Table 3.

Relevant studies on the relationship between host genetics and ARV transport and metabolism in the ethnically diverse South African population

Title of study	Province of study	Main study outcomes	References
Pharmacogenetics of antiretroviral drug response and pharmacokinetic variations in indigenous South African populations	Western Cape and Gauteng	Fifty-three variants had significant differences in allele and genotype frequencies when comparing South African colored and black African groups. Thirteen of these had strong clinical annotations, affecting efavirenz and tenofovir pharmacokinetics	[59]
CYP2B6 haplotype predicts efavirenz plasma concentration in black South African HIV-1-infected children: a longitudinal pediatric pharmacogenomic study	Gauteng	The CYP2B6 c.516T/T genotype showed significantly higher EFV plasma concentrations (p < 0.001) compared to non 516T-allele carriers. The minor allele frequencies (MAF) for CYP2B6 c.516T, c.785G, c.983C, and c.1459T were 0.410, 0.408, 0.110, and 0.000 respectively. The haplotype T-G-T presented with significantly increased EFV plasma concentrations compared to the reference G-A-T haplotype at 1, 3, and 24 months (p = 0.009; p = 0.003; p = 0.001). This suggests, the T-G-T haplotype predisposes a risk of EFV plasma concentrations > 4 lg mL−1	[63]
Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa	Not indicated	Median (IQR) mid-dose efavirenz concentrations observed were 1.44 (1.21–1.93) μg ml–1, 2.08 (1.68–2.94) μg ml–1 and 7.26 (4.82–8.34) μg ml–1 for extensive, inter- mediate and slow metabolizers, respectively. In univariate analyses, a model that included composite genotype best predicted efavirenz concentrations (β = 0.28, 95% CI 0.21, 0.35, p = 2.4 × 10–11). Among individual CYP2B6 polymorphisms, 516G → T best predicted efavirenz concentrations (β = 0.22, 95% CI 0.13, 0.30, p = 1.27 × 10_6). There was also an association with 983T → C (β = 0.27, 95% CI 0.10, 0.44, p = 0.002) and 15582C → T (β = 0.11, 95% CI 0.01, 0.22, p = 0.04). Associations were consistent in adults and children	[61]
High predictive value of CYP2B6 SNPs for steady-state plasma efavirenz levels in South African HIV/AIDS patients	Gauteng	CYP2B6 516T and 785G (*6) and CYP2B6 983C (*18) alleles were observed to be significantly associated with high plasma efavirenz levels. CYP2B6 A–G–A–C–C and A–T–G–T–C haplotypes (with respect to CYP2B6 136A>G; CYP2B6 516G>T; CYP2B6 785A>G; CYP2B6 983T>C; and CYP2B6 1459C>T) were associated with higher levels of efavirenz, whereas G–G–A–T–C and A–G–A–T–C haplotypes showed significantly lower efavirenz levels	[60]
Prevalence of MDR1 C3435T and CYP2B6 G516T polymorphisms among HIV-1 infected South African patients	Limpopo	Analysis of population-based sequences of MDR1 revealed a frequency of 89 and 11% of C and T alleles respectively (n = 197; X2 = 0.974; p = 0.324). Restriction fragment length polymorphism analysis of the CYP2B6 gene revealed a prevalence of 9.5% of GG, 78.4% of GT and 12.1% of TT genotype (n = 199; X2 = 65.204; p = 0.00). No significant difference between immune recovery and decline in viral load (n = 53) was observed with genotype after repeated calculations of analysis of variance	[64]
Influence of CYP2B6 516G>T polymorphism and inter-occasion variability (IOV) on the population pharmacokinetics of efavirenz in HIV-infected South African children	Gauteng	EFV concentrations below 1 μg mL−1 accounted for 18% (116/649), concentrations > 4 μg mL−1 accounted for 29.5% (192/649) and concentrations within the therapeutic range (1–4 μg mL−1) represented 52.5% (341/649) of all the samples determined. Age, weight and CYP2B6 G516T genotype were included in a model with population estimates for apparent clearance determined as 2.46, 4.60 and 7.33 L h−1 for the T/T, G/T and G/G genotype groups respectively	[62]
A pharmacogenetic study of CD4+ T-cell recovery in response to HIV antiretroviral therapy in two South African population groups	Western Cape	Considering CD4+ T-cell count, univariate two-way analysis of variance showed no apparent effect of ethnicity on immune recovery in response to ART. Univariate one-way ANOVA testing revealed a noticeable effect of genotype on immune recovery for T-129C (p = 0.03) and G2677A (p < 0.01) polymorphisms in the ABCB1 gene	[65]