Association of Pharmacogenetic Markers with Premature Discontinuation of First-line Anti-HIV Therapy: An Observational Cohort Study

Institute of Microbiology, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
The Journal of Infectious Diseases (Impact Factor: 6). 01/2011; 203(2):246-57. DOI: 10.1093/infdis/jiq043
Source: PubMed


Poor tolerance and adverse drug reactions are main reasons for discontinuation of antiretroviral therapy (ART). Identifying predictors of ART discontinuation is a priority in HIV care.
A genetic association study in an observational cohort to evaluate the association of pharmacogenetic markers with time to treatment discontinuation during the first year of ART. Analysis included 577 treatment-naive individuals initiating tenofovir (n = 500) or abacavir (n = 77), with efavirenz (n = 272), lopinavir/ritonavir (n = 184), or atazanavir/ritonavir (n = 121). Genotyping included 23 genetic markers in 15 genes associated with toxicity or pharmacokinetics of the study medication. Rates of ART discontinuation between groups with and without genetic risk markers were assessed by survival analysis using Cox regression models.
During the first year of ART, 190 individuals (33%) stopped 1 or more drugs. For efavirenz and atazanavir, individuals with genetic risk markers experienced higher discontinuation rates than individuals without (71.15% vs 28.10%, and 62.5% vs 14.6%, respectively). The efavirenz discontinuation hazard ratio (HR) was 3.14 (95% confidence interval (CI): 1.35-7.33, P = .008). The atazanavir discontinuation HR was 9.13 (95% CI: 3.38-24.69, P < .0001).
Several pharmacogenetic markers identify individuals at risk for early treatment discontinuation. These markers should be considered for validation in the clinical setting.

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    • "A huge literature links EFV and NVP metabolism to the activity of CYP2B6 enzyme and the modulation in pharmacokinetic parameters to different factors including genetic polymorphisms at CYP2B6 gene (on human chromosome 19). For example, it has been clearly demonstrated that poor metaboliser phenotypes of NNRTI are more prone to have higher than expected plasma concentration of the drug (Wang et al., 2006; Penzak et al., 2007; Saitoh et al., 2007; Rotger et al., 2007; Wyen et al., 2008; Bertrand et al., 2012; Sarfo et al., 2014), lower clearance (Saitoh et al., 2007; Haas et al., 2004; Lehr et al., 2011), increased half-life (Ribaudo et al., 2006), higher number of side effects episodes and then lower compliance (Haas et al., 2004; Lubomirov et al., 2011; Yuan et al., 2011; Mukonzo et al., 2013), leading to a possible treatment failure (Ribaudo et al., 2006); however, data in literature are conflicting and mostly on non-African HIV-infected patients (Ribaudo et al., 2010; Frasco et al., 2012; Haas et al., 2014; Lee et al., 2014). Although PM patients may have an increased risk to select viral drug resistance, possibly because of a reduced compliance linked to higher risk of toxicity, to our knowledge no studies have been performed in order to evaluate the association between viral resistance and CYP2B6 metaboliser phenotypes. "
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    • "with increased neurotoxicity and other CNS side effects (Haas et al., 2004; King and Aberg, 2008; Lubomirov et al., 2010; Ribaudo et al., 2010; Maimbo et al., 2011) with HAART-induced liver injury (Yimer et al., 2011), and with efavirenz treatment discontinuation and the associated risk of developing drug resistance (Ribaudo et al., 2006; Lubomirov et al., 2011; Wyen et al., 2011). Importantly, compound heterozygotes of 516T and another low activity allele (e.g., *11, *18, *27, *28) also predict high efavirenz plasma levels (Rotger et al., 2007; Ribaudo et al., 2010). "
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