Daily treatment with valganciclovir reduces immune activation in HIV positive people with cytomegalovirus

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.

By Liz Highleyman

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).

HIVandHepatitis.com

http://www.hivandhepatitis.com/

http://www.hivandhepatitis.com/2010_conference/croi/docs/0305_2010_d.html

More...