Efavirenz (EFV) and atazanavir (ATV) are key components of antiretroviral therapy (ART) for individuals living with HIV, acting as a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor, respectively. Clinical responses to these drugs vary greatly among patients, particularly regarding adverse drug reactions (ADRs). Previous studies suggest that the UGT1A1*28 and CYP2B6 c.516G>T genetic variants may increase susceptibility to ATV- and EFV-related toxicities. This study investigated whether UGT1A1*28 and CYP2B6 c.516G>T polymorphisms are associated with ADRs in Chilean HIV patients receiving EFV or ATV. A retrospective, observational, case–control study was conducted in 67 adult patients treated with either EFV or ATV at San Juan de Dios Hospital. Clinical data were extracted from medical records. Genotyping for rs887829 (proxy for UGT1A1*28) and rs3745274 (CYP2B6 c.516G>T) was performed using real-time PCR with TaqMan® probes. Associations between variants and ADRs were assessed using univariate logistic regression under codominant, recessive, and dominant models. Hyperbilirubinemia (total bilirubin >1.2 mg/dL) occurred in 61.11% of patients on ATV, with moderate-to-severe cases (bilirubin >1.9 mg/dL) significantly linked to UGT1A1*28 under recessive and codominant models (OR = 16.33, p = 0.028; OR = 10.82, p = 0.036). In EFV-treated patients, CNS-related ADRs were observed in 34.21%, with nightmares significantly associated with CYP2B6 c.516G>T (codominant OR = 12.00, p = 0.031; recessive OR = 7.14, p = 0.042). Combined CNS ADRs—including insomnia, anxiety, and suicide attempts—also showed strong associations with this variant (codominant OR = 30.00, p = 0.011; recessive OR = 14.99, p = 0.021). These results indicate that UGT1A1*28 and CYP2B6 c.516G>T significantly contribute to ATV- and EFV-related ADRs, respectively. Incorporating pharmacogenetic testing into ART could improve safety and adherence in HIV patients. Further prospective studies are warranted to confirm these findings in the Chilean population and support evidence-based, personalized therapy strategies.
