Resistance to Therapy

“The overall prevalence of primary drug resistance to at least one antiretroviral drug has been identified in 8.6% of our sample population of 1,738 newly diagnosed [Canadian] individuals who had never received treatment.”

“resistance develops during ongoing HIV replication in the presence of anti-HIV drugs”

“Results: Indinavir resistance was not detected in the 9 subjects with viral rebound during indinavir monotherapy or in the 17 subjects with rebound during triple-drug therapy, despite plasma HIV RNA levels ranging from 10^2 to 10^5 copies/mL. In contrast, lamivudine resistance was detected by phenotypic assay in rebound isolates from 14 of 17 subjects receiving triple-drug therapy, and genotypic analyses showed changes at codon 184 of reverse transcriptase in these 14 isolates. Mean random plasma indinavir concentrations in the 2 groups with rebound were similar to those of a control group with sustained viral suppression, although levels below 50 ng/mL were more frequent in the triple-drug group than in the control group (P = .03).”

“[Of 58 patients whose surrogate markers did not respond to treatment] Only 1 primary resistance mutation, M184V, was detected in 'S1' plasma samples [taken at the time of 'virologic failure'] from 4 of 6 patients in the triple-drug and in all 22 in the zidovudine-lamivudine therapy groups and in 'S2' plasma samples [taken 6 weeks later] from 3 of 6 in the triple-drug and 20 of 21 in the zidovudine-lamivudine groups. Of controls, M184V was detected in 11 of 13 'S1' plasma samples and in 10 of 11 'S2' plasma samples.”

“Naturally occurring mutations in HIV-1-infected patients have important implications for therapy and the outcome of clinical studies. However, little is known about the prevalence of mutations that confer resistance to HIV-1 protease inhibitors in isolates derived from patients naive for such inhibitors. In the first clinical application of high-density oligonucleotide array sequencing, the sequences of 167 viral isolates from 102 patients have been determined. The DNA sequence of USA HIV-1 clade B proteases was found to be extremely variable and 47.5% of the 99 amino acid positions varied. This level of amino acid diversity is greater than that previously known for all worldwide HIV-1 clades combined (40%). Many of the amino acid changes that are known to contribute to drug resistance occurred as natural polymorphisms in isolates from patients who had never received protease inhibitors.”

“There was no difference between viruses derived from patients sensitive to zidovudine and those derived from patients resistant to zidovudine”