Selection of HIV-1 variants with wide cross-resistance to reverse transcriptase inhibitors during low-level escape to first-line dual nucleoside therapy
ABSTRACT: Objective: The ALBI trail (ANRS 070) has demonstrated sustained virological response to the dual nucleoside combination stavudine/didanosine in antiretroviral-naïve patients. However, in the majority of patients, low-level viral replication was seen after several months of therapy. We have sought to evaluate the impact of this low-level escape on the development of resistance.
Methods: Resistance was measured using a recombinant phenotypic assay. Reverse transcriptase (RT) genotypes were examined by chain termination sequencing. Resistance testing was performed on 24 patients treated with stavudine/didanosine, including baseline and one or two time points after confirmed virological escape (plasma HIV RNA >200 copies/ml).
Results: Wide cross-resistance to RT inhibitors was observed in a large proportion of patients: 15 patients had developed resistance to zidovudine (59-fold mean increase in IC50), 12 to lamivudine (mean 18-fold), seven to stavudine (mean 21-fold), four to didanosine (mean 13-fold) and three to abacavir (mean 11-fold). Two patients showed a significant change in viral susceptibility to nevirapine. RT genotypes revealed mostly zidovudine resistance mutations: the T215Y mutation was dominant, most often associated with M41L. Mutations of the 151 complex were found in three cases, whereas mutation V75T was observed in two cases. Neither mutations of codon 184 nor insertions near codon 69 were seen. A novel 157A mutation, found in one case, appeared to be associated with broad cross-resistance to nucleoside analogues. In seven patients there was no sign of phenotypic or genotypic resistance. Both patients with interclass cross-resistance to non-nucleoside RT inhibitors (NNRTIs) at escape had minor mutations in the NNRTI binding domain at baseline. We hypothesize that the emergence of some nucleoside resistance mutations can enhance latent or low-level NNRTI resistance related to such polymorphisms. This hypothesis is currently being tested in reconstruction and site-directed mutagenesis experiments.
Conclusions: Continued, low-level viral replication under stavudine/didanosine pressure can lead to selection of variants with wide cross-resistance to several other reverse transcriptase inhibitors that may include non-nucleoside compounds.
