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Session 72 Poster Session Treatment Interruption Session Time: 4:30-6:30 pm Room 4E-F

532-M. Drug-Resistant HIV-1 Variants Selected in Children with Intermittent Low-Level Plasma HIV-1 RNA (Blips) during HAART N. H. Tobin*1, Y. Wang1, A. J. Melvin1, S. DeVange1, J. McKernan1, G. M. Ellis1, K. M. Mohan1, G. Pepper1, L. Heath1, W. E. Naugler1, I. A. Beck1, P. Lewis2, G. H. Learn1, J. Mullins1, and L. M. Frenkel1 1Univ. Washington, Seattle and 2Oregon Hlth. Sci. Univ., Portland Background: The significance of intermittent low-level viremia (50-500 copies/mL) in HIV-infected patients on therapy is unknown. Published data suggest the transcription of archival virus only, however, our studies demonstrate the selection of drug-resistant HIV-1 variants during effective HAART. Methods: To evaluate the replicative activity of HIV-1 when plasma RNA levels were detected between 50 and 250 copies/mL, the regions of pol encoding PRO and RT and env were amplified from the plasma. Phylogenetic analyses were conducted to reveal relationships of plasma virus to PBMC viral populations from over the course of infection. 10 or more amplicons were sequenced directly from end point dilutions of specimens from multiple time points prior to and during 3-5 years of HAART. Results: 8 children, for whom viral evolution had been characterized since near the time of primary infection, had 19 episodes of intermittent viremia between 50 and 236 copies/mL (median 68). 4 children had only 1 "blip" and 4 children had 2 or more. In phylogenetic analysis, plasma virus grouped with PBMC virus from early infection as well as recently evolved, increasingly drug-resistant virus. For example, a patient with 1 blip of 104 copies/mL during 5 years of effective HAART had plasma virus characteristic of early infection. In contrast another patient with 10 blips between 50-101 copies/mL and 12 RNA determinations <50 copies/mL during 5.5 years of HAART selected new mutations with genotypic resistance to all 3 classes of antiretrovirals. In addition, an increasing proportion of his PBMCs became infected with highly drug-resistant virus even though his plasma RNA was suppressed and continues to be <50 after multiple treatment intensifications. Conclusions: Single low-level blips did not result in measurable new mutations and this RNA appeared to reflect transcription of latent virus, suggesting insignificant infection of new cells and minimal evidence of selective pressure. Drug-resistant virus was selected in association with more frequent blips. The clinical significance of plasma blips appears to depend not only their frequency but on the selective pressure of the HAART regimen, with potent therapy limiting outgrowth of fit virus.

©2002 9th Conference on Retroviruses and Opportunistic Infections