Variability in the plasma concentration of efavirenz and nevirapine is associated with genotypic resistance after treatment interruption

Variability in the plasma concentration of efavirenz and nevirapine is associated with genotypic resistance after treatment interruption

Data de publicació online: 08/07/2008

Abstract:

Selection and persistence of non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutations during interruptions (TIs) has been attributed to the long plasma half-life of these drugs. However, little is known about the contribution of variable NNRTI plasma levels before it. We evaluated the selection of NNRTI-related mutations and the coefficient of variation of NNRTI plasma concentrations during different TI periods.

Methods: The selection of NNRTI-related mutations was examined in 50 HIV type-1 (HIV-1)-infected patients on a virologically suppressive regimen who underwent TI guided by CD4+ T-cell counts and plasma viraemia. Population and clone-based sequencing of the reverse transcriptase coding region was performed using plasma HIV-1 RNA samples during TI and proviral DNA from peripheral blood mononuclear cells before TI. NNRTI plasma concentrations were determined by HPLC.
Results: In 7/50 treated patients, de novo and transient NNRTI-related mutations appeared when treatment was interrupted. Emergence of resistant variants (including) K103N, Y181C or G190S) after interruption was associated with a higher coefficient of variation in NNRTI plasma concentrations during the treatment period. Moreover, minority HIV-1 variants containing different resistance patterns (V106I/A, K103R/E or Y188C/D/H) were detected regardless of NNRTI concentrations.
Conclusions: the emergence of NNRTI-associated mutations during TI appears to be associated with the variation of NNRTI plasma concentrations during the preceding treatment period. The selection of minority HIV-1 variants with different patterns of NNRTI resistance in the absence of drug pressure should be considered for the efficacy of future NNRTI-containing antiretroviral regimens.

Autors: Darwich, L., Esteve, A., Bellido, R., Clotet, B., and Martinez-Picado, J.
  • Codi Doi: Antivir Ther 13: 945-951

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