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Higher Efavirenz Levels--But No More Toxicity--in Nonwhites vs Whites: EuroSIDA
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www.hivpresentation.com
9th International Workshop on Clinical Pharmacology of HIV Therapy
7-9 April 2008
New Orleans
Mark Mascolini
Non-Caucasians in the EuroSIDA cohort did not have more efavirenz-related side effects than Caucasian cohort members--even though they did have higher concentrations of this nonnucleoside [1]. The findings in this 800-person EuroSIDA analysis run contrary to earlier reports linking high efavirenz levels to a steeper risk of central nervous system (CNS) side effects [2,3]. Previous research did uncover genetic factors that correlate with higher efavirenz concentrations in blacks,[4,5] but at least in EuroSIDA those higher levels posed no toxic risk.
EuroSIDA researchers considered everyone who started efavirenz after January 1, 1999 and had a plasma sample in which they could measure efavirenz concentrations. Of the 843 cohort members, 776 (92%) were Caucasian. The median efavirenz concentration of the whole group measured 2.2 mg/L (interquartile range 1.6 to 3.2 mg/L).
Fifty people (5.9%) had a subtherapeutic efavirenz level, defined as below 1 mg/L, while 119 people (14.1%) had a level above 4.0 mg/L, considered high and potentially toxic. As earlier work predicted, a significantly higher proportion of non-Caucasians than Caucasians had a high efavirenz level--18 non-Caucasians (26.9%) versus 101 Caucasians (13.0%) (P = 0.002).
The cohort included 138 people (16.4%) who stopped efavirenz because of any toxicity, including CNS side effects, or because of the patient's or physician's choice. Having hepatitis C virus along with HIV raised the risk of stopping efavirenz for these reasons 87% (odds ratio [OR] 1.87, 95% confidence interval [CI] 1.08 to 3.23, P = 0.026). And taking ddI/d4T with efavirenz more than doubled the risk of stopping efavirenz (OR 2.61, 95% CI 1.28 to 5.32, P = 0.009). But an efavirenz concentration above 3 mg/L had no impact on stopping efavirenz (OR 0.92, 95% CI 0.52 to 1.61), and being non-Caucasian actually tended to lower the risk of stopping efavirenz, though not significantly (OR 0.41, 95% CI 0.16 to 1.08, P = 0.072).
Thirty people (3.6%) quit taking efavirenz specifically because of CNS toxicity. Neither efavirenz concentration nor being non-Caucasian had any impact on risk of CNS side effects.
(Many slide sets and posters from this workshop will be available at www.hivpresentation.com shortly after the meeting ends.)
References
1. Van Luin M, Bannister WP, Mocroft A, et al. Discontinuation of efavirenz and ethnicity, a EuroSIDA PK study. 9th International Workshop on Clinical Pharmacology of HIV Therapy. 7-9 April 2008. New Orleans. Abstract P51.
2. Gutierrez F, Navarro A, Padilla S, et al. Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis. 2005;41:1648-1653.
3. Marzolini C, Telenti A, Laurent A, et al. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS. 2001;15:71-76.
4. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS. 2004;18:2391-2400.
5. Burger D, van der Heiden I, la Porte C, et al. Interpatient variability in the pharmacokinetics of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol. 2006;61:148-154.
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