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Raltegravir Intensification Did Not Reduce
Residual Viremia PLoS Medicine published
  "In this randomized, cross-over study, raltegravir intensification of ART for 12 weeks did not demonstrably reduce low-level residual viremia in HIV-positive patients receiving standard ART. It is possible that 12 weeks is too short a time to see an effect of raltegravir on residual viremia. Furthermore, although this is one of the biggest trials of this type done to date, it might be that insufficient patients were included in the trial to detect a subtle effect of raltegravir on residual viremia. Nevertheless, these findings argue against the hypothesis that residual viremia arises from ongoing cycles of viral replication and the infection of new cells. Instead, they suggest that residual viremia might be due to the release of HIV from stable reservoirs. If so, new therapeutic strategies designed to eliminate these reservoirs of latently infected cells will be required to cure HIV infection."
"This study also allowed us to examine the relationship between residual viremia and T cell a ctivation. Persistent viremia might explain the observation that T c ell activation remains higher in patients who are receiving therapy and have HIV-1 RNA levels of <50 copies/mL than in uninfected individuals [17]. This persistent immune activation may have important clinical consequences; for example, persistent T cell activation is associated with lower CD4 cell count increases in patients receiving ART [17],[18],[19] and may contribute to accelerated atherosclerosis [20] or premature immunosenescence. If residual viremia is inducing T cell activation, one might expect a correlation between the level of viremia and extent of activation. However, in those participants who had detectable residual viremia, we did not find any associations between HIV-1 RNA level at study entry and markers of T cell activation. In addition, raltegravir intensification did not clearly decrease immune activation in the blood, as measured by the percentage of T cells that express CD38 and HLA-DR."

PLoS Medicine: The Effect of Raltegravir Intensification on ...
The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV- Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial ...
Intensified HIV Therapy Fails to Eradicate Virus
MedPage Today
Published: August 10, 2010
Action Points
* Explain to interested patients that adding raltegravir (Isentress) to a successful anti-HIV regimen did not effect residual viremia.
* Note that this suggests that residual viremia does not result from continuing cycles of replication and infection of cells and that eradicating HIV infection will require new treatments aimed at depleting reservoirs of HIV-infected, long-lived cells.
In patients whose HIV is already well-controlled, intensifying the therapy has no apparent effect on residual viremia, researchers said.
In a randomized trial, low levels of HIV remained detectable even after adding the integrase inhibitor raltegravir (Isentress) to a successful anti-HIV regimen, according to Rajesh Gandhi, MD, of Massachusetts General Hospital in Boston, and colleagues.
The study suggests that the residual viremia seen even in patients whose virus is below the conventional level of detection does not result from continuing cycles of replication and infection of cells, Gandhi and colleagues said online in PLoS Medicine.
Because of that, the researchers argued, it is likely that eradicating HIV infection will require "new therapeutic strategies" aimed at depleting reservoirs of HIV-infected, long-lived cells.
Although modern treatments can reduce levels of HIV to below 40-50 copies of viral RNA per milliliter of plasma -- the limit of detectability for commercially available tests -- they don't eliminate the virus. Instead, very sensitive tests -- so-called "single copy assays" -- show that most people on treatment have at least one copy of HIV RNA per milliliter of plasma.
The origin of that residual viremia -- enough to completely revive the infection if treatment is stopped -- has been controversial.
It could arise from viral replication, in which case intensifying treatment should reduce it, the researchers noted. But if it arises from HIV release from stable reservoirs -- such as latently infected resting immune system cells -- intensifying treatment should have no effect.
To test the issue, Gandhi and colleagues enrolled 53 HIV-positive people on treatment and whose plasma HIV RNA was undetectable on commercial tests, but who also had detectable virus on the single-copy assay.
They were randomly assigned to get either raltegravir or a placebo in addition to their normal treatment for 12 weeks, before being crossed over to the other therapy for 12 more weeks. The primary endpoint was plasma HIV RNA by single-copy assay averaged in weeks 10 to 12, compared between treatment groups.
When the trial started, participants had an average plasma HIV RNA level of 1.7 copies per milliliter.
At study end, the primary endpoint did not differ significantly between those getting raltegravir and those on placebo. The median was 1.2 copies per milliliter in the raltegravir arm versus 1.7 copies in the placebo arm, with a significance level of P=0.55 on the Wilcoxon rank sum test.
There was also no difference in change from baseline between the groups. The median change in the raltegravir group was minus 0.2 copies, versus minus 0.1 in the placebo arm, a difference whose significance level was P=0.71
The researchers said there was also no significant change in HIV RNA levels from weeks 10 to 12 to weeks 22 to 24 after patients crossed over to the other arm.
CD4 cell counts increased more from baseline to week 12 in the raltegravir-intensified group -- a gain of 42 cells per cubic millimeter of plasma versus a loss of 44 cells, a difference whose significance level was P=0.082.
The CD4 cell count change reversed after the cross-over, the researchers wrote, and was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood.
Although the study was a randomized placebo-controlled trial, it may not have been long enough to show an effect, the researchers noted. However, they argued, it's unlikely that ongoing replication would occur only in long-lived cells, so that blocking infection of short-lived cells by adding raltegravir should have had a noticeable effect if replication were taking place.
They also noted that the extremely low levels of viremia at baseline limited the power of the study to identify declines in HIV, so that the results "do not completely exclude the possibility" that replication contributes part of the viremia.
The study had support from the National Institute of Allergy and Infectious Diseases, the NIH, the F.M. Kirby Foundation, and Merck Sharp & Dohme, Corp.
Gandhi reported financial links with Tibotec and Gilead. Other authors also reported links with a range of pharmaceutical manufacturers.
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