Influence Of Cyp2b6 Polymorphisms On Cd4+ T Cell Count And Hiv Rna Viral Load Changes Among Individuals On Nevirapine Containing Highly Active Antiretroviral Therapy

ABSTRACT

Human Immunodeficiency Virus (HIV) remains the leading cause of morbidity and mortality in Kenya

with a prevalence of 6.5%. Highly active antiretroviral therapy (HAART) is used to manage the disease

by increasing the number of CD4 cells and reducing the viral load concentration. Majority of these

HAART based medication contain nevirapine (NVP) that is metabolized through the cytochrome P 450

(CYP450) system. The use of NVP is however, limited by sub-optimal response from patients. This poor

response may be caused by genes responsible for its metabolism. Polymorphisms on CYP2B6 gene may

interfere with catalytic activity of the enzyme leading to either an increase or reduction in NVP plasma

concentrations. The current study aimed at determining the influence of CYP2B6 gene polymorphisms on

plasma NVP concentration, CD4+ T-cell number and viral load change among HIV infected individuals

on NVP-containing HAART regimen. This was a prospective study among 228 HIV infected adults

attending Kenyatta National Hospital in Nairobi, Kenya. Whole blood samples were collected from the

study participants at enrolment and six months post-treatment. The samples were genotyped for CYP2B6

516G>T and 983T>C mutations using real-time polymerase chain reaction (RT-PCR) technique.

Pharmacokinetic analysis was done six months post treatment using tandem quadruple mass spectrometer

to determine NVP plasma concentrations. The CD4 cell count and plasma viral load were analyzed at

both enrolment (baseline) and six months post treatment. One way analysis of variance (ANOVA) was

used to determine the relationship between the changes in CD4+ cell count, HIV-RNA viral load, and

CYP2B6 genotypes The frequency of the T variant allele on the CYP2B6 516G>T polymorphism was

45.2% while the proportion of participants with GG, GT and TT genotypes were 50%, 36%, and 14%

respectively. The frequency of the C variant allele on the CYP2B6 983T>C polymorphism was 38.6%

while participants with TT genotypes were 61.4%. Nevirapine mean plasma concentrations were higher

among homozygous participants with CYP2B6 516TT mutant at 5335.9ng/mL compared to those

heterozygous 516GT (4985.5 ng/mL) and 516GG wild type (3725.8 ng/mL). Heterozygous participants

with CYP2B6 983T>C genotype had higher mean nevirapine plasma concentration of 4748.9ng/mL

compared to the wild-type CYP2B6 TC at 4161.5 ng/mL. There was a lower mean CD4 cell count six

months post treatment among individuals with CYP2B6 516TT and CYP2B6 516GT polymorphisms

compared to those with the wild-type CYP2B6 516GG. In the general linear model controlling for

baseline CD4+ cell count, HAART regimen and NVP plasma level; GG genotype (wild type) and GT

genotype (heterozygous mutant) predicted significant change (P = 0.002) in CD4 cell count. HIV-1 RNA

plasma viral load concentration was found to be higher among those with 516GT and 516TT compared to

those with 516GG. There were no significant effect on CD4+ and viral load concentration among those

with 983T>C polymorphisms. This study indicates that CYP2B6 516G>T polymorphism is associated

with a significant (p=0.039) reduction in viral load concentration and an increase in CD4 cell count

among participants on NVP. The CYP2B6 983T>C polymorphisms were found not to have a significant

effect on NVP plasma concentration, increase in CD4+ cell count and reduction in viral load

concentration. It can therefore be concluded that polymorphisms on CYP2B6 genotype influence

enzymatic activity that affect immunological and virological changes among patients on NVP containing

therapy. The findings from this study could be adopted by HIV treatment policy makers in determining

those to receive NVP as first line HAART and formulation of treatment strategies.