CYP2B6 c.983T&gt;C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations

Carr, Daniel F.; Chaponda, Mas; Castro, Elena M. Cornejo; Jorgensen, Andrea; Khoo, Saye; Oosterhout, Joep J. van; Dandara, Collet; Kampira, Elizabeth; Ssali, Francis; Munderi, Paula; Lalloo, David G.; Heyderman, Robert S.

doi:10.1093/jac/dku315

Cited by 40 publications

(30 citation statements)

References 37 publications

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“…While some studies report genderrelated differences in terms of virological and immunological response to HAART, others do not (Anderson, 2008;Carr et al, 2014;Dong et al, 2012;Marinho et al, 2013). In this study, we report of an over-representation of females (81%).…”

Section: Demographic Characteristicscontrasting

confidence: 49%

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Mhandire

Lacerda

Castel

et al. 2015

OMICS: A Journal of Integrative Biology

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The extremely high prevalence of HIV/AIDS in sub-Saharan Africa and limitations of current antiretroviral medicines demand new tools to optimize therapy such as pharmacogenomics for person-toperson variations. African populations exhibit greater genetic diversity than other world populations, thus making it difficult to extrapolate findings from one population to another. Nevirapine, an antiretroviral medicine, displays large plasma concentration variability which adversely impacts therapeutic virological response. This study, therefore, aimed to identify sources of variability in nevirapine pharmacokinetics and pharmacodynamics, focusing on genetic variation in CYP2B6 and CYP1A2. Using a cross-sectional study design, 118 HIV-infected adult Zimbabwean patients on nevirapine-containing highly active antiretroviral therapy (HAART) were characterized for three key functional single nucleotide polymorphisms (SNPs), CYP2B6 c.516G>T (rs3745274), CYP2B6 c.983T>C (rs28399499), and CYP1A2 g.-163C>A (rs762551). We investigated whether genotypes at these loci were associated with nevirapine plasma concentration, a therapeutic biomarker, and CD4 cell count, a biomarker of disease progression. CYP2B6 and CYP1A2 were chosen as the candidate genes based on reports in literature, as well as their prominence in the metabolism of efavirenz, a drug in the same class with nevirapine. Nevirapine plasma concentration was determined using LC-MS/MS. The mean nevirapine concentration for CYP2B6 c.516T/T genotype differed significantly from that of 516G/G ( p < 0.001) and 516G/T ( p < 0.01) genotypes, respectively. There were also significant differences in mean nevirapine concentration between CYP2B6 c.983T > C genotypes ( p = 0.04). Importantly, the CYP1A2 g.-163C>A SNP was significantly associated with the pharmacodynamics endpoint, the CD4 cell count ( p = 0.012). Variant allele frequencies for the three SNPs observed in this Zimbabwean group were similar to other African population groups but different to observations among Caucasian and Asian populations. We conclude that CYP2B6 c.516G>T and CYP2B6 c.983T>C could be important sources of nevirapine pharmacokinetic variability that could be considered for dosage optimization, while CYP1A2 g.-163C>A seems to be associated with HIV disease progression. These inter-and intra-population pharmacokinetic and pharmacodynamics differences suggest that a single prescribed dosage may not be appropriate for the treatment of disease. Further research into a personalized nevirapine regimen is required.

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Section: Demographic Characteristicscontrasting

confidence: 49%

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Mhandire

Lacerda

Castel

et al. 2015

OMICS: A Journal of Integrative Biology

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“…In our study, one death occurred due to nevirapine-induced TEN. This finding is consistent with the results of previous studies wherein nevirapine-induced TEN resulted in life-threatening ADRs (38,39).…”

Section: Discussionsupporting

confidence: 93%

Highly Active Antiretroviral Therapy Induced Hematological and Dermatological Adverse Drug Reactions in People Living with HIV in India

Varma

Rajesh

Pulagam

et al. 2018

IMMINV

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Introduction: In India, HIV patients are at a high risk of developing hematological and dermatological adverse drug reactions (ADRs) leading to financial burden. Materials and Methods: A prospective observational study was conducted on hematological and dermatological ADRs in a South Indian teaching hospital from October 2011 to October 2012. The definition of ADRs established by the World Health Organization (WHO) was used to assess the causality. Predictability of ADRs was assessed by Micromedex database. Preventability of ADRs was assessed using the Schumock and Thornton criteria. Results: A total of 174 HIV patients were enrolled [133 (76.4%) males and 41 (23.6%) females], who reported 99 ADRs to HAART. Of the total ADRs, 70 (70.7%) were reported in males and 29 (29.3%) in females, indicating significantly higher reporting of ADRs in males. 67 of the 99 ADRs were hematological, while the remaining 32 were dermatological. A high number of hematological [40 (59.6%)] and dermatological [15 (46.8%)] ADRs were reported for zidovudine + lamivudine + nevirapine-based HAART regimen. In most of the reported ADRs, the suspected drug was withdrawn. The reported hematological ADRs were as follows: 1) anemia with zidovudine [35 (52.2%)]; 2) pancytopenia with zidovudine [20 (29.9%)]; 3) neutropenia with lamivudine; and 4) leucopenia, bicytopenia, and eosinophilia with zidovudine. Dermatological ADRs were maculopapular rash [7 (21.8%)] with nevirapine-, tenofovir + emtricitabine + efavirenz. Conclusion: Hematological ADRs was higher than that of dermatological ADRs. Physicians must focus on routine monitoring of all possible risk factors in PLW-HIV for early prevention of hematological and dermatological ADRs to HAART.

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“…Likewise, an association between the CYP2B6 c.983T > C SNP and the development of nevirapineinduced Stevens-Johnson syndrome or toxic epidermal necrolysis, but not other hypersensitivity reactions, has been described in Malawian and Ugandan HIV-infected individuals [37] . Considering that this SNP is found in a small part of African populations, but not in Caucasians, these findings would point out to an ethnicspecific predisposing factor.…”

Section: Non-nucleoside Reverse Transcriptase Inhibitors-associated Hmentioning

confidence: 99%

Can antiretroviral therapy be tailored to each human immunodeficiency virus-infected individual? Role of pharmacogenomics

Asensi¹

2015

WJV

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Pharmacogenetics refers to the effect of single nucle otide polymorphisms (SNPs) within human genes on drug therapy outcome. Its study might help clinicians to increase the efficacy of antiretroviral drugs by improving their pharmacokinetics and pharmacodynamics and by decreasing their side effects. HLAB*5701 genotyping to avoid the abacavir-associated hypersensitivity reaction (HSR) is a cost-effective diagnostic tool, with a 100% of negative predictive value, and, therefore, it has been included in the guidelines for treatment of human immunodeficiency virus (HIV) infection. HALDRB*0101 associates with nevirapine-induced HSR. CYP2B6 SNPs modify efavirenz plasma levels and their genotyping help decreasing its central nervous system, hepatic and HSR toxicities. Cytokines SNPs might influence the development of drug-associated lipodystrophy. APOA5 , APOB , APOC3 and APOE SNPs modify lipids plasma levels and might influence the coronary artery disease risk of HIV-infected individuals receiving antiretroviral therapy. UGT1A1*28 and ABCB1 (MDR1) 3435C > T SNPs modify atazanavir plasma levels and enhance hyperbilirubinemia. Much more effort needs to be still devoted to complete large prospective studies with multiple SNPs genotyping in order to reveal more clues about the role played by host genetics in antiretroviral drug efficacy and toxicity. genotyping to prevent the abacavir-associated hypersensitivity reaction. Diverse other single nucleotide polymorphisms have been described as related to certain pharmacokinetic characteristics and adverse effects of antiretroviral drugs. In this Editorial we summarize the current knowledge on this rapidly evolving field.Asensi V, Collazos J, Valle-Garay E. Can antiretroviral therapy be tailored to each human immunodeficiency virus-infected individual?

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CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations

Cited by 40 publications

References 37 publications

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Highly Active Antiretroviral Therapy Induced Hematological and Dermatological Adverse Drug Reactions in People Living with HIV in India

Can antiretroviral therapy be tailored to each human immunodeficiency virus-infected individual? Role of pharmacogenomics

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