Virological Response in Multidrug-Experienced HIV-1-Infected Subjects Failing Highly Active Combination Regimens after Shifting from Lamivudine to Didanosine

Abstract

The aim of this study (the RESCUE trial) was to verify the effect of a shift from a lamivudine-containing to a didanosine-containing regimen on viral replication in HIV-1-infected subjects who had experienced prior treatment failure. Sixteen patients (didanosine-experienced in 14/16 cases) were consecutively enrolled: eight patients shifted from lamivudine to didanosine without other changes in their drug regimen. The other eight shifted from lamivudine to didanosine and changed one or more of their other drugs according to their physician's judgement. At the time of the regimen shift, all the subjects exhibited a high-level phenotypic resistance to both zidovudine and lamivudine with changes at codons 70–219 in 100% of cases, at codon 215 in 13 of 16 patients, and the M184V substitution in 13/16 patients. Phenotypic susceptibility to didanosine was maintained in the majority of cases (14/16) despite the high prevalence of changes at codon 184. A statistically significant decrease in viral load ( P<0.005) without a significant increase in CD4 lymphocytes ( P=0.514) was observed after 3 and 6 months from the introduction of the didanosine-containing regimen. These findings suggest the possibility of achieving a viral load response to didanosine-containing regimens in patients with reverse transcriptase (RT) M184V mutations who were previously treated with this drug and its possible use in salvage combinations.

Anti-HIV Activity of (−)-(2R,4R)-1- (2-Hydroxymethyl-1,3-dioxolan-4-yl)- thymine against Drug-Resistant HIV-1 Mutants and Studies of Its Molecular Mechanism

“…2a In the presence of thymidine analogue mutations (TAMs), M184V decreases susceptibility to zidovudine, stavudine, and tenofovir. 6 On the other hand, T215Y mutation on its own results in intermediate (10-to 15fold) zidovudine resistance. 7 The Q151M complex or multidrug resistance (MDR) mutation (A62V, V75I, F77L, F116Y, and Q151M) has been shown to confer cross-resistance to most of the NRTIs.…”

“…However, during the long-term therapy, resistance to chemotherapy can develop in a significant number of patients. In recent years, resistance data from clinical trials have revealed important information on the patterns, prevalence, and effects of resistance seen among patients experiencing virologic failure. − The prevalence of some mutations such as M184V and Q151M has remained relatively constant, while the L74V mutation, the 69 insertions, and thymidine analogue mutations have decreased in prevalence. Other mutations such as K65R and Y115F, while still relatively uncommon, are increasing in prevalence.…”

“…M184V mutation emerges rapidly in patients receiving lamivudine monotherapy 3 and is also selected during therapy with emtricitabine, abacavir, and less commonly didanosine 2a. In the presence of thymidine analogue mutations (TAMs), M184V decreases susceptibility to zidovudine, stavudine, and tenofovir . On the other hand, T215Y mutation on its own results in intermediate (10- to 15-fold) zidovudine resistance .…”