CROI 2013: Antiretroviral Therapy Intensification plus IL-7 Does Not Reduce HIV Reservoir

 An intensive antiretroviral regimen containing raltegravir (Isentress) and maraviroc (Selzentry) plus the immune-modulator interleukin 7 (IL-7) was unable to decrease the amount of residual HIV in resting CD4 T-cells, investigators with the ERAMUNE-01 trial reported at the recent 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta.

As part of a renewed interest in finding a functional cure for HIV, researchers have tried various strategies including intensified antiretroviral therapy (ART), agents that awaken resting T-cells harboring latent virus, and stimulating natural immune responses against HIV. Many experts think a combined approach is likely to be most effective.

The multinational Phase 2 ERAMUNE-01 trial evaluated a combination of intensified ART plus the cytokine IL-7. Most studies have shown that simply adding more antiretroviral drugs is not enough to eliminate HIV. But researchers hypothesized that including IL-7 to activate resting T-cells might help "flush out" latent virus, causing it to begin replicating and thereby become susceptible to the potent antiretroviral combination.

 

 

The study included 29 people with suppressed HIV viral load (<50 copies/mL) on standard ART at baseline. More than 90% were men and the mean age was 47 years. They had been on ART for 12 years on average, with viral suppression for about 2 years. The median CD4 count was approximately 600 cells/mm³, but the nadir (lowest-ever level) was about 250 cells/mm³. The median HIV proviral DNA level was about 350 copies per million peripheral blood mononuclear cells (PBMCs).

All participants added raltegravir and maraviroc to their current regimen, and after 8 weeks they were randomly assigned (1:1) to either remain on the intensified ART regimen alone for 56 weeks or to also receive 3 injections of IL-7 at weeks 8, 9, and 10.

Results

• No decrease in the size of the HIV reservoir was observed in any participants.
• No change in HIV DNA level was observed in the arm receiving ART intensification alone over 56 weeks.
• The mean cell-associated HIV DNA level increased transiently in the IL-7 arm at week 12, but by week 56 it did not differ significantly from baseline.
• The estimated HIV DNA level in CD4 cells levels followed the same dynamics, while mean HIV DNA levels in whole blood were higher both at week 12 and week 56 in the IL-6 arm.
• CD4 cell counts rose significantly more in the IL-7 arm and remained higher at week 56.
• This was largely attributable to an increase in the proportion of central memory T-cells, while other T-cell subsets remained stable or decreased.
• IL-7 also induced a major expansion of CD8 T-cells.
• ART intensification alone was associated with a slight increase in CD4/CD8 ratio, but this effect was not seen in the IL-7 arm.
• Both CD4 and CD8 cell activation and immune senescence markers decreased.
• 3 serious adverse events were reported, all of which resolved without further consequences.

"Intensification with maraviroc plus raltegravir with or without IL-7 was not able to decrease the total HIV-DNA reservoir in peripheral blood cells," the researchers concluded.

However, they added, "Whether the massive CD4 cell proliferation induced by IL-7 could have masked the reactivation of HIV transcription from some latently infected cells targeted by IL-7" requires further investigation.

4/10/13

Reference

C Katlama, S Lambert, L Assoumou, et al. Impact of Interleukin-7 and Raltegravir + Maraviroc Intensification on Total HIV DNA Reservoir: Results from ERAMUNE 01. 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013). Atlanta, March 3-6, 2013. Abstract 170aLB.