Determinants Of Nevirapine Plasma Levels And Clinical Outcomes In Hiv Patients At Kenyatta National Hospital, Kenya
Background Nevirapine is a non-nucleoside reverse transcriptase inhibitor used as an antiretroviral agent for the treatment of HIV/AIDS. Current dosing schedules are based on pharmacokinetic studies in Caucasian populations and thus there may be high incidences of toxicity or sub-optimal nevirapine plasma levels that might limit its use and therapeutic success in non-Caucasians. Objective This study determined variability of steady-state nevirapine plasma levels and the influence of factors such as genetic polymorphisms, adherence and co-administered antiretroviral drugs in HIV positive patients at the Comprehensive Care Centre (CCC) at Kenyatta National Hospital (KNH). This study also evaluated the influence of nevirapine plasma levels on clinical outcomes such as maximum CD4 cell counts attainable during treatment. Methods A high performance liquid chromatography (HPLC) method utilizing ultraviolet (UV) detection was optimized and validated for determination of nevirapine in plasma. A descriptive one arm cross sectional study was conducted nested in a larger study on 241 HIV patients on nevirapine based antiretroviral therapy (ART) who attended the KNH CCC in 2014. Historical blood samples collected from the patients on ART for at least six months were analyzed using the HPLC-UV method to determine the steady-state nevirapine plasma levels. Previously collected data on baseline sociodemographic characteristics, clinical data for at least six months ART treatment and CYP2B6 genotypes was collated with the nevirapine levels. Descriptive, inferential, and linear regression analysis was performed to determine predictors of nevirapine plasma levels and clinical outcomes. Results The HPLC-UV method was selective and sensitive with a limit of quantification of 0.5 μg/mL. The accuracy of the method was 2.3% with inter- and intra-day precision of 7.2% and 4.7% respectively. The analytical range of the method was wide from 0.5 to 25 μg/mL with a recovery of 91.8%. xvii Steady-state nevirapine plasma levels varied widely among patients (46%) and within patients (28%) with a median of 5.675 μg/mL. Eighteen percent of participants had supra-therapeutic nevirapine plasma levels (above 8.0 μg/mL) while 6.3% had sub-therapeutic nevirapine plasma levels (below 3.0 μg/mL). Seventy eight percent of the patients had nevirapine plasma levels above 4.3 μg/mL reported to offer lasting viral suppression. This study found that CYP2B6 genotypes may play a significant role in influencing nevirapine plasma levels. Interestingly, homozygous CYP2B6 983CC (10.60 μg/mL) [β =2.619 (95% CI 1.337-3.901; P<0.001] and 516TT (8.450 μg/mL) [β =1.332 (95% CI 0.665-1.999); p<0.000] genotypes had higher nevirapine plasma levels compared to heterozygous (CYP2B6 983TC, 6.858 μg/mL and 516GT, 5.518 μg/mL) and wild type (CYP2B6 983TT, 5.533 μg/mL and 516GG, 5.575 μg/mL) genotypes. Participants who switched to tenofovir based ART regimens had higher nevirapine plasma levels than those who were on stavudine and zidovudine based regimens [β=1.202 (95% confidence interval (CI) 0.402-1.587); p=0.003]. Adherence to nevirapine dosing schedule resulted in an increase in nevirapine plasma levels (p=029). Nevirapine plasma levels influenced the maximum CD4 cell counts attainable during ART treatment (p=0.0420 but not the occurrence and severity of skin reactions and hepatotoxicity. Discussion and conclusion: Nevirapine plasma levels were affected by CYP2B6 genotypes (CYP2B6 983 T>C and 516 G>T) as the SNPs may affect expression and activity of nevirapine metabolizing enzymes. Adherence to dosing schedules may result in higher nevirapine plasma levels whereas those who do not adhere might have erratic nevirapine plasma levels. Nevirapine plasma levels may influence the maximum CD4 cell counts where higher nevirapine plasma levels might lead to greater viral suppression and better immunological recovery. In conclusion, a simple and improved HPLC-UV method that may be utilized in resource limited settings was used to determine nevirapine in plasma. Nevirapine plasma levels were influenced by CYP2B6 genotypes, adherence and use of tenofovir based ART regimens. Nevirapine plasma levels influenced the maximum immunological response in patients on ART but not the occurrence and severity of skin and hepatotoxic adverse drug reactions. Comprehensive population pharmacokinetic studies may be performed to inform and redesign dosing schedules so as to maximize clinical benefits and minimize occurrence of toxicity in patients using nevirapine based ART in the population.
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