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CROI 2009: Treatment Intensification with Raltegravir (Isentress) Does Not Eradicate Residual HIV

Effective combination antiretroviral therapy can reduce HIV viral load to an undetectable level in the blood using standard tests, but it does not completely eradicate the virus from the body. As Robert Siliciano of Johns Hopkins School of Medicine discussed in a plenary address at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal, experts have long debated whether residual HIV is the result of continuing low-level viral replication or release of virus from stable reservoir sites.

If residual HIV viremia is due to ongoing replication despite HAART, adding more drugs to a regimen -- in particular those that target different stages of the HIV lifecycle -- might lead to eradication. Two research teams presented studies looking at whether the newly approved integrase inhibitor raltegravir (Isentress) could further reduce HIV levels.

Study 1

In the first study, Javier Martinez-Picado, Maria Jose Buzon, and colleagues evaluated levels of proviral DNA following raltegravir treatment intensification. A "provirus" refers to viral genetic material integrated into the chromosomes of a host cell; this DNA serves as a "blueprint" for producing new virus particles.

The INTEGRAL pilot study included 65 individuals with plasma HIV RNA < 50 copies/mL for at least 1 year. About one-third (21 patients) were randomly assigned to stay on their current standard HAART regimen consisting of 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI), while 44 were assigned to intensify therapy by adding raltegravir.

Viral DNA was extracted from peripheral blood mononuclear cells (PBMCs) for analysis at weeks 0, 2, 4, and 12.

Results

• All patients maintained undetectable plasma HIV RNA (<50 copies/mL) and had stable CD4 cell counts during the study period.
• Total and proviral HIV DNA levels did not change significantly after treatment intensification.
• However, patients in the intensification arm experienced a significant increase in episomal HIV DNA -- that is, DNA existing outside of a host cell chromosome -- at week 2.
• This increase was transient, and was no longer evident by week 4.

"Our results indicate that de novo viral infection continues in the face of HAART," the investigators concluded.

After raltegravir was added, they suggested, genetic material produced during viral replication was prevented from integrating into a host cell's chromosomes to direct production of new viral proteins, but instead took the form of episomes. As to whether this has any clinical relevance, presenter Martinez-Picado said "the jury is still out."

"The lack of any fluctuation in total and proviral DNA upon intensification reinforces the notion that the majority of viral DNA in patients is archival and non-dynamic," the researchers added.

Study 2

In the second study, Joseph Jones from the University of Pittsburgh and colleagues assessed residual HIV viremia in 10 patients (all but 1 men) on PI- or NNRTI-based HAART who had been treated for 9 years on average and had viral load < 50 copies/mL for at least 1 year.

All participants intensified therapy by adding 400 mg twice-daily raltegravir to their current regimen for 30 days. Using a sensitive single copy assay, the investigators measured HIV RNA before, during, and after intensification.

Results

• Median plasma HIV RNA during raltegravir intensification was not significantly different from the pre-intensification level.
• No significant decreases in HIV viral load were observed during treatment intensification in any individual patient.
• Drug intensification was well tolerated with no reported adverse events.
• The researchers concluded that treatment intensification with raltegravir for 4 weeks had "no detectable effect on level of persistent viremia."

"These results are inconsistent with the hypothesis that persistent viremia results from ongoing, complete cycles of viral replication," they added. "New therapeutic approaches will be required to eliminate HIV-1 reservoirs."

Overview

In his plenary discussion, Siliciano said that treatment intensification studies such as these support the hypothesis that residual HIV is due to release from stable reservoir sites, not continued replication despite the presence of HAART.

"We have reached the theoretical limit of antiretroviral therapy," he concluded. "In an adherent patient, the drugs we have now can completely stop the virus from replicating."

Further evidence comes from studies showing that residual virus is genetically similar, and does not exhibit evolutionary changes or resistance mutations, as would be expected with ongoing replication. "Transcriptionally silent" HIV genomes in latent cells, he said, "allows virus to persist as information."

Latent or resting CD4 T-cells are known reservoir site for HIV, but recent studies indicate that a majority of residual virus arises from an additional, not-yet-identified source, which Siliciano suggested might be progenitor cells in the monocyte-macrophage lineage.

Given the disappointing results of treatment intensification studies, Silciano concluded that, "Progress toward eradication of the infection will require novel approaches to target the stable reservoirs that persist even when viral replication is completely halted."

3/03/09

Reference

M Buzon, J Llibre, J Gatell, and others. Transient increase in episomal viral cDNA following raltegravir intensification of a stable HAART regimen. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 423a.

J Jones, D McMahon, A Wiegand, and others. No decrease in residual viremia during raltegravir intensification in patients on standard ART. CROI 2009. Abstract 423b.

R Siliciano. New approaches for understanding and evaluating the efficacy of ARVs. CROI 2009. Abstract 16.