Pharmacogenetic Associations Between Atazanavir/UGT1A1*28 and Efavirenz/rs3745274 (CYP2B6) Account for Specific Adverse Reactions in Chilean Patients Undergoing Antiretroviral Therapy

Abstract

Background: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and atazanavir (ATV), a protease inhibitor, are drugs widely used in antiretroviral therapy (ART) for people living with HIV. These drugs have shown high interindividual variability in adverse drug reactions (ADRs). UGT1A1*28 and CYP2B6 c.516G>T have been proposed to be related with higher toxicity by ATV and EFV, respectively.Objective: To study the association between genetic polymorphisms and ADRs related to EFV or ATV in patients living with HIV treated at a public hospital in Chile.Methods: Epidemiologic, case–control, retrospective, observational study in 67 adult patients under EFV or ATV treatment was conducted, in the San Juan de Dios Hospital. Data were obtained from patients’ medical records. Genotype analyses were performed using rtPCR for rs887829 (indirect identification of UGT1A1*28 allele) and rs3745274 (CYP2B6 c.516G>T), with TaqMan® probes. The association analyses were performed with univariate logistic regression between genetic variants using three inheritance models (codominant, recessive, and dominant).Results: In ATV-treated patients, hyperbilirubinemia (total bilirubin >1.2 mg/dl) had the main incidence (61.11%), and moderate and severe hyperbilirubinemia (total bilirubin >1.9 mg/dl) were statistically associated with UGT1A1*28 in recessive and codominant inheritance models (OR = 16.33, p = 0.028 and OR = 10.82, p = 0.036, respectively). On the other hand, in EFV-treated patients adverse reactions associated with CNS toxicity reached 34.21%. In this respect, nightmares showed significant association with CYP2B6 c.516G>T, in codominant and recessive inheritance models (OR = 12.00, p = 0.031 and OR = 7.14, p = 0.042, respectively). Grouped CNS ADRs (nightmares, insomnia, anxiety, and suicide attempt) also showed a statistically significant association with CYP2B6 c.516G > T in the codominant and recessive models (OR = 30.00, p = 0.011 and OR = 14.99, p = 0.021, respectively).Conclusion: Our findings suggest that after treatment with ATV or EFV, UGT1A1*28 and CYP2B6 c.516G>T influence the appearance of moderate-to-severe hyperbilirubinemia and CNS toxicity, respectively. However, larger prospective studies will be necessary to validate these associations in our population. Without a doubt, improving adherence in patients living with HIV is a critical issue to the success of therapy. Hence, validating and applying international pharmacogenetic recommendations in Latin American countries would improve the precision of ART: a fundamental aspect to achieve the 95–95–95 treatment target proposed by UNAIDS.

Pharmacogenetic effects of single nucleotide polymorphisms commonly associated with antiretroviral therapy metabolism

“…In other studies, the deficient CYP2B6 516G>T allele was also associated with higher EFV plasma drug levels and more frequent CNS-related symptoms in the Caucasian population. [11,33] However, in the Thai population a different CYP2B6 polymorphism, c.18492T>C, was associated with lower EFV concentrations, but particularly in patients with high body weight who are coinfected with tuberculosis and who carry CYP2B6 haplotype 1*/1* [34,35]. This might be a risk factor for successful virus suppression but needs to be confirmed in other populations.…”

“…Consideration of UGT1A1*28 (rs8175347) homozygosity was unveiled to lower ATV discontinuation rate in patients down to 4,7%, and it was recommended for patients with high bilirubin levels detected prior to, or in the duration of treatment [10]. ATV-associated hyperbilirubinemia is also linked with UGT1A1*80 rs887829 allele (which is in very strong linkage disequilibrium (LD) with UGT1A1*28), baseline bilirubin levels, and baseline haemoglobin level, while is best predicted using all these factors combined [11,12]. Clinical Pharmacogenetics Implementation Consortium (CPIC) reported a 60% positive predictive value of rs887829 T/T for bilirubin-associated ATV discontinuation in White patients, which supports its use as a potential marker [8].…”

Insights into clinical pharmacy practice in Latin America

“…29 32,33 Some of the most notable innovations in clinical pharmacy in Chile include the development of advanced clinical pharmacokinetics, 34 recognition of pharmaceutical specialties, elaboration of clinical guides, and collaboration with clinical teams specialized in the assistance of complex patients. 35 In addition, networking for the development of Clinical Pharmacogenetics in complicated pathologies has become important. Also, the involvement of clinical pharmacists in critical care teams, with their specialized knowledge of medications and their possible interactions and adverse effects, can provide valuable input and guidance to ensure patients receive the appropriate medications and dosages in critical care settings, which can also have a positive impact in reducing health care expenditures.…”

Pharmacogenetics of HIV therapy: State of the art in Latin American countries

“…Data analyses were also adjusted for genetic ancestry to control for confounding. Recently, +516G>T was significantly associated to CNS adverse effects to EFV in a small (N=38) Chilean cohort ( Poblete et al , 2021 ). Prevalence of +516T was also determined for a cohort from Argentina (38.2%), although no association analysis was performed ( Galván et al , 2012 ).…”

“…Moreover, polymorphisms at NR1I2 were not associated to lopinavir levels in a cohort of 38 perinatally infected children from Argentina ( Bellusci et al , 2013 ). Studies of adverse reactions to PIs have showed that UGT1A1*28 allele was associated with increased risk of atazanavir related hyperbilirubinemia among Brazilians ( Turatti et al , 2012 ) and Chileans ( Poblete et al , 2021 ). The study by Arruda et al (2016 ) has also investigated the role of metabolism enzymes in intolerance to PIs, but no association was found.…”