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    • In our study those participants

    2018-10-30

    In our study, those participants with the highest genetic risk score of 6 had an increased risk for EFV discontinuation compared to those participants with risk scores 1–5. We therefore performed a post hoc analysis of pooled data of 781 patients starting EFV-based regimens from our cohort and the patients in the Swiss Cohort (Lubomirov et al., 2011) and that showed the risk of EFV discontinuation did not change in patients with genetic risk scores of 1–5, likely reflecting the known redundancy in EFV metabolizing pathways, and is consistent with data in patients with CYP2B6 polymorphisms 516G>T and 983T>C where plasma EFV plasma concentrations were elevated only in those patients who also had other accessory pathway mutations (Haas et al., 2014). Black participants in our cohort had a higher prevalence (14.1%) of high genetic risk compared to other races (2.4%), consistent with reported population allele frequencies for variants in those genes (http://www.ncbi.nlm.nih.gov.eleen.top/snp/). A high prevalence of CYP2B6 516G>T (rs3745274) has been previously reported in Ghanaian patients (Sarfo et al., 2014), and racial differences in the prevalence are evident in HapMap and 1000 Genomes data (35–42% in Sub-Saharan Africans, 23–27% in Europeans, 15–18% in Asians). Thus if an individual with this allele also happens to have other LOF/DOF trk inhibitor in EFV metabolizing enzymes, it is logical that they might be intolerant to EFV. It is noteworthy however that race alone did not predict EFV discontinuation in our analyses — indicating that the pharmacogenetic risk stratification employed in our study is more discriminatory than determination of race alone. In addition, it is likely that factors other than genetic risk contribute to disparities in treatment discontinuation which could contribute to an attenuation of observed genetic risk. There are potential limitations of our study. Our study focused on three CYP enzymes, and thus on pharmacokinetic pharmacogenetics. There might be other pharmacokinetic factors, e.g., genetically polymorphic transporters, that contribute to premature discontinuation of EFV that were not assessed here. It is also conceivable that some of the side effects might also be influenced by pharmacodynamic pharmacogenetics — i.e., genetic variation in the targets for the drug. In addition, since we included only those participants with 12months of follow up data, there is the potential for survivorship bias. Finally, data was not available in all studies regarding pregnancy as a potential cause for premature treatment discontinuation. Future studies should take these potential factors into account.
    Conflict of Interest
    Funding This publication was made possible in part by through the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health through grants U01AI042170, U01AI46957, U01AI046362, U01AI068641, R01AI110173 and R56AI102959; CTSA Grant Number UL1 TR000135 and 8KL2TR000136-08 from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH; as well as NIH grants R01 GM28157 and U19GM61388 (Pharmacogenomics Research Network); and the Swiss National Science Foundation (no. 141234). It was also supported by the Pharmacogenomics Translational Program of the Mayo Center for Individualized Medicine. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. We thank the staff of the Medical Genome Facility Genotyping Core (GTC) at the Mayo Clinic for carrying out the genotyping analyses for this study. The GTC is supported in part by the NCI Cancer Center Support Grant P30 CA 15083.
    Acknowledgments
    Introduction The RV144 human immunodefiency virus (HIV) vaccine efficacy trial utilized a regimen combining recombinant canarypox vector ALVAC-HIV (i.e. expressing HIV type 1 (HIV-1) Gag, Pro and membrane-linked gp120 (vCP1521)) with HIV clades B and E gp120 envelope (Env) glycoprotein (Rerks-Ngarm et al., 2009), and showed an estimated vaccine efficacy of 31.2% (Rerks-Ngarm et al., 2009). Gp120 V1V2 antibodies were correlates of decreased transmission risk for RV144 (Haynes et al., 2012), primarily due to V2 antibodies (Karasavvas et al., 2012), and high levels of antibody dependent cellular cytotoxicity (ADCC) in the absence of high Env IgA levels were inversely correlated with infection risk (Haynes et al., 2012). A molecular sieve analysis demonstrated Lys169 within the V1V2 region to be a site of immune pressure with an estimated 48% vaccine efficacy when the challenging HIV strain matched the vaccine at this position (Rolland et al., 2012).