SUMMARY: The CCR5 antagonist maraviroc (Selzentry) was associated with reduced immune activation and inflammation in 3 studies presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010) last month in San Francisco. The integrase inhibitor raltegravir (Isentress) may also have some inflammation-dampening effect, but 3 recent studies produced mixed results.

By Liz Highleyman

A growing body of evidence indicates that inflammation and excessive immune activation may play a role in increased risk of non-AIDS conditions among people with HIV, as well as progression of HIV/AIDS and death. To address this issue, researchers are exploring a variety of anti-inflammatory and immune-dampening therapies.

Maraviroc

Pivotal clinical trials of maraviroc showed that the drug produced larger CD4 cell gains than competitors. The CCR5 co-receptor plays a role in immune response, so investigators sought to determine whether drugs like maraviroc that block CCR5 might have an effect on immune activation and inflammation.

Timothy Wilkin and fellow investigators with the ACTG 5256 team (abstract 285) conducted a small pilot study looking at the effect of ART intensification with maraviroc on CD4 gains in 34 patients with suboptimal CD4 cell recovery despite good viral suppression.

The researchers found, as in previous studies, that adding maraviroc to an existing suppressive combination regimen for 24 weeks did not eradicate HIV (according to ultra-sensitive tests). In this analysis, however, maraviroc intensification also did not significantly increase CD4 counts.

But levels of several biomarkers of CD4 and CD8 T-cell activation and apoptosis ("cell suicide") decreased from baseline to week 24, including a reduction in the number and percentage of T-cells with CD38+HLA-DR+ markers.

"Maraviroc intensification was associated with decreased immune activation as shown by reduced [CD38+ percentage] and [HLA-DR+/CD38+ percentage], and improvement in markers of apoptosis," the investigators concluded, but added that "the clinical significance of these findings is unknown" and "[f]urther studies of CCR5 antagonists to dampen immune activation associated with HIV infection are warranted."

"Decreased activation did not correlate with CD4+ T-cell change suggesting that persistently low CD4+ T-cell counts in this population may not be related to ongoing immune activation," they continued. "Further studies of CCR5 antagonists to dampen immune activation associated with complications of chronic HIV infection are warranted."

A related European study by Carolina Gutiérrez and colleagues (abstract 284) looked at 9 patients who maintained viral suppression on ART for 2 years and had CD4 counts above 350 cells/mm3. In addition to finding that maraviroc appeared to speed up decay of viral reservoirs, this analysis also revealed a significant decrease in CD4 T-cell activation at week 12 (again, based on proportion of CD38+HLA-DR+ cells), but the reduction in CD8 T-cell activation did not reach statistical significance.

Looking at other measures of inflammation in a laboratory study, researchers at Sapienza University in Rome (abstract 512) found that adding maraviroc to cell samples taken from healthy HIV negative donors led to down-regulation of the chemotactic or migration-inducing activity of immune system white blood cells (e.g., neutrophils, dendritic cells, and macrophages), a key step in the inflammatory process. However, when using maraviroc at concentrations comparable to normal therapeutic doses, the drug only inhibited mature, not immature macrophages and dendritic cells.

"These data indicate that the CCR5 antagonist maraviroc has a direct effect on innate immune cells by mechanism which could be independent from anti-HIV activity," the researchers concluded. "These findings suggest that maraviroc might have a potential role in the down-regulation of HIV-associated chronic inflammation by blocking the recirculation and trafficking of macrophages and dendritic cells."

Raltegravir

Researchers also reported data from studies looking at the immunological effects of raltegravir. At least year's CROI, studies showed that raltegravir did not eradicate all traces of HIV, suggesting that residual virus is being released from a reservoir, and is not attributable to continued viral replication in the blood.

M.J. Buzon and colleagues (abstract 100LB) looked at 69 patients with viral load suppressed to < 50 copies/mL for more than 1 year who added raltegravir to their current suppressive 3-drug regimen. The researchers saw a reduction in a specific type of viral genetic material known as 2-LTR circle DNA after adding raltegravir. Participants who had detectable 2-LTR had higher levels of immune activation at baseline, but levels normalized after intensification.

"The observed normalization of immune activation in those patients suggests that active replication under [highly active ART] is a cause of aberrant immune activation rather than a consequence of it."

In a related study by Hiroyu Hatano and colleagues (abstract 101LB), 30 participants on suppressive ART with undetectable viral load for at least 1 year were randomly assigned to add raltegravir or placebo to their existing regimen for 24 weeks. In this analysis, raltegravir intensification did not have a significant effect on levels of HIV genetic material, CD4 or CD8 T-cell activation in the blood, or T-cell activation in gut lymphoid tissue.

Finally, Steven Yukl and colleagues (abstract 279) evaluated whether decreased HIV RNA and reduced immune activation might be seen in the gut tissue of patients undergoing raltegravir intensification. The intestines are a major site of CD4 cells infected with HIV, and the resulting damage to the gut lining can release bacteria, triggering a systemic inflammatory response.

This study included 7 HIV positive men with viral loads < 40 copies/mL for 3-12 years. Participants added raltegravir, raltegravir plus efavirenz (Sustiva), or raltegravir plus boosted darunavir (Prezista) to their existing regimen. At baseline, gut biopsies revealed detectable HIV DNA and RNA in the duodenum (first section of the small intestine), ileum (final section of the small intestine), colon, and rectum of most participants.

After raltegravir intensification for 12 weeks, HIV RNA did not decrease in the plasma or gut. However, there was a trend towards decreased CD4 and CD8 T-cells activation at all sites, which was greatest for CD8 cells in the ileum and peripheral blood cells.

"In suppressed patients, most HIV RNA in the plasma, peripheral blood mononuclear cells, and gut is not the result of ongoing replication that can be reduced by short-term intensification with raltegravir," the researchers concluded. "However, intensification reduced HIV RNA, reduced immune activation, and increased CD4+ T-cells in the ileum, suggesting that the ileum may support ongoing productive infection in some patients on ART, even if the contribution to plasma RNA is not discernible."

Abstract 285: Weill Cornell Medical College, New York, NY; Harvard School of Public Health, Boston, MA; Rush Univ Medical Center, Chicago, IL; Univ of Pittsburgh School of Medicine, Pittsburgh, PA; Massachusetts General Hospital, Boston, MA; Univ of California, Los Angeles, CA.

Abstract 284: Hosp Univ Ramón y Cajal, Madrid, Spain; Hosp General Univ Gregario Marañón, Madrid, Spain; Swedish Inst of Infectious Diseases Control and Karolinska Inst, Stockholm, Sweden.

Abstract 512: Sapienza Univ, Rome, Italy; Sapienza Univ, Polo Pontino, Latina, Italy.

Abstract 100LB: Fndn irsiCaixa, Badalona, Spain; Fndn Lluita contra la SIDA, Badalona, Spain; CEEISCAT, Badalona, Spain; Swedish Institute for Infectious Disease Control, Solna, Sweden; Univ of Massachusetts Medical School, Worcester, MA; ICREA, Barcelona, Spain.

Abstract 101LB: Univ of California, San Francisco, CA; Univ of California, Davis, CA; Karolinska Inst, Solna, Sweden; Blood Systems Research Institute, San Francisco, CA.

Abstract 279: San Francisco VAMC, Univ of California, San Francisco, and San Francisco General Hospital, San Francisco, CA; Univ Hospital Zurich, Switzerland.

3/16/10

References

T Wilkin, C Lalama, A Tenorio, and others. Maraviroc Intensification for Suboptimal CD4+ Cell Response Despite Sustained Virologic Suppression: ACTG 5256. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. (Abstract 285).

C Gutiérrez, L Diaz, B Hernández-Novoa, and others. Effect of the Intensification with a CCR5 Antagonist on the Decay of the HIV-1 Latent Reservoir and Residual Viremia. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. (Abstract 284).

I Sauzullo, M Lichtner, F Mengoni, and others. Effect in vitro of CCR5 Antagonists on Innate Immune System: Maraviroc Inhibits the Migration of Neutrophils, Macrophages, and DC. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. (Abstract 512).

MJ Buzon, M Massanella, J Llibre, and others. HIV-1 Replication and Immune Dynamics Are Impacted by Raltegravir Intensification of HAART-suppressed Patients. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 100LB.

H Hatano, T Hayes, V Dahl, and others. Raltegravir Intensification in Antiretroviral-treated Patients Exhibiting a Suboptimal CD4+ T Cell Response. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 101LB.

S Yukl, A Shergill, S Gianella, and others. Effect of Raltegravir-containing Intensification on HIV Burden and T Cell Activation in the Gut of HIV+ Adults on Suppressive ART. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. (Abstract 279).