/10) showed INSTI resistance at failure. Among the seven patients who failed on second-generation INSTIs with drug resistance reports available, one harbored E157Q and another with R263K mutations, respectively. Multivariable logistic regression analysis showed that patients with INSTI failure were less likely to have pol resistance (p = 0.007, adjusted odds ratio [OR], 0.176, 95% CI, 0.050-0.618), less previous exposure to NNRTI (p = 0.003, aOR, 0.063, 95% CI, 0.010-0.401), PIs (p = 0.002, aOR, 0.030, 95% CI, 0.003-0.272), and with long duration of HAART (p = 0.018, aOR, 1.02, 95% CI, 1.003-1.037).
INSTI resistance was uncommon when used as the first-line single tablet regimen in Taiwan. The results confirmed the robustness of ABC/DTG/3TC and BIC/FTC/TAF regarding integrase resistance in cases of virological failure in routine clinical care.
本研究旨在描述在台湾南部经历过抗逆转录病毒治疗 (ART) 失败的患者中整合酶抑制剂 (INSTI) 的耐药谱。我们专注于先前接受过高效抗逆转录病毒治疗 (HAART) 方案治疗的个体，深入了解 INSTI 耐药在更广泛的治疗经验人群中的意义。
我们收集了 2009 年至 2022 年间台湾南部一家医疗中心因 INSTI 方案治疗失败的患者的数据。病毒学失败定义为血浆病毒载量>1000 拷贝/ml。在失败时对逆转录酶、蛋白酶和整合酶编码区进行测序。使用 2022 年国际抗病毒学会 (IAS)-美国耐药相关突变列表中包含的耐药相关突变。使用 HIV Stanford HIVDB 9.4 版算法分析药物耐药性。采用 logistic 回归分析方法分析与 INSTI 失败相关的风险因素。
共有 184 名患者因病毒学失败接受了基因耐药性检测，其中 104 名患者对非核苷类逆转录酶抑制剂（NNRTI）耐药，58 名患者对蛋白酶抑制剂（PI）耐药，21 名患者对 INSTI 耐药。在 21 名 INSTI 治疗失败的患者中，6 名患者失败于 raltegravir 为基础的治疗，3 名患者失败于 elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide（EVG/COBI/FTC/TAF），2 名患者失败于 bictegravir/emtricitabine/tenofovir alafenamide（BIC/FTC/TAF），10 名患者失败于 abacavir/dolutegravir/lamivudine（ABC/DTG/3TC）。仅有 10 名患者获得了 INSTI 药物耐药性检测结果，其中 40%（4/10）在失败时显示出 INSTI 耐药。在有耐药报告的 7 名对第二代 INSTI 治疗失败的患者中，有 1 名患者携带 E157Q 突变，另 1 名患者携带 R263K 突变。多变量 logistic 回归分析显示，INSTI 治疗失败的患者发生 pol 耐药的可能性较低（p=0.007，调整后的比值比[OR]，0.176，95%可信区间[CI]，0.050-0.618），先前较少暴露于 NNRTI（p=0.003，调整后的比值比[OR]，0.063，95%CI，0.010-0.401），PI（p=0.002，调整后的比值比[OR]，0.030，95%CI，0.003-0.272），以及 HAART 治疗时间较长（p=0.018，调整后的比值比[OR]，1.02，95%CI，1.003-1.037）。
在台湾，INSTI 作为一线单片治疗方案时，耐药性并不常见。这些结果证实了 ABC/DTG/3TC 和 BIC/FTC/TAF 在常规临床护理中治疗病毒学失败时对整合酶耐药性的稳健性。
