The overwhelming majority of HIV-infected persons reside in the developing world. As such, recent efforts have focused on providing antiretroviral pharmacotherapy to this population. However, there are a number of factors indigenous to non-Western HIV-infected patients that may alter their virologic, immunologic, and/or toxicologic response to antiretroviral therapy. Absorption, distribution, and clearance of antiretroviral medications may differ among patients residing in non-Western countries secondary to dietary influences, parasitic infection, and malabsorption. Genetic polymorphisms of drug metabolizing enzymes (cytochrome P450; CYP) and drug transporters (i.e. P-glycoprotein) as well as generic formulations of antiretroviral medications may also contribute to altered pharmacokinetics among these patients. The purpose of this pilot, hypothesis-generating study is (1) to characterize the pharmacokinetics of the non-nucleoside reverse transcriptase inhibitor nevirapine in a non-Western HIV-infected population (Kampala, Uganda) and in a similar cohort of HIV-infected individuals in the United States and (2) to compare pharmacokinetic parameter values between the groups. ? ? Polymorphisms in the cytochrome P450 (CYP) 2B6 gene have been shown to influence nevirapine plasma concentrations in HIV-infected European Caucasians. CYP2B6 polymorphisms have not been examined for their affect on nevirapine exposure in HIV-infected patients in Africa, where nevirapine is widely used. The purpose of this portion of the study was to determine the influence of CYP2B6 genotype at position 516 on nevirapine trough concentrations in HIV-infected patients in Kampala, Uganda. Nevirapine trough concentrations were determined in 23 HIV-infected patients who were generally healthy and taking nevirapine 200 mg twice daily for at least 14 days. Nevirapine concentrations were determined using high performance liquid chromatography. CYP2B6 genotyping at position 516 was accomplished using PCR-RFLP. ANOVA and the Student?s T test were used to compare nevirapine concentrations among CYP2B6 genotype groups (516TT vs. 516GG vs. 516GT, and 516TT/GT vs. 516GG, respectively). The median nevirapine trough concentration in individuals homozygous for the variant allele (TT) was 7607 ng/mL vs. 4181 ng/mL and 5559 ng/mL for GG and GT individuals, respectively (P=0.011 for GG vs. TT). When individuals possessing either 1 or 2 variant alleles (GT and TT) were grouped together and compared to individuals homozygous for the common allele (GG) the median nevirapine trough concentration was 1.46 fold higher in the GT/TT group (P=0.018).In conclusion, CYP2B6 G516T influences nevirapine trough concentrations in HIV-infected patients in Uganda. Persisting nevirapine plasma concentrations in 516TT individuals may hasten the development of resistance mutations after single-dose nevirapine administration for prevention of mother-to-child HIV transmission, or upon drug discontinuation (i.e.structured treatment interuption). These results were reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy (December, 2005, Washington DC) and a manuscript was recently accepted by the journal HIV Medicine. Of note, all subjects in the U.S. cohort have also completed the study and their data is currently being analyzed.? ? Lastly, in order to assess the integrity of nevirapine-containing dosage forms in africa, tablets containing nevirapine (from 6 international sources representing 3 manufacturers) were assayed for drug content. This quality-control investigation preceded the clinical portion of the study. All nevirapine formulations were found to contain the labeled amount of drug (200 mg); these results were presented at two international meetings as well as in the Journal of the American Medical Association (JAMA). A second report describing the content of medications (other than nevirapine-containing products) obtained from developing countries was recently reported in the journal Clinical Infectious Diseases.
|Penzak, S R; Kabuye, G; Mugyenyi, P et al. (2007) Cytochrome P450 2B6 (CYP2B6) G516T influences nevirapine plasma concentrations in HIV-infected patients in Uganda. HIV Med 8:86-91|
|Penzak, Scott R; Acosta, Edward P; Turner, Michele et al. (2004) Antiretroviral drug content in products from developing countries. Clin Infect Dis 38:1317-9|
|Penzak, Scott R; Acosta, Edward P; Turner, Michele et al. (2003) Analysis of generic nevirapine products in developing countries. JAMA 289:2648-9|