Nevirapine pharmacokinetics and risk of rash and hepatitis among HIV-infected sub-Saharan African women

Abstract

Objectives To estimate nevirapine pharmacokinetics and examine its association with rash and/or hepatotoxicity in women starting antiretroviral treatment in the ACTG A5208/OCTANE study in Africa. Design In HIV-infected, non-pregnant women with screening CD4<200 cells/mm3 randomized to nevirapine (twice daily, after 14-day once-daily lead-in period) plus tenofovir/emtricitabine, single nevirapine blood samples were collected 14 and 28 days following randomization. Rash and hepatotoxicity that occurred during therapy, or within 7 days after the last dose of nevirapine, were defined as toxicity. Methods Nevirapine pharmacokinetics were modeled by population pharmacokinetic analysis. Individual Bayesian pharmacokinetic estimates were used to calculate clearance, 24-hour area under the curve, and predicted plasma concentrations. Results Median week 4 nevirapine clearance was 2.0 L/hr. Among the 359 women, 194 (54%) developed a rash of any grade; 82 (23%) had grade 2+ and 9 (3%) had grade 3+ rash. Median clearance was 1.7L/hr for subjects exhibiting 3+ rash versus 2.0 L/hr in women without 3+ rash (p=0.046). The odds of developing 3+ rash was 50% higher for every 20% decrease in clearance (p=0.046). Nevirapine discontinuation due to rash/liver toxicity was significantly more common among women with pretreatment CD4 count > 250 cells/mm3 (p=0.003). Conclusions In this study, HIV-infected African women starting a nevirapine-based antiretroviral regimen had a lower nevirapine clearance compared to previous reports. Severe rash, but not hepatotoxicity, was associated with higher NVP exposure. Albeit observed in a small number of women, baseline CD4≥250 cells/mm3 was significantly associated with NVP toxicity.

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

“…While some studies report genderrelated differences in terms of virological and immunological response to HAART, others do not (Anderson, 2008;Carr et al, 2014;Dong et al, 2012;Marinho et al, 2013). In this study, we report of an over-representation of females (81%).…”

“…2011) 0.31 0.07 N/A Ugandan (Mukonzo et al, 2009) 0.36 0.10 NA Ghanaian (Bains et al, 2013;Griese et al 1999) 0 that it could be due to differential drug biotransformation, fat content, and exogenous and endogenous hormonal expression differences in males and females (Bersoff-Matcha et al, 2001;Dong et al, 2012;Marinho et al, 2013). Expression of liver enzymes responsible for drug metabolism has also been shown to vary with gender and BMI (Antinori et al, 2001;Bersoff-Matcha et al, 2001).…”

The pharmacokinetics of nevirapine when given with isoniazid in South African HIV-infected individuals [Short communication]

“…[4] Nevirapine is metabolized to some extent by the CYP3A isoenzyme and co-administration with isoniazid may alter nevirapine concentrations, which could alter toxicity. [5,6]…”

Stevens Johnson Syndrome and Toxic Epidermal Necrolysis Induced by Nevirapine among HIV-Infected Pregnant Women: Five Cases

“…The favorable outcome in all our patients could be related to the young age, the absence of factors of co morbidities, the stoppage of the ARV and the multidisciplinary early management (between dermatologist and obstetricians). We did not observe fetal complications to the type of prematurity that is reported by some authors [10][11][12]. Anti-proteases were used as a therapeutic alternative in the antiretroviral treatment protocol because nevirapine toxidermia is associated with a 10% cross-reactivity risk with efavirenz.…”