Nevirapine pharmacokinetics and risk of rash and hepatitis among HIV-infected sub-Saharan African women.
OBJECTIVE
To estimate nevirapine (NVP) pharmacokinetics and examine its association with rash and/or hepatotoxicity in women starting antiretroviral treatment in the AIDS Clinical Trials Group A5208/OCTANE study in Africa.


METHODS
In HIV-infected, nonpregnant women with screening CD4 cell count less than 200 cells/μl randomized to NVP (twice daily, after 14-day once-daily lead-in period) and tenofovir/emtricitabine, single NVP 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 NVP, were defined as toxicity.


METHODS
NVP pharmacokinetics were modeled by population pharmacokinetic analysis. Individual Bayesian pharmacokinetic estimates were used to calculate clearance, 24-h area under the curve, and predicted plasma concentrations.


RESULTS
Median week 4 NVP clearance was 2 l/h. Among the 359 women, 194 (54%) developed a rash of any grade; 82 (23%) had grade 2+ and nine (3%) had grade 3+ rash. Median clearance was 1.7 l/h for participants exhibiting 3+ rash versus 2 l/h 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). NVP discontinuation due to rash/liver toxicity was significantly more common among women with pretreatment CD4 cell count more than 250 cells/μl (P = 0.003).


CONCLUSIONS
In this study, HIV-infected African women starting a NVP-based antiretroviral regimen had a lower NVP 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 cell count at least 250 cells/μl was significantly associated with NVP toxicity.
University of California, San Francisco, 94143-0622, USA. dongb@pharmacy.ucsf.edu
Betty J
BJ
Dong
Yu
Y
Zheng
Michael D
MD
Hughes
Adam
A
Frymoyer
Davide
D
Verotta
Patricia
P
Lizak
Frederick
F
Sawe
Judith S
JS
Currier
Shahin
S
Lockman
Francesca T
FT
Aweeka
D000328:Adult; D017954:Africa South of the Sahara; D018791:CD4 Lymphocyte Count; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D004359:Drug Therapy, Combination; D005076:Exanthema / Q000139:chemically induced*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D019829:Nevirapine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012307:Risk Factors; D016896:Treatment Outcome
D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine