Cytochrome P450 pharmacogenetics in African populations: implications for public health

Dandara, Collet; Swart, Marelize; Mpeta, Bafokeng; Wonkam, Ambroise; Masimirembwa, Collen

doi:10.1517/17425255.2014.894020

Cited by 52 publications

(59 citation statements)

References 110 publications

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“…Effective antiretroviral (ARV) therapy largely depends on adequate drug exposure to suppress viral replication and allow the immune system to recover (Panel on Antiretroviral Guidelines for Adults and Adolescents, 2009). However, approximately 35% of HIVinfected patients on HAART still fail to achieve durable virological suppression, while 45%-80% of those who do achieve virological suppression develop toxicities related to the ARV drugs (Cressey and Lallemant, 2007;Dandara et al, 2014a;Smyth et al, 2012;World Health Organization, 2010). These differences in treatment outcomes are attributed to inter-individual differences in the metabolism of ARV drugs (Pozniak et al, 2011;Rivero et al, 2007).…”

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confidence: 99%

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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confidence: 99%

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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“…Despite the similarity in allele and genotype frequencies for the CYP2B6 g.15582C > T SNP between South Africans, Cameroonians, Yoruba, and African-Americans, previous studies have shown that differences in minor allele frequencies for SNPs exist between these populations (Swart et al, 2012). African populations are, however, consistently shown to be significantly different from European and Asian populations (Dandara et al, 2014b) and this has major implications for personalised medicine in Low-and MiddleIncome Countries (LMIC).…”

Section: Resultsmentioning

confidence: 99%

“…I dentification of genetic variation that is of pharmacogenomics (PGx) relevance in African populations is an enormous endeavour and will continue to be a research priority in the next decade (Dandara et al, 2014a;2014b). Although there is an explosion in the generation of human DNA sequences using next generation sequencing (NGS) technologies, the accessibility of these technologies in the developing world is severely limited.…”

Section: Introductionmentioning

confidence: 99%

A Global Health Diagnostic for Personalized Medicine in Resource-Constrained World Settings: A Simple PCR-RFLP Method for Genotyping CYP2B6 g.15582C>T and Science and Policy Relevance for Optimal Use of Antiretroviral Drug Efavirenz

Evans

Swart

Soko

et al. 2015

OMICS: A Journal of Integrative Biology

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The use of pharmacogenomics (PGx) knowledge in treatment of individual patients is becoming a common phenomenon in the developed world. However, poorly resourced countries have thus far been constrained for three main reasons. First, the cost of whole genome sequencing is still considerably high in comparison to other (non-genomics) diagnostics in the developing world where both science and social dynamics create a dynamic and fragile healthcare ecosystem. Second, studies correlating genomic differences with drug pharmacokinetics and pharmacodynamics have not been consistent, and more importantly, often not indexed to impact on societal end-points, beyond clinical practice. Third, ethics regulatory frames over PGx testing require improvements based on nested accountability systems and in ways that address the user community needs. Thus, CYP2B6 is a crucial enzyme in the metabolism of antiretroviral drugs, efavirenz and nevirapine. More than 40 genetic variants have been reported, but only a few contribute to differences in plasma EFV and NVP concentrations. The most widely reported CYP2B6 variants affecting plasma drug levels include c.516G > T, c.983T > C, and to a lesser extent, g.15582C > T, which should be considered in future PGx tests. While the first two variants are easily characterized, the g.15582C > T detection has been performed primarily by sequencing, which is costly, labor intensive, and requires access to barely available expertise in the developing world. We report here on a simple, practical PCR-RFLP method with vast potentials for use in resource-constrained world regions to detect the g.15582C > T variation among South African and Cameroonian persons. The effects of CYP2B6 g.15582C > T on plasma EFV concentration were further evaluated among HIV/AIDS patients. We report no differences in the frequency of the g.15582T variant between the South African (0.08) and Cameroonian (0.06) groups, which are significantly lower than reported in Asians (0.39) and Caucasians (0.31). The g.15582C/T and T/T genotypes were associated with significantly reduced EFV levels ( p = 0.006). This article additionally presents the policy relevance of the PGX global health diagnostics and therefore, collectively makes an original interdisciplinary contribution to the field of integrative biology and personalized medicine in developing world. Such studies are, in fact, broadly important because resource-constrained regions exist not only in developing world but also in major geographical parts of the G20 nations and the developed countries.

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“…Pharmacogenetic profiles based on these studies are then extrapolated for use in other populations, despite the fact that variant frequencies can differ markedly between different populations (Ikediobi et al, 2011). Dandara et al (2014) provide a review on the importance of CYP450 pharmacogenetics in African populations and the implications for public health. The authors highlight that a large number of ethnic groups need to be characterized to capture the full Population based dosing results in standard dosing levels being representative of the level required by EM individuals.…”

Section: Pharmacogenetics In Africamentioning

confidence: 99%

“…The review by Dandara et al (2014) provides a summary of efavirenz metabolism and CYP2B6 pharmacogenetics in African populations, specifically the effect of the CYP2B6 516G4T variant. However, other CYP2B6 polymorphisms may also play a role in altered enzyme activity, as may polymorphisms in CYP2A6 and UGT2B7.…”

Section: Pharmacogenetics and Hiv Therapymentioning

confidence: 99%

Pharmacogenetics of CYP2B6, CYP2A6 and UGT2B7 in HIV treatment in African populations: focus on efavirenz and nevirapine

Čolić

Alessandrini

Pepper

2014

Drug Metabolism Reviews

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The CYP450 and UGT enzymes are involved in phase I and phase II metabolism of the majority of clinically prescribed drugs, including the non-nucleoside reverse transcriptase inhibitors, efavirenz and nevirapine, used in the treatment of HIV/AIDS. Variations in the activity of these enzymes due to gene polymorphisms can affect an individual's drug response or may lead to adverse drug reactions. There is an inter-ethnic distribution in the frequency of these polymorphisms, with African populations exhibiting higher genetic diversity compared to other populations. African specific alleles with clinical relevance have also emerged. Given the high prevalence of HIV/AIDS in subSaharan Africa, understanding the frequency of pharmacogen-etically relevant alleles in populations of African origin, and their impact on efavirenz and nevirapine metabolism, is becoming increasingly critical. This review aims to investigate ethnic variation of CYP2B6, CYP2A6 and UGT2B7, and to understand the pharmacogenetic relevance when comparing frequencies in African populations to other populations worldwide.

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Cytochrome P450 pharmacogenetics in African populations: implications for public health

Abstract: The variability in the pattern of genetic variation between populations translates into differences in drug response. Understanding CYP variability improves rational drug use and has public health significance.

Cited by 52 publications

References 110 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

A Global Health Diagnostic for Personalized Medicine in Resource-Constrained World Settings: A Simple PCR-RFLP Method for Genotyping CYP2B6 g.15582C>T and Science and Policy Relevance for Optimal Use of Antiretroviral Drug Efavirenz

Pharmacogenetics of CYP2B6, CYP2A6 and UGT2B7 in HIV treatment in African populations: focus on efavirenz and nevirapine

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