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Background:  Achieving and maintaining suppression of HIV-1 RNA levels below the limit of detection is the goal of antiretroviral therapy (ART). Unfortunately, many treated HIV-infected patients do not achieve or maintain this goal. The virologic threshold for changing ART in the setting of detectable viremia and stable CD4⁺ T-cell counts has not been established. Some studies have suggested clinical and immunologic benefits can be maintained in patients with low-level viremia on ART though the sustainability of these benefits may be limited by the accumulation of drug resistance mutations. We investigated the frequency with which new drug resistance mutations develop during prolonged low-level viremia in a group of HIV⁺ patients followed in the NIAID-CC HIV/AIDS program.

Methods:  We conducted a study of antiretroviral experienced HIV⁺ patients with stable, detectable viral replication (<10,000 copies/mL) persisting over at least 12 months with no change in ART. Viral RT and PR genotype sequences from at least 2 samples separated by at least 12 months were analyzed using commercial population-based genotypes (Visible Genetics) to quantify the development of new drug resistance mutations; phylogenetic analyses were also performed on the composite sequences. Additionally, CD4⁺ T-cell counts and HIV-1 RNA levels were assessed to identify changes in immunologic and virologic parameters over time.

Results:  We identified 45 patients with stable low-level viremia from a total of 188 viremic patients on ART (24%). Overall the patients included represented a treatment-experienced group with an average of 6 RT mutations (range 1 to 10) and 5 PR mutations (range 0 to 10) seen on initial genotyping. Genotypes were obtained an average of 819 days apart (range 370 to 1897 days). In the initial 12 patients, comparison of population genotypes obtained at the start and after at least 1 year of persistent viremia revealed no new clinically significant drug resistant mutations. Phylogenetic analysis performed on 18 genotypes from 7 of these patients showed little genetic change, with mean nucleotide divergence of 0.37% (range 0 to 1.1%) in the pro-pol region during the period of observation. Additionally, no clinically significant declines in immune parameters were noted in this group.

Conclusion:  In a select group of patients, stable low-level viremia was not associated with accumulation of new clinically significant resistance mutations.

Keywords: drug resistance; resistance evolution; HIV-1 viremia