The role of genetic polymorphisms in cytochrome P450 and effects of tuberculosis co-treatment on the predictive value of CYP2B6 SNPs and on efavirenz plasma levels in adult HIV patients
Introduction
Among people infected with human immunodeficiency virus (HIV), tuberculosis (TB) is the most common opportunistic infection, with almost 50% of TB patients in Africa being co-infected (WHO, 2012). Managing HIV and TB infections requires multidrug therapy. The standard regimen for the treatment of TB is a combination of two to four drugs, where a rifamycin agent (usually rifampicin) is combined with non-rifamycin agents (ethambutol, isoniazid, and pyrazinamide). Streptomycin may be indicated when one of these drugs is contraindicated (WHO, 2010). The recommended first line antiretroviral therapy (ART) for the management of HIV/AIDS involves a combination of three drugs consisting of two nucleoside reverse transcriptase inhibitors with a non-nucleoside reverse transcriptase inhibitor (NNRTI). Efavirenz (EFV) is the NNRTI commonly administered as part of ART either in patients infected with HIV alone or co-infected with TB (Pozniak et al., 2011).
EFV plasma levels below 1 μg/ml and above 4 μg/ml have been associated with increased risks of virologic failure and central nervous system side effects, respectively (Marzolini et al., 2001). EFV is mainly metabolized in humans through hydroxylation by cytochrome P450 (CYP) 2B6, and to a lesser degree by CYP1A2, CYP2A6, CYP3A4, and CYP3A5 (Bélanger et al., 2009, di Iulio et al., 2009, Ogburn et al., 2010, Pozniak et al., 2011, Ward et al., 2003). EFV has been shown to exhibit interindividual variability in pharmacokinetics, which is thought to be caused by interindividual differences in CYP activities and expression (Bélanger et al., 2009, di Iulio et al., 2009, Holzinger et al., 2012, King and Aberg, 2008, Sánchez et al., 2011). Thus, factors affecting the metabolism of EFV could influence EFV exposure and the treatment response. Genetic influence is the most important among multiple factors affecting the pharmacokinetics of EFV (Sánchez et al., 2011). To our knowledge, there is no study that investigated in Rwandan adult HIV subjects the relationship between EFV exposure and single nucleotide polymorphisms (SNPs) with respect to EFV metabolizing enzymes, and the utility of genotyping as a way of improving the prediction of EFV plasma levels.
Despite the important role of genetics, drug–drug interactions deserve a particular attention because it is difficult to predict the outcome of complex interactions, such as those that might occur when several substrates for same CYP enzymes are used concomitantly, some being inhibitors or inducers of the CYP system (CDC, 2007). Non-rifamycin agents have been reported to induce or inhibit the hepatic CYP enzymes (Court et al., 2013, Rodríguez-Nóvoa et al., 2006, Manzi and Shannon, 2005, Wen et al., 2002) and interactions between rifamycin TB agents and antiretrovirals have been investigated, with focus on the induction effect of rifampicin on CYP2B6 enzyme and its impact on EFV disposition in different populations (Kwara et al., 2011a, Rodríguez-Nóvoa et al., 2006). Thus, the therapeutic management of HIV/TB co-infection may result in complex pharmacokinetic drug–drug interactions taking place collectively between ART components and TB drugs, impacting on blood levels of both HIV and TB drugs. Here we hypothesized that in HIV/TB co-infected patients, the genetic influence on EFV levels when patients are treated with EFV-containing therapy alone may differ from when the patients are treated with EFV-containing therapy combined with rifampicin-based TB treatment.
Therefore, the aim of this study was twofold, first to investigate the effects of 10 SNPs in five drug-metabolizing enzymes on EFV levels and treatment response in adult HIV/TB co-infected patients recruited in Rwanda when they are treated with EFV-containing therapy alone and when combined with rifampicin-based TB treatment, and secondly, to evaluate the effects of rifampicin-based TB treatment including its impact on the validity of genotyping for CYP2B6 SNPs in predicting EFV plasma levels above 4 μg/ml.
Section snippets
Study design and patients
This study was open-label and observational, and was conducted in Rwanda. Medications were administered in accordance with the Rwandan guidelines for the management of HIV/TB co-infection. Adherence to ART was assessed at each weekly visit by means of patient self-report. The patient had received a diary and was explained how to use it, writing down the date and time of every dose intake. The diary was brought to the clinic every visit, where the investigator asked the patient adherence related
Population characteristics
The gender ratio (male:female) was 1.05 (39:37) and the mean ± SD (range) age was 38.0 ± 7.8 (21–57) years. There were no statistically significant associations (P > 0.05) when baseline characteristics (patient gender, age, body weight, alanine transaminase ALAT, aspartate transaminase ASAT, total bilirubin and baseline CD4 cell counts and viral loads) were compared to EFV plasma levels, whether when with or without concomitant rifampicin-based TB treatment (results not shown).
Efavirenz plasma levels and patients’ genotypes
The categorization of
Discussion
Our data indicate a difference in association with exposure to EFV between CYP1A2 −739T/G and T/T genotypes during concomitant HIV and rifampicin-based TB treatment, but not during HIV treatment alone. Our regression model indicates that CYP2B6 516G>T, CYP2A6 1093G>A, and CYP2B6 983T>C were independent predictors for EFV plasma levels in the presence of rifampicin-based TB treatment, with CYP2B6 516T/T genotype being associated with high EFV plasma levels in the absence and presence of
Conclusion
This study indicated an association with EFV plasma levels for CYP1A2 −739T/G genotype only during concomitant HIV and TB treatment, and validated the findings on the effects of CYP2B6 516G>T polymorphism on EFV plasma levels in the Rwanda population, particularly the association of CYP2B6 516T/T genotype with elevated EFV plasma levels, with an added value to demonstrate the same effects not only during HIV treatment alone, but also during concomitant HIV and TB treatment. In addition to
Transparency declarations
Marelize Swart and Collet Dandara are supported by the Medical Research Council of South Africa and the University of Cape Town.
Disclaimer
The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations. All authors contributed to the conception, data analysis and revision of the manuscript and the final version of the article.
Acknowledgements
This work was financially supported by the Swedish International Development Cooperation Agency (Sida) [Agreement 2008-03-04, Decision no. 2006-006238, Contribution no. 75007334].
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