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Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings: a sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342).

ABSTRACT: The multinational PEARLS (ACTG A5175) study, conducted mainly in resource-limited settings, identified an increased treatment failure rate among HIV-infected individuals randomized to once-daily unboosted atazanavir, didanosine-EC, and emtricitabine compared with efavirenz-based regimens. We evaluated associations between selected human genetic polymorphisms and atazanavir pharmacokinetics in PEARLS.Polymorphisms in CYP3A5, ABCB1, SLCO1B1 and NR1I2 were genotyped in PEARLS participants randomized to atazanavir plus didanosine-EC plus emtricitabine in Peru, South Africa and the USA, who also consented to genetic analysis. Non-linear mixed-effects population pharmacokinetic modelling was used to predict atazanavir oral clearance (CL/F) and concentration at 24 h (C24). Atazanavir mono-oxidation metabolites M1 and M2 were quantified from the same single-point plasma sample used to quantify the parent drug. Data were log10 transformed for statistical analysis using unpaired t-tests and one-way ANOVA and are presented as geometric mean (95% CI).Eighty-four HIV-infected participants were genotyped, including 44 Black Africans or African Americans and 28 women. Median age was 34 years. We identified 56 CYP3A5 expressers and 28 non-expressers. Atazanavir CL/F and C24 did not differ between CYP3A5 expressers and non-expressers: 13.2 (12.1-14.4) versus 12.7 L/h (11.7-13.9), P?=?0.61, and 75.3 (46.1-123.0) versus 130.9 ng/mL (86.9-197.2), P?=?0.14, respectively. M1/atazanavir and M2/atazanavir ratios were higher in expressers than in non-expressers: 0.0083 (0.0074-0.0094) versus 0.0063 (0.0053-0.0075), P?=?0.008, and 0.0065 (0.0057-0.0073) versus 0.0050 (0.0042-0.0061), P?=?0.02, respectively.Expression of CYP3A5 appears to be associated with increased M1 and M2 atazanavir metabolite formation, without significantly affecting parent compound pharmacokinetics.

SUBMITTER: Castillo-Mancilla JR

PROVIDER: S-EPMC4867099 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings: a sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342).

Castillo-Mancilla Jose R JR Aquilante Christina L CL Wempe Michael F MF Smeaton Laura M LM Firnhaber Cynthia C LaRosa Alberto M AM Kumarasamy Nagalingeswaran N Andrade Adriana A Baheti Gautam G Fletcher Courtney V CV Campbell Thomas B TB Haas David W DW MaWhinney Samantha S Anderson Peter L PL

The Journal of antimicrobial chemotherapy 20160217 6

<h4>Objectives</h4>The multinational PEARLS (ACTG A5175) study, conducted mainly in resource-limited settings, identified an increased treatment failure rate among HIV-infected individuals randomized to once-daily unboosted atazanavir, didanosine-EC, and emtricitabine compared with efavirenz-based regimens. We evaluated associations between selected human genetic polymorphisms and atazanavir pharmacokinetics in PEARLS.<h4>Methods</h4>Polymorphisms in CYP3A5, ABCB1, SLCO1B1 and NR1I2 were genotyp ...[more]

PMID: 26892777

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Project description:IntroductionLipodystrophy is a term used to describe a metabolic complication of fat loss, fat gain, or a combination of fat loss and gain, which is associated with some antiretroviral (ARV) therapies given to HIV-infected individuals. There is limited research on lipodystrophy in low- and middle-income countries, despite accounting for more than 95% of the burden of HIV/AIDS. The objective of this review was to evaluate the prevalence, pathogenesis and prognosis of HIV-related lipoatrophy, lipohypertrophy and mixed syndrome, to inform clinical management in resource-limited settings.MethodsWe conducted a structured literature search using MEDLINE electronic databases. Relevant MeSH terms were used to identify published human studies on HIV and lipoatrophy, lipohypertrophy, or mixed syndrome in low-, low-middle- and upper-middle-income countries through 31 March 2014. The search resulted in 5296 articles; after 1599 studies were excluded (958 reviews, 641 non-human), 3697 studies were extracted for further review. After excluding studies conducted in high-income settings (n=2808), and studies that did not meet inclusion criteria (n = 799), 90 studies were included in this review.Results and discussionOf the 90 studies included in this review, only six were from low-income countries and eight were from lower middle-income economies. These studies focused on lipodystrophy prevalence, risk factors and side effects of antiretroviral therapy (ART). In most studies, lipodystrophy developed after the first six months of therapy, particularly with the use of stavudine. Lipodystrophy is associated with increased risk of cardiometabolic complications. This is disconcerting and anticipated to increase, given the rapid scale-up of ART worldwide, the increasing number and lifespan of HIV-infected patients on long-term therapy, and the emergence of obesity and non-communicable diseases in settings with extensive HIV burden.ConclusionsLipodystrophy is common in resource-limited settings, and has considerable implications for risk of metabolic diseases, quality of life and adherence. Comprehensive evidence-based interventions are urgently needed to reduce the burden of HIV and lipodystrophy, and inform clinical management in resource-limited settings.

Project description:Association studies have shown and continue to show a substantial amount of success in identifying links between multiple single nucleotide polymorphisms (SNPs) and phenotypes. These studies are also believed to provide insights toward identification of new drug targets and therapies. Albeit of all the success, challenges still remain for applying and prioritizing these associations based on available biological knowledge. Along with single variant association analysis, genetic interactions also play an important role in uncovering the etiology and progression of complex traits. For gene-gene interaction analysis, selection of the variants to test for associations still poses a challenge in identifying epistatic interactions among the large list of variants available in high-throughput, genome-wide datasets. Therefore in this study, we propose a pipeline to identify interactions among genetic variants that are associated with multiple phenotypes by prioritizing previously published results from main effect association analysis (genome-wide and phenome-wide association analysis) based on a-priori biological knowledge in AIDS Clinical Trials Group (ACTG) data. We approached the prioritization and filtration of variants by using the results of a previously published single variant PheWAS and then utilizing biological information from the Roadmap Epigenome project. We removed variants in low functional activity regions based on chromatin states annotation and then conducted an exhaustive pairwise interaction search using linear regression analysis. We performed this analysis in two independent pre-treatment clinical trial datasets from ACTG to allow for both discovery and replication. Using a regression framework, we observed 50,798 associations that replicate at p-value 0.01 for 26 phenotypes, among which 2,176 associations for 212 unique SNPs for fasting blood glucose phenotype reach Bonferroni significance and an additional 9,970 interactions for high-density lipoprotein (HDL) phenotype and fasting blood glucose (total of 12,146 associations) reach FDR significance. We conclude that this method of prioritizing variants to look for epistatic interactions can be used extensively for generating hypotheses for genomewide and phenome-wide interaction analyses. This original Phenome-wide Interaction study (PheWIS) can be applied further to patients enrolled in randomized clinical trials to establish the relationship between patient's response to a particular drug therapy and non-linear combination of variants that might be affecting the outcome.

Dataset Information

Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings: a sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342).

Publications

Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings: a sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342).

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