Pharmacogenomic associations with HIV-1 virologic suppression in TB/HIV patients

Background: 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. Methods: 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 CYP2B6 (rs3745274, rs28399499, rs4803419; affects efavirenz metabolism) and UGT1A1 (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). Results: 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 CYP2B6 normal metabolizers (n=8, 44%); and 30% (n=30) used INSTI-based ART and the UGT1A1 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 CYP2B6 and UGT1A1 genotypes. Conclusions : 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.