Therapeutic efavirenz (EFV) troughs attained in majority of HIV-infected individuals receiving rifampin (RIF) containing tuberculosis therapy: preliminary data from AIDS Clinical Trials Group Study A5221, a multinational trial comparing early ART within 2 weeks of starting TB therapy (E-ART) vs. ART within 8-12 weeks in HIV-infected subjects with CD4+ counts of < 250 cells/mm3
A.F. Luetkemeyer1, M.A. Kendall2, F. Marzan3, P.S. Lizak3, J. Andersen2, S. Swindells4, J. Kumwenda5, I. Sanne6, D.V. Havlir1, F. Aweeka7, Adult AIDS Clinical Trials Group A5221
1San Francisco General Hospital, UCSF, HIV/AIDS Division, San Francisco, United States, 2Harvard School of Public Health, Statistical and Data Analysis Center, Boston, United States, 3San Francisco General Hospital, UCSF, Department of Clinical Pharmacy, San Francisco, United States, 4University of Nebraska Medical Center, Infectious Diseases, Omaha, United States, 5University of Malawi, College of Medicine, Blantyre, Malawi, 6University of the Witswatersrand, Clinical HIV Research Unit, Johannesburg, South Africa, 7San Francisco General Hospital, Department of Clinical Pharmacy, San Francisco, United States
Background: Limited data exist on the effect of RIF on EFV levels in resource-limited settings. Pre-specified analyses estimated EFV troughs in A5221. Subjects received RIF-based therapy with daily EFV(600 mg), emtricitabine and tenofovir.
Methods: EFV Cmin was measured 20-28 hours after last EFV dose at weeks 4 and 8 after start of E-ART in subjects with no missed EFV/RIF doses for 3 days, using HPLC (LLQ=100ng/ml; < 1000ng/ml pre-specified as subtherapeutic). Exact confidence intervals(CI), Spearman correlation coefficients(SCC), logistic regression models(LR), and Fisher's Exact tests(FE) evaluated at 10% 2-sided Type I error.
Results: 92 subjects had both weeks 4 and 8 EFV Cmin available. Self-reported race: 70 black, 16 white, 6 other. Origin: South Africa (38), Brazil (28), Malawi (21), other (5).
| ||Baseline||Week 4||Week 8|
|Weight, kg||52 (37.5-86.6)||52 (35.2-85.2)||54 (33.5-86.8)|
|Body Mass Index (BMI), kg/m2||20 (14.2-36.5)||20 (14.2-35.9)||20 (13.9-36.6)|
|EFV Cmin, ng/ml|| ||1803 ( 0-19964)||2018 (0-23791)|
|% < 1000 ng/ml|| ||21% [14%, 29%]||18% [12%, 26%]|
|% 1000-4000 ng/ml|| ||53% [44%, 62%]||58% [48%, 66%]|
|% >4000 ng/ml|| ||26% [19%, 35%]||24% [17%, 32%]|
43(47%, [38%,56%]) had Cmin 1000-4000ng/ml at both weeks 4 and 8. 14 (15%, [9%,23%]) had Cmin< 1000 ng/ml and 18 (20%, [13%,28%]) had Cmin>4000 ng/ml at both times. Correlations included: week 4 Cmin with weight -0.14(p=0.20) and BMI -0.09(p=0.38); week 8 Cmin with weight -0.16(p=0.13) and BMI -0.12(p=0.24). There was an association between Cmin< 1000ng/ml and weight at week 8 (LR p=0.04) but not week 4 (p=0.44). Weight >50kg or >60kg was not associated with either week 4 or 8 subtherapeutic trough(FE p≥0.22).
Conclusions: Majority(66%) of RIF-treated subjects taking 600mg EFV had therapeutic EFV Cmin at both weeks 4 and 8. Weight did not reliably predict subtherapeutic EFV levels.
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