SUMMARY: Daily treatment with the anti-herpes drug valganciclovir for 8 weeks led to a significant reduction in CD8 T-cell immune activation in HIV positive people coinfected with cytomegalovirus (CMV), researchers reported at the 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010) last month in San Francisco. C-reactive protein levels appeared to decline, but other inflammation biomarkers remained stable.

By Liz Highleyman

Immune activation and inflammation is increasingly recognized as a potential contributor to non-AIDS conditions in people with HIV, including those on antiretroviral therapy (ART) with undetectable HIV viral load. As such, researchers are exploring the benefits of anti-inflammatory and immune-dampening therapies.

Cytomegalovirus, a member of the herpesvirus family, is a common latent infection in both HIV positive and HIV negative people. Responsible for sight-threatening retinitis in the pre-ART era, it typically does not cause symptomatic illness as long as immune function remains relatively intact. But CMV does trigger systemic immune activation, characterized by CD8 T-cells bearing the CD38 and HLA-DR markers.

Peter Hunt from the University of California at San Francisco and colleagues previously reported that people with HIV often have a high percentage of chronically activated CD8 T-cells, and that immune activation is associated with poor CD4 cell recovery after starting ART.

In the study presented at CROI, the researchers hypothesized that treating asymptomatic CMV coinfection might decrease T-cell activation in this setting, potentially providing an immunologic benefit.

This small pilot study included 30 asymptomatic HIV and CMV positive participants with a high percentage of CD38 HLA-DR CD8 T-cells. They had been on stable combination ART for more than 1 year with suboptimal CD4 cell recovery (< 350 cells/mm3). Most (93%) were men, the median age was 49 years, 70% had HIV viral load < 75 copies/mL, but the median CD4 count was just 190 cells/mm3.

Participants were randomly assigned (1:1) to receive either 900 mg/day valganciclovir or placebo for 8 weeks, followed by a 4-week washout period. Changes in percentage of activated T-cells, CMV shedding, and inflammatory biomarkers were assessed every 4 weeks.

Results

	At baseline, 40% of participants had detectable CMV DNA in their saliva, plasma, or semen.
	None of the patients receiving valganciclovir showed detectable CMV DNA at weeks 4, 8, or 12, compared with 44% of placebo recipients.
	At baseline, the median percentage of activated CD8 T-cells was 20% in both arms.
	In the valganciclovir arm, CD8 cell activation decreased by 4.1% at week 12, a relative reduction of 20%.
	CD8 cell activation remained below the baseline level after the 4-week washout period in the valganciclovir group.
	Compared with participants in the placebo arm, those receiving valganciclovir showed significantly greater reductions in CD8 cell activation at weeks 8 and 12.
	These differences remained significant when restricting the analysis to patients with undetectable plasma HIV RNA.
	High-sensitivity C-reactive protein (CRP) plasma levels appears to decline in the valganciclovir arm by week 8, while remaining stable in the placebo arm.
	However, plasma levels of other inflammatory, cardiovascular, and kidney function biomarkers including interleukin 6 (IL-6), D-dimer, and cystatin C did not differ between the 2 groups.
	There were also no differences in CD4 T-cell count, percentage of activated CD4 T-cells, or plasma HIV viral load.
	Valganciclovir was well-tolerated overall, with no evidence of treatment-related toxicity including anemia, neutropenia, or kidney dysfunction.

These findings led the researchers to conclude, "Valganciclovir durably suppresses CMV replication and CD8+ T-cell activation in HIV-infected patients with poor CD4 recovery during ART."

"This reduction in CD8 activation does not appear to be mediated by a direct effect on HIV replication, but appears to be the result of reductions in CMV (or other herpesvirus) replication," they continued. "Thus, CMV (and possibly other herpesviruses) appears to be a major determinant of CD8+ T-cell activation during antiretroviral therapy."

"Given the potential impact of inflammation and immune activation on clinical outcomes, and the potential role of CMV in cardiovascular disease, T-cell senescence, and aging, strategies to reduce CMV replication in HIV-infected individuals are worth pursuing in larger trials," they recommended.

Univ of California, San Francisco, CA; Univ of Vermont, Colchester, VT; Univ of Washington, Seattle, WA.

3/5/10

Reference
P Hunt, J Martin, E Sinclair, and others. Valganciclovir Reduces CD8+ T Cell Activation among HIV-infected Patients with Suboptimal CD4+ T Cell Recovery during ART. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. (Abstract 380).