Tenofovir
and Valganciclovir Reduce Inflammation in People with HIV
SUMMARY
The antiretroviral drug tenofovir and the anti-herpes
drug valganciclovir may help reduce harmful immune activation
and inflammatory activity in HIV positive people. |
By
Liz Highleyman
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
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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
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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.
