SUMMARY: Adding the CCR5 antagonist maraviroc (Selzentry) to an antiretroviral regimen that is already fully suppressing HIV viral load did not produce larger CD4 cell gains among people whose immune recovery was stalled, according to a small study presented at the 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010) last week in San Francisco. Maraviroc did, however, appear to dampen immune activation.

By Liz Highleyman

A proportion of HIV positive people who start antiretroviral therapy (ART) do not achieve adequate immune recovery even though their viral load becomes undetectable, a phenomenon known as discordant response.

Some clinical trials of maraviroc indicated that the drug produced larger and faster CD4 cell gains than placebo or competing regimens, although the primary end-points of these studies involved virological suppression not immune restoration.

To learn more about this issue, Timothy Wilkin from Weill Cornell Medical College and colleagues performed a small study looking at the effect of ART intensification with maraviroc on CD4 counts in patients with suboptimal CD4 cell recovery.

ACTG 5256 was a single-arm pilot trial that included 34 participants with a CD4 count < 250 cells/mm3, a calculated CD4 slope (rate of decline) between -20 and +20 cells/mm3 per year, and undetectable plasma viral load for 48 weeks prior to study entry.

All but 2 of the participants were men, about 70% were white, and the median age was 50 years; notably, this is older than the typical average age of participants in HIV clinical trials, reflecting the tendency toward poorer immune recovery among older patients. The median duration of viral load suppression on ART was 3 years prior to starting the study.

Participants added maraviroc to their existing virologically suppressive ART regimen for 24 weeks. The primary end-point was the change in averaged CD4 counts from baseline to week 22-24.

The researchers also performed extensive immuno-phenotyping -- or characterization of immune cells and the chemical messengers they produce -- at baseline and at the end of maraviroc treatment.

Results

	At baseline, the median CD4 count was only 153 cells/mm3, despite suppressive therapy, with a slope of +5.8 cells/mm3 per year.
	2 participants discontinued maraviroc due to virological failure and were excluded as per protocol (which only allowed people with viral suppression).
	The mean increase in CD4 count from baseline to week 22-24 was 12 cells/mm3.
	Only 2 participants achieved a gain of 50 cells/mm3 or more.
	CD4 cell slope increased to +24.7 cells/mm3 per year.
	A statistical analysis showed that maraviroc did not produce the expected CD4 cell increase.
	Several biomarkers of CD4 and CD8 T-cell immune activation and apoptosis ("cell suicide") decreased from baseline to week 22-24, including CD38 percentage, HLA-DR/CD38, Ki-67, and caspase 3.
	However, the CD38 changes were was not associated with a CD4 cell gain.

Based on these findings the researchers concluded, "Adding maraviroc to a suppressive antiretroviral regimen was not associated with the hypothesized increase in CD4 counts."

However they noted, "Maraviroc intensification was associated with decreased immune activation" as shown by reduced CD38 percentage and HLA-DR/CD38, and improvement in markers of apoptosis."

"The clinical significance of these findings is unknown," they continued. "Further studies of CCR5 antagonists to dampen immune activation associated with HIV infection are warranted."

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

2/23/10

Reference
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 & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. (Abstract 285).