AUTHOR=Poblete Daniela , Bernal Fernando , Llull Gabriel , Archiles Sebastian , Vasquez Patricia , Chanqueo Leonardo , Soto Nicole , Lavanderos María A. , Quiñones Luis A. , Varela Nelson M. 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.660965

DOI=10.3389/fphar.2021.660965

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> 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). <italic>UGT1A1*28</italic> and <italic>CYP2B6</italic> c.516G&gt;T have been proposed to be related with higher toxicity by ATV and EFV, respectively.</p><p><bold>Objective:</bold> 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.</p><p><bold>Methods:</bold> 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 <italic>UGT1A1*28</italic> allele) and rs3745274 (<italic>CYP2B6</italic> c.516G&gt;T), with TaqMan® probes. The association analyses were performed with univariate logistic regression between genetic variants using three inheritance models (codominant, recessive, and dominant).</p><p><bold>Results:</bold> In ATV-treated patients, hyperbilirubinemia (total bilirubin &gt;1.2 mg/dl) had the main incidence (61.11%), and moderate and severe hyperbilirubinemia (total bilirubin &gt;1.9 mg/dl) were statistically associated with <italic>UGT1A1*28</italic> in recessive and codominant inheritance models (OR = 16.33, <italic>p</italic> = 0.028 and OR = 10.82, <italic>p</italic> = 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 <italic>CYP2B6</italic> c.516G&gt;T, in codominant and recessive inheritance models (OR = 12.00, <italic>p</italic> = 0.031 and OR = 7.14, <italic>p</italic> = 0.042, respectively). Grouped CNS ADRs (nightmares, insomnia, anxiety, and suicide attempt) also showed a statistically significant association with <italic>CYP2B6</italic> c.516G &gt; T in the codominant and recessive models (OR = 30.00, <italic>p</italic> = 0.011 and OR = 14.99, <italic>p</italic> = 0.021, respectively).</p><p><bold>Conclusion:</bold> Our findings suggest that after treatment with ATV or EFV, <italic>UGT1A1*28</italic> and <italic>CYP2B6</italic> c.516G&gt;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.</p>