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HIV latency and persistent, low-level viremia
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12th CROI Feb 2005
Reported for NATAP by David Margolis, MD
Univ of Texas, Southwestern Medical Center Dallas; VA Dallas; ACTG
Sarah Palmer presented work from the NCI Frederick group, using a single-copy HIV RNA assay that she has previously described (abstr. 163). Using samples from the Abbott 863 Kaletra study the group assayed low-level viremia in subject who received Kaletra or nelfinavir with D4T/3TC in the trial and consistently had <50 copies/ml of HIV RNA. In both groups studied, about 75% of the patients had detectable low-level viremia ranging from 1 to 43 HIV RNA copies/mL. The distribution of HIV RNA levels was identical in all groups, with a mean of 3.2 copies/mL, and was independent of the treatment regimen. Although no difference was observed based on treatment regimen, despite the fact that the Kaletra regimen was presumably more potent, there was a highly significant association (p < 0.001) between viremia at week 60 and baseline RNA levels. In these samples, and other samples from NIH clinical center studies of stably suppressed patients, low-level persistent viremia appeared to decay very slowly (half-life estimated to be 88 weeks). This pattern was seen with both PI regimens and with NNRTI-based therapy. Palmer and coworkers cannot say where this persistent viremia originates, but they hypothesize that it is the product of random, occasional activation of HIV from within the latently infected resting CD4 cell pool.
Bob Siliciano discussed the latent reservoir and current therapy (abstr. 179), and reported similar findings. Dr. Siliciano agreed that in patients on suppressive HAART regimens, there is always a low level of viremia that represents the sum of residual ongoing replication and virus release from stable reservoirs including the reservoir in resting memory CD4+ T cells and a newly identified "second reservoir". The location of this second reservoir is still mysterious. The best that HAART can do is to suppress viremia to a new steady state called the "release point" which represents the level of viruses released from stable reservoirs when new cycles of replication are completely stopped by HAART. Thus the goal of therapy should be to suppress viremia to this release point. For most patients, the release point is somewhat below 50 copies/ml. In most patients on HAART, there are episodes of intermittently detectable viremia ("blips"). A detailed analysis of blips recently published by his group in JAMA utilized sampling every 2-3 days. Blips were common, short in duration, low in magnitude (<200 copies), and represent random biological and statistical variation around a mean level of viremia below 50 copies/ml. Ultrasensitive genotyping indicates that no new drug resistance mutations appeared before, during or immediately after blips.
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