Effects of CYP2B6 and CYP1A2 Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients.
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-to-person 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.
1 Department of Chemical Pathology, College of Health Sciences, University of Zimbabwe , Harare, Zimbabwe .
Doreen
D
Mhandire
2 Department of Statistical Sciences, Faculty of Science, University of Cape Town , Cape Town, South Africa .
Miguel
M
Lacerda
3 Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
Sandra
S
Castel
1 Department of Chemical Pathology, College of Health Sciences, University of Zimbabwe , Harare, Zimbabwe .
Kudakwashe
K
Mhandire
4 Department of Medical Laboratory Sciences, College of Health Sciences, University of Zimbabwe , Harare, Zimbabwe .|7 Institute of Clinical Medicine, University of Oslo , Oslo, Norway .
Danai
D
Zhou
5 Division of Human Genetics, Department of Clinical Laboratory Sciences and Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
Marelize
M
Swart
6 Newlands Clinic , Harare, Zimbabwe .
Tinei
T
Shamu
3 Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
Peter
P
Smith
4 Department of Medical Laboratory Sciences, College of Health Sciences, University of Zimbabwe , Harare, Zimbabwe .
Tutsirai
T
Musingwini
3 Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
Lubbe
L
Wiesner
7 Institute of Clinical Medicine, University of Oslo , Oslo, Norway .
Babill
B
Stray-Pedersen
5 Division of Human Genetics, Department of Clinical Laboratory Sciences and Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
Collet
C
Dandara
D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D003430:Cross-Sectional Studies; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use
D019380:Anti-HIV Agents; D019829:Nevirapine; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6