Ridolfi Felipe, Amorim Gustavo, Haas David W, Arriaga Maria, Staats Cody, Cordeiro-Santos Marcelo, Kritski Afrânio L, Figueiredo Marina C, Andrade Bruno B, Sterling Timothy R, Rolla Valeria C
Vanderbilt University Medical Center.
Fundação Medicina Tropical Dr. Heitor Vieira Dourado.
Res Sq. 2024 Dec 16:rs.3.rs-5418156. doi: 10.21203/rs.3.rs-5418156/v1.
Human genetic variants can affect TB and HIV drug metabolism, which may lead to toxicity or treatment failure. We evaluated associations between genetic variants of antiretroviral therapy (ART) and HIV-1 outcomes among TB/HIV patients.
We included RePORT-Brazil participants with TB/HIV who initiated standard TB treatment [2 months of isoniazid/rifampicin (or rifabutin)/pyrazinamide/ethambutol, then 4 months or more of isoniazid/rifampicin (or rifabutin)], and ART. The endpoint was HIV-1 virologic suppression (defined as <1,000 HIV-1 RNA copies/mL, for primary analysis, and <50 HIV-1 RNA copies/mL, for secondary analysis) after at least 2 weeks of ART. We compared non-nucleoside reverse transcriptase inhibitor (NNRTI)-based and integrase strand transfer inhibitor (INSTI)-based ART regimens. We genotyped (rs3745274, rs28399499, rs4803419; affects efavirenz metabolism) and (rs887829; affects dolutegravir and raltegravir metabolism); all have defined normal, intermediate, and slow genotypes. Genotyping was performed by MassARRAY iPLEX Gold. We compared outcome proportions (Fisher's test) and time-to-virologic suppression (survival analysis, Wilcoxon-Gehan test).
Among 194 TB/HIV participants included, efavirenz was the most frequent NNRTI ([n=76], one participant received etravirine), and raltegravir was the most frequent INSTI (n=88). The overall virologic suppression was suboptimal, with 32% (n=62) of participants not achieving HIV-1 virologic suppression. Among them, 36% (n=28) used efavirenz-based ART and were more likely to be normal metabolizers (n=8, 44%); and 30% (n=30) used INSTI-based ART and the normal genotype was also the most common (n=13, 50%). The median time to virologic suppression for efavirenz-based ART was 184 days (95% Confidence Interval (CI)160-207), and for INSTI-based ART, 188 days (95% CI 144-231) (p=0.84). No significant associations were found comparing the proportions and time to virologic suppression among and genotypes.
In this observational cohort of patients treated for TB/HIV, the proportion of participants achieving virologic suppression was low, and genetic variants affecting ART metabolism were not significantly associated with the likelihood of virologic suppression.
人类基因变异可影响结核病和艾滋病药物代谢，这可能导致毒性反应或治疗失败。我们评估了抗逆转录病毒疗法（ART）的基因变异与结核病/艾滋病患者中HIV-1治疗结果之间的关联。
我们纳入了巴西RePORT研究中开始标准结核病治疗（2个月的异烟肼/利福平（或利福布汀）/吡嗪酰胺/乙胺丁醇，然后4个月或更长时间的异烟肼/利福平（或利福布汀））并接受ART治疗的结核病/艾滋病患者。终点是在接受ART至少2周后实现HIV-1病毒学抑制（主要分析定义为HIV-1 RNA拷贝数<1000/mL，次要分析定义为<50 HIV-1 RNA拷贝数/mL）。我们比较了基于非核苷类逆转录酶抑制剂（NNRTI）和基于整合酶链转移抑制剂（INSTI）的ART方案。我们对（rs3745274、rs28399499、rs4803419；影响依非韦伦代谢）和（rs887829；影响多替拉韦和拉替拉韦代谢）进行基因分型；所有这些都有明确的正常、中间和慢代谢基因型。基因分型通过MassARRAY iPLEX Gold进行。我们比较了结局比例（Fisher检验）和达到病毒学抑制的时间（生存分析，Wilcoxon-Gehan检验）。
在纳入的194名结核病/艾滋病参与者中，依非韦伦是最常用的NNRTI（[n = 76]，一名参与者接受了依曲韦林），拉替拉韦是最常用的INSTI（n = 88）。总体病毒学抑制效果欠佳，32%（n = 62）的参与者未实现HIV-1病毒学抑制。其中，36%（n = 28）使用基于依非韦伦的ART，且更可能是正常代谢者（n = 8，44%）；30%（n = 30）使用基于INSTI的ART，正常基因型也是最常见的（n = 13，50%）。基于依非韦伦的ART达到病毒学抑制的中位时间为184天（9
