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Efavirenz Concentrations Do Not Signal Discontinuation in Swiss Study
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13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona
Mark Mascolini
Adults starting an efavirenz-based regimen reached higher efavirenz and efavirenz metabolite concentrations if they had impaired efavirenz-metabolizing pathways, an 89-person Swiss study found [1]. But high efavirenz or N-glucuronide efavirenz levels themselves did not predict discontinuation.
Poor tolerance or drug reactions account for most efavirenz discontinuations. Previous work by researchers at the University Hospital of Lausanne found that people with impairment of all efavirenz metabolic pathways--CYP2B6, CYP2A6, and CYP3A--had a high likelihood of stopping efavirenz [2]. These people with impaired pathways had higher plasma levels of efavirenz metabolites, especially N-glucuronide efavirenz [3].
The Lausanne team planned this analysis of a subgroup from this study to see if efavirenz and N-glucuronide efavirenz concentrations in themselves explained why people stopped efavirenz. This observational cohort included 89 people taking efavirenz in their first year of antiretroviral therapy. The investigators classified them according to function of the three efavirenz metabolic pathways, CYP2B6, CYP2A6 and CYP3A [2]. Scores ranged from 1, meaning all pathways were functional, to 6, meaning no pathways were functional.
Efavirenz concentrations in plasma ranged from 466 to 19,037 ng/mL and rose progressively as metabolic pathway function declined. Average efavirenz levels were 1470 ng/mL in people with the best metabolic function (score 1) and 9361 ng/mL in people with the worst function (score 6). Respective average N-glucuronide efavirenz concentrations were 6601 ng/mL and 28,022 ng/mL (P < 0.0001).
Thirty-six of these 89 people (40%) stopped efavirenz during the first year of treatment. But neither efavirenz concentrations nor N-glucuronide efavirenz concentrations differed between people who quit efavirenz and those who continued treatment (P = 0.75 and P = 0.78). A Cox regression model could find no association between efavirenz discontinuation and efavirenz or N-glucuronide efavirenz concentrations. But 8 of 9 people with genetic score 6 stopped efavirenz because of toxicity.
The Lausanne investigators noted that their analysis may be limited by the relatively small number of patients. In addition, they suggested that other markers of efavirenz toxicity--such as unstudied efavirenz metabolites or secondary biomarkers--may play roles in determining plasma concentrations and efavirenz discontinuation. At this point, the investigators proposed that the previously described pharmacogenetic score [2] appears to offer the best prediction of stopping efavirenz.
References
1. Aouri M, Buclin T, Rotger M, Telenti A, Decosterd LA, Swiss HIV Cohort Study. Impact of efavirenz and N-glucuronide efavirenz plasma concentrations on premature discontinuation of efavirenz treatment. 13th International Workshop on Clinical Pharmacology of HIV Therapy. April 16-18, 2012. Barcelona. Abstract O_04.
2. Lubomirov R, Colombo S, di Iulio J, et al, Swiss HIV Cohort Study. Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study. J Infect Dis. 2011;203:246-257.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071070/?tool=pubmed.
3. di Iulio J, Fayet A, Arab-Alameddine M, et al, Swiss HIV Cohort Study. In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function. Pharmacogenet Genomics. 2009;19:300-309.
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