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Pharmacogenetics of efavirenz, adherence and virologic outcomes
Prolonged efavirenz half-life as a protective factor in non-adherence?
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Jean B. Nachega, M.D., M.P.H. Johns Hopkins University, Dept. of International Health, Baltimore, Maryland, USA, Gary Maartens, M.B.Ch.B., F.C.P., University of Cape Town, Dept. of Medicine, Division of Clinical Pharmacology, Cape Town, South Africa
Send rapid response to journal:
jnachega{at}jhsph.edu Jean B. Nachega, et al.
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We thank Dr. Cennimo for raising this interesting point. The primary aim of our analysis was to assess the relationship between adherence and virologic outcomes on nonnucleoside reverse transcriptase inhibitor regimens, and we caution that our finding of superior outcomes for efavirenz compared with nevirapine must be regarded as preliminary. The homozygous CYP2B6 position 516 TT genotype was found in 3.4% of European-Americans and 20% of African-Americans in the AIDS Clinical Trials Group study A5097s(1), and in 13.1% of a recent South African study(2).The CYP2B6 TT genotype increases the efavirenz half-life, but, as pointed out in the article Dr. Cennimo cites(3), this would be expected to result in a higher risk for the selection of drug resistant mutations in poorly adherent patients as the interruption of their other antiretroviral drugs with shorter half lives will result in prolonged effective monotherapy with efavirenz. The CYP2B6 TT genotype is also associated with an increased incidence of efavirenz-induced neuropsychiatric symptoms(1), which may reduce adherence. Therefore one could argue that in populations such as ours with a higher proportion of patients with the CYP2B6 TT genotype that efavirenz should be associated with poorer outcomes. Finally, efavirenz has also been shown to be more effective than nevirapine in a collaborative study of twelve cohorts from Europe and North America(4), populations in which the prevalence of the CYP2B6 TT mutation is low. This suggests that population pharmacogenetic differences are not the likely explanation for our preliminary finding that efavirenz is more effective than nevirapine. References 1.Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 2004;18(18):2391-400. 2.Cohen K, Dandara C, McIlleron H, Pemba L, Churchyard G, Maartens G, et al. The effect of rifampicin and cytochrome P450 2B6 genotype on efavirenz mid-dosing interval plasma concentrations in South African adults. 8th International Workshop on Clinical Pharmacology of HIV Therapy; 16-18 April 2007; Budapest, Hungary. 3.Ribaudo HJ, Haas DW, Tierney C, Kim RB, Wilkinson GR, Gulick RM, et al. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group study. Clin Infect Dis 2006;42:401-7. 4.The Antiretroviral Therapy Cohort Collaboration. Rates of disease progression according to initial highly active antiretroviral therapy regimen: a collaborative analysis of 12 prospective cohort studies. J Infect Dis 2006;194:612-22. Conflict of Interest R.E. Chaisson (Bristol-Myers Squibb); Honoraria: J.B. Nachega (GlaxoSmithKline, Merck-Sharp-Dohme for continuing medical education lectures), G. Maartens (Merck-Sharp-Dohme); Grants received: G. Maartens (Merck-Sharp-Dohme); Other: J.B. Nachega (Aspen Pharmaceuticals for conferences and travel grants). |
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David J. Cennimo, MD UMDNJ-New Jersey Medical School
Send rapid response to journal:
davidcennimo{at}hotmail.com David J. Cennimo
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In their article, Nachenga and colleagues describe the virologic response to NNRTI usage across a spectrum of adherence in a predominantly (96.9%) black South African patient cohort. (1) Their findings suggest a superiority of efavirenz (EFV) based regimens over nevirapine even when adjusted for adherence and other baseline variables. One potential confounding variable is the delayed hepatic clearance of efavirenz noted in some American patients of African descent. (2) This has been attributed to mutation in CPY2B6 gene (516G→T) which can prolong EFV half-life to 48 hours in TT homozygous mutants. In comparison, the half-lives in GG homozygotes and GT heterozygotes are 23 and 27 hours respectively. (3) This prolonged half-life, if present, could have ameliorated the effects of inconsistent adherence by maintaining effective levels until the next dose was taken. If this is the case, these effects may not be seen in alternate patient populations. 1. Nachega J, Hislop M, Dowdy D, Chaisson R, Regensberg L, Maartens G. Adherence to nonnucleoside reverse transcriptase inhibitor–based HIV therapy and virologic outcomes. Ann Intern Med. 2007;146:564-573. 2. Pfister M, Labbe´ L, Hammer S, Mellors J, Bennett K, Rosenkranz S, Sheiner L. Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir: Adult AIDS Clinical Trial Group Study 398. Antimicrob. Agents Chemother. 2003;47:130-137. 3. Ribaudo H, Haas D, Tierney C, Kim R, Wilkinson G, Gulick R, et al. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: An Adult AIDS Clinical Trials Group Study. Clin Infect Dis. 2006;42:401-407. Conflict of Interest:D Cennimo reports receiving a BMS Virolgy Fellows Research Grant. |
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