Genotypic correlates of in vivo resistance to efavirenz.
authors
L. T. BACHELER, B. ANTON, D. BAKER, M. BECKER, A. LASUT, M. AUJAY, L. BOLLING, K. KRAKOWSKI, J. BUNVILLE, V. WANG AND K. ABREMSKI.
publication
6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 109.
ABSTRACT
Efavirenz (SUSTIVA(TM), DMP 266) is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. In order to assess the genotypic basis of efavirenz treatment failure, characterization of plasma virus from patients participating in clinical trials of efavirenz in combination with indinavir or ZDV/3TC was undertaken. Multiple independently amplified plasma virus genomes were sequenced over a 1.1Kb region covering the protease gene and the first 229 amino acids of RT.
For most patients whose viral load rebounded on efavirenz-containing combination therapy, sequencing of plasma virus revealed the emergence of mutant viruses with a K103N substitution in the HIV-1 RT gene at the time of the initial rebound in viral load. Many patients subsequently developed viruses carrying K103N in combination with additional linked mutations (most commonly L100I, V108I, or P225H). 10-20% of patients developed viruses with mutations at RT position 190 (G to S, A, or E). The emergence of a Y188L mutant virus, with or without a linked V106I mutation, was observed in a small number of patients. Mutations at position 181 of the RT gene, previously associated with high level resistance to other NNRTIs, were not observed. Most patients who experienced a significant rebound in viral load on efavirenz combination therapy developed a plasma virus population carrying mutations associated with resistance to efavirenz in all viral genomes sequenced. In three patients who stopped efavirenz dosing, the frequency of NNRTI resistance mutations subsequently declined. In two efavirenz treatment failures, viruses with resistance mutations were only detected in a minority of the viruses sequenced, possibly as a consequence of incomplete adherence to the antiretroviral regime.
