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Pharmacokinetics and 12 Weeks Efficacy of Nevirapine, 400 mg vs 600 mg per day in HIV-infected Patients with Active TB Receiving Rifampicin: A Multicenter Study
Anchalee Avihingsanon*1, W Manosuthi2, P Kantipong3, C Chuchotaworn4, S Moolphate5, N Yamada5, H Yanai5, P Phanuphak1, D Burger6, and K Ruxrungtham7
1HIV Netherlands Australia Thailand (HIV-NAT) Res Collaboration, Thai Red Cross AIDS Res Ctr, Bangkok; 2Bamrasnaradura Inst, Nonthaburi, Thailand; 3Chiang Rai Hosp, Thailand; 4Chest Disease Inst, Nonthaburi, Thailand; 5TB/HIV Res Project, Res Inst of Tuberculosis-Japan Anti-TB Assn, Chaing Rai, Thailand; 6Radboud Univ Med Ctr, Nijmegen, The Netherlands; and 7Faculty of Med, Chulalongkorn Univ, Bangkok, Thailand
Background: In HIV/tuberculosis (TB) co-infection, nevirapine
(NVP) -based ART regimens are widely used concomitantly with rifampicin (RIF) in most
resource-limited settings. Because of a pharmacokinetic interaction, the
appropriate dose of NVP is unclear.
Methods: We randomized 30 HIV-infected adults (15 per arm) with CD4
<200 cells/µL and active TB, receiving RIF 2 to 6 weeks to receive NVP 400
(arm 1) or 600 mg (arm 2) per day plus zidovudine
(AZT) and lamivudine. A NVP lead-in was performed in
both groups at 200 and 400 mg/day, respectively. Plasma NVP level was obtained
at week 2, 4 and 12. We obtained 12-hour pharmacokinetic profiles for NVP for
19 patients (10:9) at week 4 by high-performance liquid chromatography (HPLC). Pharmacokinetic
parameters were calculated by non-compartmental methods.
Results: Baseline characteristics; median body weight
(46 vs 55 kg, p = 0.09) were comparable in 2
groups. Median NVP Cmin (IQR) (mg/L) at
week 2 and week 4 was higher in the arm 2 (1.9, 0.7 to 3.0 vs
5.3, 3.3 to 7.8, p = 0.001; and 3.9, 2.9 to 4.8 vs
5.7, 4.5 to 7.1, p = 0.03, respectively). There were more patients with NVP Cmin
<3.1 mg/L at week 2 in the arm1 (77 vs 13 %; p = 0.01).
However, the proportions were comparable among the arms at week 4 and 12. The
12-hour pharmacokinetic study at week 4: median NVP AUC0-12 hour was comparable
between groups (64.8, 54 to 78.3 vs 85.2, 72.6 to
107.2 mg*h/L, p = 0.05]. The median Cmin
and Cmax were lower in the arm 1 than the
arm 2 (4.1, 3.6 to 4.6 vs 5.8, 4.8 to 7.4 mg/L, p = 0.03; and 6.6, 6.1 to 8.0 vs 8.7, 7.4 to 11.2 mg/L, p = 0.04, respectively). By week 12, 10 (33%) patients had permanently
discontinued: 4 from NVP
hypersensitivity (all from arm 2), 3 from RIF-induced cholestatic
jaundice (2 from arm 1), and death 2 cases (1 each), 1 NTM (arm 1). Immune recovery syndrome occurred in 33%
(5:5) and 30% had severe AZT-induced anemia. The 12-week efficacy showed no
differences in the median CD4 rise (76 vs 88 cells/µL),
or proportion with HIV RNA (intent to treat) <50 copies/mL
(53% vs 43%, p
= 0.58 ) [OT; 73% vs 75%]
Conclusions: In NVP+RIF concomitantly treated patients, as many as 80%
of patients in the 400-mg arm had suboptimal levels at 2 weeks after the lead
in period, whereas NVP 600 mg/day was associated with a high rate of NVP
hypersensitivity. While, short-term efficacy is comparable and long-term
efficacy study is under way, NVP 400 mg/day may be sufficient for Asian
HIV-infected patients receiving RIF, but the
NVP 200-mg lead-in should be avoided. In addition, AZT should also be avoided
during the first 3 months of advanced HIV/TB.
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