IN RESPONSE:
We thank Dr. Cennimo for bringing up this interesting point. The primary aim of our analysis was to assess the relationship between adherence and virologic outcomes on NNRTI 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), close to 50% in participants in a study from Ghana (2), and 13.1% of participants in a recent South African study (3). The CYP2B6 TT genotype increases the efavirenz half-life, but as pointed out in the article Dr. Cennimo cites (4), this would be expected to result in a higher risk for drug-resistant mutations in poorly adherent patients, because the interruption of 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 efavirenz should be associated with poorer outcomes in populations, such as that in our study, with a relatively higher proportion of patients with the CYP2B6 TT genotype. Finally, efavirenz has also been shown to be more effective than nevirapine in a collaborative study of 12 cohorts from Europe and North America (5) and in recent study of U.S. Veterans Affairs patients (6), 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.
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;18:2391-400. [PMID: 15622315].[Medline]
2. Klein K, Lang T, Saussele T, Barbosa-Sicard E, Schunck WH, Eichelbaum M, et al. Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz. Pharmacogenet Genomics. 2005;15:861-73. [PMID: 16272958].[Medline]
3. Cohen K, Grant A, Dandara C, McIlleron H, Pemba L, Churchyard G, et al. The effect of rifampicin and cytochrome P450 2B6 genotype on efavirenz mid-dosing interval plasma concentrations in South African adults [Abstract]. Presented at the 8th International Workshop on Clinical Pharmacology of HIV Therapy, Budapest, Hungary, 16-18 April 2007.
4. 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. [PMID: 16392089].[Medline]
5. 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. [PMID: 16897660].[Medline]
6. Braithwaite RS, Kozal MJ, Chang CC, Roberts MS, Fultz SL, Goetz MB, et al. Adherence, virological and immunological outcomes for HIV-infected veterans starting combination antiretroviral therapies. AIDS. 2007;21:1579-89. [PMID: 17630553].[Medline]
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