DESCRIPTION (provided by applicant): Antiretroviral resistance in antiretroviral therapy (ART) na ve HIV-infected individuals is a growing problem. As many as 18% of treatment-na ve patients in the United States are infected with HIV-1 with resistance to at least one antiretroviral drug class. Resistance testing prior to initiating ART is recommended by widely followed treatment guidelines; however, the population-based genotypic resistance testing (PBGRT) in clinical use can detect resistant viral variants only if they constitute at least 20% of the circulating viral population. This brings up the distinct and worrisome possibility, supported by recent preliminary findings, that undetected resistance that pre-dates the initiation of ART can compromise the eventual efficacy of ART. The hypothesis behind this proposal is that the prevalence of non-nucleoside reverse transcriptase inhibitor (NNRTI) and nucleoside reverse transcriptase inhibitor (NRTI) resistant-HIV in treatment na ve individuals is higher than what is detected by PBGRT as it is currently used. This study will demonstrate that it is possible to increase the rate of detection of pre-existing antiretroviral resistance in individuals who are initiating ART. This will be accomplished through the use of PBGRT before and 7 days after starting NNRTI-NRTI ART. It is expected that by day 7, replication of wild-type, drug susceptible HIV-1 variants will have been suppressed by therapy whereas drug-resistant variants, under the selective pressure of therapy, will have a competitive advantage over drug-susceptible ones and will have increased both in absolute number and as a proportion of the circulating pool of HIV-1 variants. This "enrichment" of the resistant variants will allow for their successful detection through the same PBGRT that failed to detect them prior to initiating ART. These findings will be confirmed by performing more sensitive resistance assays at the same time points: a clonal analysis and the recently developed parallel allele-specific sequencing (PASS) assay. A limited assessment of the association between the presence of NNRTI-NRTI resistance and the short-term (3-month) response to NNRTI- NRTI therapy will also be performed. The latter will provide a general sense of the virological response to ART of subjects with unrecognized resistance compared to the response of subjects without resistance. Identification of a higher prevalence of antiretroviral resistance among treatment-na ve patients than what is currently recognized is an important public health issue. It brings into question the efficacy of current resistance detection strategies and raises the possibility that new methodologies or techniques are needed. Most importantly, unrecognized resistance might impair the efficacy of antiretroviral therapy, and its timely identification could lead to better treatment outcomes.
|Effective start/end date||9/24/07 → 8/31/10|
- National Institutes of Health: $189,476.00
- National Institutes of Health: $244,646.00