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Intensifying Standard Regimens Does Not Lower Residual Plasma HIV RNA
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XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
Adding efavirenz or lopinavir/ritonavir to an already suppressive standard regimen did not further reduce residual low levels of HIV RNA in plasma, according to results of a study at the US National Cancer Institute (NCI) HIV Drug Resistance Program [1]. In fact, average plasma loads rose slightly after intensification. The results contradict findings of a similar earlier study and raise doubts about one theory on the source of residual viremia.
Frank Maldarelli and colleagues studied 5 men and 1 woman whose plasma load lay below 50 copies for more than 1 year with a standard regimen including two nucleosides and either one nonnucleoside or one protease inhibitor (PI). The study goal was to learn whether ongoing low-level viremia reflects active cycles of HIV replication or represents a slow drip from long-lived infected cells.
A single-copy assay detected more than 1 HIV RNA copy in all 6 people before intensification, 4 of them while taking a PI combination and 2 while taking a nonnucleoside. The PI group added efavirenz for 30 days, and the nonnucleoside group added lopinavir/ritonavir. No one who added efavirenz had taken a nonnucleoside earlier, and no one who added lopinavir had taken a PI.
The 6 study participants had been infected for an average 9 years (range 4 to 16 years) and had taken combination antiretroviral therapy for an average 4 years (range 1 to 10 years). Before adding efavirenz or lopinavir, the group averaged a plasma HIV RNA load of 4.5 copies, similar to levels measured in earlier studies of residual viremia [2].
Average residual RNA rose to 5.3 copies during intensification and settled at 5.2 copies after intensification. These changes from before intensification were not statistically significant (P = 0.76 and 0.79) and could represent biological or assay variation. Adding the extra drugs for 1 month had no toxic consequences and did not affect CD4 counts.
Measuring residual viremia in another 25 people with well-controlled HIV replication, Maldarelli found that 20 (80%) had intra-assay variability within expected limits. That finding, he proposed, suggests viremia variation in most samples is random. The NCI team also used the single-copy assay to track low-level virus in 14 people who gave two to six samples over the course of a year or more. Eight of those 14 (57%) had variation within statistical 95% confidence limits, which indicated random variation in viremia. Five people (36%) had day-to-day variation beyond 95% confidence limits, indicating biological variation. One person (7%) had within-day variation greater than 95% confidence limits, suggesting that assay variation exceeded random variation.
Maldarelli concluded that the failure of intensification to lower residual viremia "is inconsistent with the idea that persistent viremia results from ongoing, complete cycles of viral replication." Rather, long-lived chronically infected cells are the probable source of persistent viremia.
San Francisco clinician Steven Deeks challenged those conclusions, pointing to a similarly designed uncontrolled study in which 5 patients with viremia suppressed for more than 5 years added abacavir [3]. Four of these 5 people saw their low-level HIV RNA drop farther--quickly--right after they started abacavir. That result led Diane Havlir and colleagues to a conclusion opposite Maldarelli's--that "productive infection contributes to residual ongoing viremia and can be inhibited with therapy intensification."
Maldarelli suggested that the differing results reflect different patient populations. Havlir's patients, he proposed, had not yet shut down viral replication as tightly as they could have with a standard triple regimen because three of the four rapid responders had blips above 50 copies. None of Maldarelli's patients had blips. With the AIDS Clinical Trials Group, Maldrelli plans to repeat the study adding the integrase inhibitor raltegravir, a potent drug with a different mechanism of action.
References
1. Maldarelli F, Wiegand A, Palmer S, et al. Intensification with efavirenz or lopinavir/ritonavir does not reduce residual HIV-1 viraemia in patients on standard antiretroviral therapy. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 72.
2. Maldarelli F, Palmer S, King MS, et al. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog. 2007;3(4):e46.
3. Havlir DV, Strain MC, Clerici M, et al. Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years. J Virol. 2003 Oct;77(20):11212-11219 (http://jvi.asm.org/cgi/reprint/77/20/11212).
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