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Tenofovir and Valganciclovir Reduce Inflammation in People with HIV

The antiretroviral drug tenofovir and the anti-herpes drug valganciclovir may help reduce harmful immune activation and inflammatory activity in HIV positive people.

A growing body of evidence indicates that persistent immune activation and inflammation due to chronic HIV infection contributes to a variety of non-AIDS conditions such as cardiovascular disease, and may accelerate immune cell aging and death, even in the presence of effective antiretroviral therapy (ART).

An increasing number of HIV studies are measuring markers of immune activation and inflammation, and researchers are looking at agents that might play a role in dampening excessive inflammation.

Tenofovir

As described in the April 5, 2011, Journal of Acquired Immune Deficiency Syndromes, Jesper Melchjorsen from Aarhus University Hospital Skejby in Denmark and colleagues studied the possible immune-modulating effects of 3 HIV nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): abacavir (Ziagen, also in the Trizivir and Epzicom coformulations), tenofovir (Viread, also in Truvada and Atripla), and zidovudine (AZT; Retrovir, also in Combivir and Trizivir).

The researchers evaluated the effects of these NRTIs on production of pro-inflammatory cytokines in monocytes and human peripheral blood mononuclear cells (PBMCs) in a laboratory study, focusing on the balance between interleukin 12 and 10 (IL-12 and IL-10).

To trigger inflammation, they stimulated cells with toll-like receptor (TLR) ligands, tumor necrosis factor-alfa (TNF-alfa), and the pathogens cytomegalovirus (CMV, an opportunistic infection in people with AIDS), Neisseria meningitides (bacteria that cause meningitis), Escherichia coli (bacteria that can cause gastrointestinal food poisoning), and Streptococcus pneumoniae (bacteria that cause pneumonia and other infections).

Tenofovir was found to decrease production of the cytokines IL-8 and CCL3 (also known as macrophage inflammatory protein-1-alfa) by monocytes after stimulation with TLR ligands, TNF-alfa, or live pathogens. Zidovudine, in contrast, increased production. Tenofovir also decreased CCL3 levels in human PBMCs. Tenofovir strongly reduced expression of IL-10, but increased levels of IL-12. Zidovudine did not affect either IL-10 or IL-12 levels. Abacavir did not appear to have an effect on any of these markers.

"Our data suggest divergent effects of tenofovir and zidovudine on pro-inflammatory responses in monocytes (CCL3 and IL-8) and PBMCs (CCL3)," the researchers concluded. "Moreover, tenofovir shifts the IL-10/IL-12 balance after cell stimulation with TLR ligands or infection with live bacteria, thus suggesting that the choice of NRTI affects overall inflammation and early immune responses against secondary pathogens."

Valganciclovir

In the second study, described in the May 15, 2011, Journal of Infectious Diseases, Peter Hunt from the University of California at San Francisco and colleagues studied the effect of valganciclovir (Valcyte), an anti-herpes drug used to treat CMV, on immune cell activation in HIV positive people who had not achieved adequate CD4 cell recovery on ART.

Just as persistent HIV infection appears to cause continuous immune activation and inflammatory responses, the researchers hypothesized that asymptomatic CMV replication might also contribute to immune activation, and treating it might therefore reduce activation.

This study included 30 HIV and CMV seropositive patients on ART. Most were men and the mean age was 49 years. All participants had CD4 T-cell counts < 350 cells/mm3 (median 190 cells/mm3); 30% had HIV RNA > 75 copies/mL and 40% had detectable CMV DNA in saliva, plasma, or semen at baseline. Participants were randomly assigned to receive 900 mg daily valganciclovir or placebo for 8 weeks, followed by an additional 4-week observation period.

All patients treated with valganciclovir had undetectable CMV viral load after 8 weeks of treatment, while 44% of those in the placebo group still had detectable CMV. In addition, valganciclovir-treated participants had significantly greater reductions in CD8 T-cell activation (defined as CD38+HLA-DR+ marker profile) compared with placebo recipients at weeks 8 and 12 -- a reduction of about 20%. Patients in the valganciclovir arm also had reduced levels of high-sensitivity C-reactive protein (CRP), a blood biomarker of inflammation.

Based on these findings, the researchers concluded, "CMV (and/or other herpesvirus) replication is a significant cause of immune activation in HIV-infected individuals with incomplete antiretroviral therapy-mediated CD4+ T-cell recovery."

"Because we observed no change in plasma HIV RNA levels among viremic participants and the reduction in T-cell activation remained significant when analysis was restricted to those with undetectable plasma HIV RNA levels, the reduction in T-cell activation with valganciclovir therapy does not seem to be explained by a direct effect on HIV replication," they elaborated in their discussion. "These results suggest that CMV and/or other herpesvirus coinfections are a substantial cause of in vivo T-cell activation among treated HIV- and CMV-coinfected individuals."

CD4 cell changes were not seen during this 12-week observation period, but the authors explained that since prior studies suggest that decreasing CD8 cell activation would likely only enable small absolute CD4 cell gains, this trial
"was far too small and short to rule out an effect on CD4 T-cell counts."

"Although the clinical relevance of this finding remains unclear, persistent immune activation and inflammation is a major predictor of premature morbidity and mortality among these patients," they concluded. "Furthermore, given persistent functional T-cell defects and immunosenescence even in treated HIV-infected individuals with optimal CD4+ T cell recovery, and the clear associations between CMV and immunosenescence in HIV-uninfected individuals, a larger trial of anti-CMV therapy for treated HIV-infected patients is clearly warranted."

Investigator affiliations:

Tenofovir study: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark; Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, NY; Ontario Cancer Institute, Princess Margarets Hospital, Toronto, Canada; Department of Medical Microbiology and Immunology, Aarhus University, Aarhus, Denmark; Department of Clinical Microbiology, Aarhus University Hospital Skejby, Aarhus, Denmark.

Valgancyclovir study: Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco, CA; Departments of Pathology and Biochemisty, University of Vermont College of Medicine, Burlington, VT; Departments of Laboratory Medicine, Medicine and Microbiology, University of Washington, Fred Hutchison Cancer Research Center, Seattle, WA.

4/26/11

References

J Melchjorsen, MW Risor, OS Sogaard, et al. Tenofovir selectively regulates production of inflammatory cytokines and shifts the IL-12 / IL-10 balance in human primary cells. Journal of Acquired Immune Deficiency Syndromes (abstract). April 5, 2011 (Epub ahead of print).

PW Hunt, JN Martin, E Sinclair, S Deeks, et al. Valganciclovir Reduces T Cell Activation in HIV-infected Individuals With Incomplete CD4+ T Cell Recovery on Antiretroviral Therapy. Journal of Infectious Diseases 203(10):1474-1483 (free full text). May 15, 2011.