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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Available from: Huldrych F Günthard,
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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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    ABSTRACT: The prescription of patients' tailored anti-infectious treatments is the ultimate goal of pharmacogenetics/genomics applied to antimicrobial treatments, providing a basis for personalized medicine. Despite the efforts to screen Africans for alleles underlying defective metabolism for a panel of different drugs, still more research is necessary to clarify the interplay between host genetic variation and treatments' response. HIV is a major infectious disease in sub-Saharan African countries, and the main prescribed anti-HIV combination therapy includes efavirenz (EFV) or nevirapine (NVP). The two drugs are both mainly metabolised by cytochrome P450 2B6 liver enzyme (CYP2B6). Defective variants of CYP2B6 gene, leading to higher drug exposure with subsequent possible side effects and low compliance, are well known. However, little is known about CYP2B6 alleles in Cameroon where only one study was done on this subject. The main objective of the present work is to assess, in a subset of HIV-exposed subjects from Dschang in West Cameroon, the prevalence of two SNPs in the CYP2B6 gene: 516G>T (rs3745274) and 983T>C (rs28399499), both associated to a defective EFV and NVP metabolism. We analyzed 168 DNA samples collected during two cross-sectional surveys performed in Dschang, West Cameroon. In the population studied the observed allele frequencies of 516G>T and 983T>C were 44.35% (95%CI, 36.84-51.86%) and 12.80% (95%CI, 7.75-17.85%), respectively. Moreover, concerning the CYP2B6 expected phenotypes, 28.57% of the population showed a poor metaboliser phenotype, while 27.38% and 44.05% showed an extensive (wild-type) and an intermediate metaboliser phenotype, respectively. Here we found that an important fraction of the subjects is carrying EFV/NVP poor metaboliser alleles. Our findings could help to improve the knowledge about the previewed efficacy of anti-HIV drug therapy in Cameroon. Finally, we designed a new method of detection for the 983T>C genetic variation that can be applied in resource-limited laboratories. Copyright © 2015 Elsevier B.V. All rights reserved.
    Infection Genetics and Evolution 08/2015; 35:122-126. DOI:10.1016/j.meegid.2015.08.003 · 3.02 Impact Factor
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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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    ABSTRACT: Cytochrome P450 2B6 (CYP2B6) belongs to the minor drug metabolizing P450s in human liver. Expression is highly variable both between individuals and within individuals, owing to non-genetic factors, genetic polymorphisms, inducibility, and irreversible inhibition by many compounds. Drugs metabolized mainly by CYP2B6 include artemisinin, bupropion, cyclophosphamide, efavirenz, ketamine, and methadone. is one of the most polymorphic CYP genes in humans and variants have been shown to affect transcriptional regulation, splicing, mRNA and protein expression, and catalytic activity. Some variants appear to affect several functional levels simultaneously, thus, combined in haplotypes, leading to complex interactions between substrate-dependent and -independent mechanisms. The most common functionally deficient allele is [Q172H, K262R], which occurs at frequencies of 15 to over 60% in different populations. The allele leads to lower expression in liver due to erroneous splicing. Recent investigations suggest that the amino acid changes contribute complex substrate-dependent effects at the activity level, although data from recombinant systems used by different researchers are not well in agreement with each other. Another important variant, [I328T], occurs predominantly in Africans (4-12%) and does not express functional protein. A large number of uncharacterized variants are currently emerging from different ethnicities in the course of the 1000 Genomes Project. The polymorphism is clinically relevant for HIV-infected patients treated with the reverse transcriptase inhibitor efavirenz, but it is increasingly being recognized for other drug substrates. This review summarizes recent advances on the functional and clinical significance of CYP2B6 and its genetic polymorphism, with particular emphasis on the comparison of kinetic data obtained with different substrates for variants expressed in different recombinant expression systems.
    Frontiers in Genetics 03/2013; 4:24. DOI:10.3389/fgene.2013.00024
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    • "Therefore, in addition to clinical validity and clinical utility, another potential barrier to test implementation is demonstration of cost-effectiveness of the companion diagnostic test. Ideally, the pharmacogenomic biomarker will result in cost-effective improved clinical care in patients who will benefit from individualized therapy with the drug and avoidance of cost-ineffective treatment for patients who likely will not benefit from the drug, either as a result of lack of response or increased adverse drug reactions [86, 87]. "
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    02/2013; 2013(8):641089. DOI:10.1155/2013/641089
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