ObjectivesPolymorphisms in the cytochrome P450 (CYP) 2B6 gene have been shown to influence nevirapine plasma concentrations in HIV-infected European Caucasians. Although nevirapine is used extensively in Africa, the influence of CYP2B6 genotype on nevirapine exposure has not been assessed in this population. We aimed to determine the influence of CYP2B6 genotype at position 516 on nevirapine trough concentrations in HIV-infected patients in Kampala, Uganda. Additional polymorphisms in the CYP and multidrug resistance protein-1 (MDR-1) genes were also assessed for their impact on nevirapine concentrations. MethodsThe following genotypes were determined in all subjects using polymerase chain reaction-restriction fragment length polymorphism: CYP2B6 G516T, MDR-1 C3435T and G2677T, CYP3A4*1B and CYP3A5*3. Nevirapine plasma concentrations were determined using high-performance liquid chromatography in 23 HIV-infected patients who were generally healthy and had been taking nevirapine 200 mg twice daily for at least 14 days. Analysis of variance with post hoc testing was used to compare nevirapine concentrations among CYP2B6 genotype groups. ResultsThe median nevirapine trough concentration in individuals homozygous for the variant allele (TT) was 7607 ng/mL vs 4181 and 5559 ng/mL for GG and GT individuals, respectively (GG vs TT median ratio 5 1.82; P 5 0.011). The mean ratio for TT vs GG individuals (95% confidence interval) was 1.51 (1.18, 1.84). No associations were observed between the other polymorphisms studied and nevirapine concentrations. ConclusionsCYP2B6 G516T significantly influenced nevirapine trough concentrations in HIV-infected patients in Uganda. Additional studies in larger patient populations are necessary to further define the potential clinical impact of these preliminary findings.Keywords: Africa, CYP2B6, HIV, nevirapine, pharmacogenomics IntroductionNevirapine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that is widely used in combination with nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infection. Nevirapine has also proved to be effective in reducing mother-to-child transmission (MTCT) of HIV-1 by 50% [1]. For these reasons, and because nevirapine is generally affordable and available in a fixed-dose combination, it is used extensively in African nations.The relationship between nevirapine plasma concentrations and virological response and/or toxicity has not been Among the factors that are capable of influencing nevirapine exposure is the gene that encodes the cytochrome P450 (CYP) 2B6 enzyme. The CYP2B6 isoform, which plays a significant role in nevirapine metabolism, is characterized by marked interindividual variability in expression and activity as a result of the presence of genetic polymorphisms [9][10][11][12][13][14]. A single nucleotide polymorphism (SNP) in exon 4 (G516T) is associated with a significant reduction in CYP2B6 catalytic activity [13,15,16]. This SNP (G516T) was recently noted to influence the pharmacokinetics of efavirenz,...

HIV-infected patients are at approximately 100-fold greater risk of developing osteonecrosis than the general population. Disease progression is slower in asymptomatic patients than in symptomatic patients. Given the high frequency of total hip replacement in symptomatic patients, studies to assess preventive and treatment strategies are essential.

Milk thistle in commonly administered dosages should not interfere with indinavir therapy in patients infected with the human immunodeficiency virus.

Objective: Animal and in vitro data suggest that Ginkgo biloba extract (GBE) may modulate CYP3A4 activity. As such, GBE may alter the exposure of HIV protease inhibitors metabolized by CYP3A4. It is also possible that GBE could alter protease inhibitor pharmacokinetics (PK) secondary to modulation of P-glycoprotein (P-gp). The primary objective of the study was to evaluate the effect of GBE on the exposure of lopinavir in healthy volunteers administered lopinavir/ritonavir. Secondary objectives were to compare ritonavir exposure pre-and post-GBE, and assess the effect of GBE on single doses of probe drugs midazolam and fexofenadine.Methods: This open-label study evaluated the effect of 2 weeks of standardized GBE administration on the steady-state exposure of lopinavir and ritonavir in 14 healthy volunteers administered lopinavir/ritonavir to steady-state. In addition, single oral doses of probe drugs midazolam and fexofenadine were administered prior to and after 4 weeks of GBE (following washout of lopinavir/ritonavir) to assess the influence of GBE on CYP3A and P-gp activity, respectively.Results: Lopinavir, ritonavir and fexofenadine exposures were not significantly affected by GBE administration. However, GBE decreased midazolam AUC 0-∞ and C max by 34% ( p = 0.03) and 31% ( p = 0.03), respectively, relative to baseline. In general, lopinavir/ritonavir and GBE were well tolerated. Abnormal laboratory results included mild elevations in hepatic enzymes, cholesterol and triglycerides, and mild-to-moderate increases in total bilirubin.Conclusions: Our results suggest that GBE induces CYP3A metabolism, as assessed by a decrease in midazolam concentrations. However, there was no change in the exposure of lopinavir, likely due to ritonavir's potent inhibition of CYP3A4.Thus, GBE appears unlikely to reduce the exposure of ritonavir-boosted protease inhibitors, while concentrations of unboosted protease inhibitors may be affected. Limitations to our study include the single sequence design and the evaluation of a ritonavir-boosted protease inhibitor exclusively.

Our results confirm that efavirenz induces CYP2B6 enzyme activity in vivo, as demonstrated by an increase in bupropion hydroxylation after 2 weeks of efavirenz administration.