Presence Of Drug Resistance Mutations Research Articles

HIV-1 Subtype C Reverse Transcriptase Sequences from Drug-Naive Pregnant Women in South Africa

The HIV-1 reverse transcriptase genes from 37 HIV-1-positive pregnant women attending an antenatal clinical in Soweto, South Africa were sequenced and analyzed for the presence of drug resistance mutations. All women were antiretroviral drug naive, but were being screened as potential participants in clinical trials of antiretroviral drugs aimed at preventing mother-to-child transmission. Sequence analysis revealed that all belonged to HIV-1 subtype C, the predominant subtype among heterosexual populations in South Africa. Twenty-three amino acid loci associated with resistance to zidovudine, lamivudine, didanosine, stavudine, and nevirapine were examined and found not to encode mutations that would confer resistance to these drugs. Polymorphisms at these loci occurred infrequently, with three patients harboring the A98S and V179I polymorphisms. An additional three patients harbored V118I, which can function as an accessory resistance mutation, but in this context is also likely to be a polymorphism. These data show that pregnant women who are candidates for receiving antiretroviral drug therapies do not contain naturally occurring or preexisting drug resistance mutations and that such drug therapies are likely to be highly effective in this setting.

Impact of HIV type 1 drug resistance mutations and phenotypic resistance profile on virologic response to salvage therapy.

This study examines the association between presence of drug resistance mutations and phenotypic resistance at baseline to virologic response to salvage therapy in a community setting. The study population consisted of 58 antiretroviral drug-experienced patients with HIV-1 infection who had recently switched therapy because of virologic failure. Drug resistance mutations in the reverse transcriptase- and protease-coding regions and phenotypic susceptibility to 13 antiretroviral drugs were assessed at baseline. Plasma HIV-1 RNA levels were assessed at baseline and at subsequent clinic visits. Results showed that three variables were significant in predicting virologic response: HIV-1 levels at baseline, number of protease mutations, and phenotypic sensitivity score for the regimen at baseline. For four drugs there was a significant association between the presence of specific drug resistance mutations and >10-fold phenotypic resistance to that drug. With phenotypic resistance defined as >4-fold resistance, the association between specific drug resistance mutations and phenotypic resistance was significant for seven drugs. Overall, these data show that phenotypic susceptibility and absence of drug resistance mutations, particularly protease mutations, are significant predictors of virologic response. For several drugs, specific combinations of drug resistance mutations are associated with decreased phenotypic susceptibility and might provide useful clinical guidelines in selecting therapeutic options.

Transient relapses ("blips") of plasma HIV RNA levels during HAART are associated with drug resistance.

In a large number of patients on HAART who achieved plasma HIV RNA levels below the limit of detection (50 copies/ml), transient relapses of HIV RNA levels ("blips") are observed. To determine whether relapses of plasma HIV RNA during HAART are associated with development of drug resistance. Plasma samples from 15 patients with a transient viral load relapse during HAART were studied. All regimens contained lamivudine (3TC). We used an ultrasensitive sequence approach to analyze the presence of drug resistance mutations during the relapse. The median plasma HIV RNA load of the relapse was 76 copies/ml (range 50-1239). In 11 of 15 cases, a genotype of HIV could be obtained. Mutations in the RT and protease gene conferring resistance to one or more drugs were observed in 8 of 11 patients, 6 of whom had the M184V substitution. During a median follow-up of 27 months after the relapse, plasma HIV RNA levels remained undetectable in 13 of 15 patients. Plasma HIV RNA blips during HAART can be associated with selection of drug-resistant HIV. This indicates that viral replication may occur during HAART, probably caused by a temporary decrease in active drug concentrations. A blip containing only wild-type virus is not necessarily caused by viral replication. In this situation the raise of HIV RNA could also originate from release of wild-type viruses, caused by activation of the latent virus reservoir. Independent of the mechanism, blips did not preclude successful inhibition of viral replication during 2-year follow-up in the majority of these cases.

Transient Relapses (“Blips”) of Plasma HIV RNA Levels During HAART Are Associated With Drug Resistance

Introduction: In a large number of patients on HAART who achieved plasma HIV RNA levels below the limit of detection (50 copies/ml), transient relapses of HIV RNA levels (“blips”) are observed. Objective: To determine whether relapses of plasma HIV RNA during HAART are associated with development of drug resistance. Methods: Plasma samples from 15 patients with a transient viral load relapse during HAART were studied. All regimens contained lamivudine (3TC). We used an ultrasensitive sequence approach to analyze the presence of drug resistance mutations during the relapse. Results: The median plasma HIV RNA load of the relapse was 76 copies/ml (range 50-1239). In 11 of 15 cases, a genotype of HIV could be obtained. Mutations in the RT and protease gene conferring resistance to one or more drugs were observed in 8 of 11 patients, 6 of whom had the M184V substitution. During a median follow-up of 27 months after the relapse, plasma HIV RNA levels remained undetectable in 13 of 15 patients. Conclusions: Plasma HIV RNA blips during HAART can be associated with selection of drug-resistant HIV. This indicates that viral replication may occur during HAART, probably caused by a temporary decrease in active drug concentrations. A blip containing only wild-type virus is not necessarily caused by viral replication. In this situation the raise of HIV RNA could also originate from release of wild-type viruses, caused by activation of the latent virus reservoir. Independent of the mechanism, blips did not preclude successful inhibition of viral replication during 2-year follow-up in the majority of these cases.