[27] SIGNIFICANCE OF INTERMITTENT LOW-LEVEL PLASMA HIV-1 RNA (BLIPS) DURING HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

5th International Workshop on HIV Drug Resistance & Treatment Strategies

4-8 June 2001, Scottsdale, Arizona

[TITLE:] SIGNIFICANCE OF INTERMITTENT LOW-LEVEL PLASMA HIV-1 RNA (BLIPS) DURING HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

[AUTHOR(S):] NH Tobin¹, Y Wang¹, AJ Melvin¹, S DeVange¹, J McKernan¹, GM Ellis¹, KM Mohan¹, G Pepper¹, L Heath¹, WE Naugler1, I Beck¹, P Lewis², GH Learn¹, JI Mullins¹ and LM Frenkel¹
¹ University of Washington, Seattle, Wash., USA; and ² Oregon Health Sciences University, Portland, Oreg., USA
Antivir Ther. 2001;6 Suppl 1:22

HYPOTHESIS: Low-level intermittent viraemia reflects transcription of latent virus, while greater levels reflect complete cycles of viral replication with selection of new resistance mutations.

METHODS: To evaluate the source and replicative activity of HIV-1 when plasma RNA levels were detected between >50 and <500 copies/ml, pol and env were amplified from the so called ‘viral blips’ and phylogenetic analyses conducted to reveal relationships to peripheral blood mononuclear cell (PBMC) viral populations from over the course of infection. Ten or more amplicons were sequenced directly from multiple time points prior to and during 3–5 years of highly active antiretroviral therapy (HAART), using dilutions of PBMC and plasma with a high probability of having only one HIV-1 template. Plasma HIV-1 RNA was measured every 2–3 months after initiation of HAART using the Amplicor Monitor 1.0 through 1997 and the Ultrasensitive Amplicor assay (Roche) from 1998 to 2001.

RESULTS: Seven children, for whom viral evolution had been characterized since near the time of primary infection, had intermittent viraemia between 50 and 236 copies/ml, median 68, on one or more occasions. In phylogenetic analysis plasma virus grouped with PBMC virus from early in infection as well as recently evolved, increasingly drug-resistant virus. For example, a patient with one blip of 104 copies/ml during 4.3 years of effective HAART had plasma virus characteristic of early infection. In contrast another patient with eight blips between 50–101 copies/ml and 11 RNA determinations <50 copies/ml during 5 years of HAART developed new mutations with genotypic resistance to all three classes of antiretrovirals, however, his plasma RNA was suppressed and continues to be <50 copies/ml after multiple treatment intensifications.

CONCLUSIONS: Infrequent low-level blips do not result in measurable new mutations and this RNA appears to reflect transcription of latent virus, with insignificant infection of new cells and with 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 magnitude and frequency but on the selective pressure of the HAART regimen, with potent therapy limiting outgrowth of fit virus.

PRESENTING AUTHOR: NH Tobin

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