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

Abstract

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.

Seroprevalence of Cytomegalovirus Infection Among HIV-Infected and HIV-Uninfected Pregnant Women Attending Antenatal Clinic in Harare, Zimbabwe

“…More importantly, the HIV-infected study participants were on ART, which in successful cases is sufficient for immune restoration, hence protection against CMV infection. However, the occurrence of CMV in some of the HIV-infected women who are also on ART may suggest differences in response to ART among the HIV-infected participants (33).…”

“…The median age of HIV-infected women was significantly higher ( p < 0.001) (30 years, 25th-75th percentile: 25-34) compared with that of HIV-uninfected women (26 years, 25th-75th percentile: [21][22][23][24][25][26][27][28][29][30][31][32]. The median age of gestation among the pregnant women was 33 weeks (25th-75th percentile: [29][30][31][32][33][34][35][36] and was significantly higher ( p < 0.001) in the HIV-uninfected group (33 weeks, 25th-75th percentile: 30-36) compared with the HIV infected (32 weeks, 25th-75th percentile: [28][29][30][31][32][33][34][35]. The earlier presentation of HIV-infected women to clinic (measured by lower gestation age) could be due to improved healthseeking behavior induced by HIV treatment programs.…”

A Pharmacist’s Role in the Individualization of Treatment of HIV Patients

“…However, compared with other CYPs, there have been relatively few reports of pharmacogenetics relationships. However, a recent study suggests that the CYP1A2 g.-163C>A polymorphism is associated with HIV disease progression in Zimbabwean HIV-infected patients treated with nevirapine (NVP) [70].…”

CYP2B6*6 Screening; Potential Benefits and Challenges in HIV Therapy in Sub-Saharan Africa

“…Likewise, studies have also been done in African populations to evaluate the clinical implications of the CYP2B6*6 allele in the use of efavirenz [15][16][17][18], and nevirapine [19][20][21]. CYP2B6*6 has been associated with higher efavirenz plasma concentrations due to lower clearance rates, which may lead to CNS side effects [22,23].…”