VIEWS: 3 PAGES: 11 POSTED ON: 4/12/2011
The Aurum Vision Aurum Health intends to be an internationally recognised, independent and self sustaining research and health systems organisation, aiming to improve the health of individuals and communities in Africa. Rationale • Efavirenz is widely used in first-line antiretroviral therapy – severe central nervous system (CNS) neuropsychiatric side-effects, including dizziness, disturbed sleep, nightmares, headaches, mood disturbance and psychosis • The therapeutic range is 1-4mg/l – increased rate of virological failure with levels below 1mg/l, – increased central nervous system (CNS) side-effects with levels above 4mg/l …rationale • Tuberculosis occurs commonly in HIV-infected patients • Rifampicin, a key component of tuberculosis treatment – is a potent inducer of hepatic cytochrome P450 enzymes, including isoenzyme 2B6 (CYP2B6), the main route of efavirenz metabolism. – decrease efavirenz plasma levels by enhancing hepatic metabolism – may lead to ART failure and development of viral resistance • Concerns about prescribing efavirenz at standard doses together with rifampicin – CDC guidelines increase EFV to 800mg • The cytochrome P450 2B6 G516T polymorphism may lead to increased efavirenz levels Objectives • To describe efavirenz mid-dosing interval levels in HIV-infected patients taking efavirenz-based ART in South Africa. • To identify risk factors for efavirenz levels outside the therapeutic range in this population. • To investigate the association between the CYP2B6 G516T polymorphism and efavirenz levels. • To compare efavirenz levels in the presence of concomitant rifampicin to levels in participants not taking rifampicin. Methods • Participants taking efavirenz-based antiretroviral therapy • Blood for efavirenz level was sampled 12-20 hours after last dose • A sample for genetic analysis • 2 Arms – those on rifampicin : sampled twice - whilst on rifampicin, and 1 month or more after stopping rifampicin – Efavirenz-only participants were sampled once Analysis • EFV-only participants with EFV-RIF participants at 1st sampling occasion (sample 1) • EFV-only participants with EFV-RIF participants at 2nd sampling occasion (sample 2) • EFV-RIF participants during and on discontinuation of RIF Results • 142 participants – 40 on RIF • 17 had 2nd specimen off RIF • Mean age 41 years • Females 27% • Median efavirenz level was 1.9mg/l (IQR 1.4- 3.8) – 39/159(24.5%) in 38/142(26.7%) were > 4mg/l – 27/159(17.0%) in 25/142(17.6%) were < 1mg/l. • The G516T polymorphism was common: – 48/129(37.2%) had the wild-type G/G genotype, – 36/129(27.9%) were G/T heterozygotes – 45/129(34.9%) T/T homozygotes Effect of RIF on EFV levels • Median efavirenz level – 2.4 (IQR 1.3-3.1) in the 40 participants on EFV-RIF – 1.8 (IQR 1.4-4.4) in 102 participants on EFV-only – A Wilcoxon signed-rank test on paired efavirenz levels on and off rifampicin in 17 participants, confirmed this finding (p=0.113) Effect of genotype on EFV levels • Genotype G/G - 1.6mg/(IQR 1.0-2.6) • Genotype G/T - 2.4mg/l(IQR 1.4-4.8) • Genotype T/T - 2.3mg/l(IQR 1.6-5.5) • strong evidence for a difference between genotypes (Kruskal-Wallace p= 0.0083). Risk factor analysis • G516T polymorphism was strongly associated with efavirenz levels above 4mg/l – odds ratios • GG = 1 • GT = 6.61 (95%CI 1.82-24.01 Wald test p=0.004) • TT = 5.19 (95%CI 1.46-18.35 Wald test p=0.011) • No association between high levels and CNS side-effects, except severe sleep disturbance • In those on ART for ≥ 6 months, efavirenz levels below 1mg/l were associated with virological failure (> 400 copies/ml) Conclusion • Efavirenz can be used at standard 600mg doses together with rifampicin in this population, without dose adjustment. • The G516T polymorphism was common and associated with efavirenz levels above 4mg/l. • High levels were not associated with CNS side-effects, except for insomnia.
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