Although antiretroviral therapy has dramatically improved the health of HIV-infected individuals, abnormal immune activation persists in most of these individuals and predicts subsequent morbidity and earlier mortality. To assess whether low-level asymptomatic CMV replication contributes to persistent immune activation in these patients, we conducted a randomized placebo-controlled trial of valganciclovir among HIV-infected individuals with persistently low CD4+ T cell counts despite antiretroviral therapy. Eight weeks of valganciclovir therapy resulted in potent suppression of CMV DNA levels, which persisted for at least 4 weeks after therapy was discontinued. Valganciclovir also resulted in significantly greater declines in the frequency of activated CD8+ T cells than placebo, which persisted for at least 4 weeks after treatment cessation. Reductions in hs-CRP levels were also observed with valganciclovir. 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. 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.
Treating herpesvirus coinfections has long been pursued as a potential strategy to delay HIV disease progression. Prior to the introduction of protease inhibitors in the mid-1990s, several small trials established a mortality benefit to high-dose acyclovir when used in combination with 1 or 2 antiretroviral drugs [44
]. More recently, standard prophylactic doses of acyclovir to prevent genital ulcer disease have been shown to decrease the rate of CD4+
T cell decline in untreated HIV- and HSV-2–coinfected individuals in a large international trial [45
]. Although some research groups have suggested that acyclovir might exhibit a direct antiviral effect on HIV replication [46
], these in vitro studies have used much higher concentrations of acyclovir than used in current dosing regimens and evidence of acyclovir-associated resistance mutations in HIV-1 reverse transcriptase has not been demonstrated in vivo. This has led many to hypothesize that the beneficial effect of acyclovir on HIV progression is mediated by a reduction in HSV-2–induced immune activation [45
Because asymptomatic chronic CMV infection elicits massive immune responses in HIV-uninfected individuals [20
] and even higher responses in HIV-infected individuals receiving antiretroviral therapy [21
], we suspect that the valganciclovir-mediated reductions in T cell activation that we observed were largely mediated by reductions in CMV replication. While we have not seen a relationship between detectable salivary CMV DNA levels and T cell activation in this trial or in a recent observational study [48
], the relationship between CMV replication and immune activation is likely to be complex. For example, individuals with the strongest immune responses to very low amounts of CMV replication are likely to have the strongest antiviral responses, limiting the detection of CMV in bodily fluids.
However, we cannot definitively exclude the possibility that valganciclovir's effect on T cell activation is mediated by suppression of other herpesviruses. EBV DNA levels also declined significantly during valganciclovir therapy but, unlike those of CMV DNA, rebounded to pretreatment levels 4 weeks after treatment cessation. Because CD8+
T cell activation remained suppressed at this time, it seems unlikely that valganciclovir's effect on CD8+
T cell activation is mediated by a reduction in EBV replication. Although we observed no evidence for a decline in HHV-8 or HHV-6 levels during valganciclovir therapy, a recent trial using the exact same dose and duration of valganciclovir—but more frequent sampling of the oropharynx and enrichment for participants with high salivary HHV-8 DNA levels—found significant reductions in HHV-8 DNA [39
]. Valganciclovir also has known antiviral activity against HHV-6 [49
]. Last, although there seemed to be reductions in CD8+
T cell activation even in valganciclovir-treated participants who were either HSV-2 seronegative or receiving concurrent acyclovir prophylaxis, we cannot rule out the possibility that reductions in HSV-2 replication may have partially contributed to the effects observed. A similar trial of acyclovir in HIV-infected individuals receiving antiretroviral therapy might help address this possibility, because acyclovir has excellent activity against HSV-2 but very little activity against CMV. Last, although acyclovir clearly reduces plasma HIV RNA levels in untreated HIV-infected individuals [45
], we observed no evidence for a reduction in plasma HIV RNA levels in viremic valganciclovir-treated participants, and the effect of valganciclovir on CD8+
T cell activation remained significant even when analysis was restricted to participants with undetectable plasma HIV RNA levels.
While we did not observe any evidence for a change in CD4+
T cell counts during the 12-week observation period, our prior cross-sectional study suggests that each absolute 4% increase in the frequency of activated CD8+
T cells would be associated with just 28 fewer CD4+
T cells gained over a median of 2 years of suppressive antiretroviral therapy, so our trial was far too small and short to rule out an effect on CD4+
T cell counts [14
]. However, it remains possible that T cell activation caused by CMV replication may have a lesser effect on CD4+
T cell recovery than T cell activation caused by other factors (ie, HIV release from latently infected cells, microbial translocation, and so forth). Similarly, although we observed some evidence for a valganciclovir-mediated decrease in hs-CRP levels, a larger trial would be necessary for adequate power to detect changes in other surrogate markers of interest, including the inflammatory biomarkers IL-6, D-dimer, and endothelial function, given the high within-subject variability of these measurements. Subsequent studies will also need to assess whether these findings are generalizable to individuals with higher CD4+
T cell counts and lower CD8+
T cell activation levels.
The clinical relevance of the observed valganciclovir-mediated reduction in immune activation is also unclear, and still larger studies would be necessary to establish a benefit of valganciclovir (or other anti-CMV therapy) in preventing AIDS- and non–AIDS-associated morbidity and mortality. Although we did not observe any toxic effects of valganciclovir in this study, the known marrow-suppressive and teratogenic effects of valganciclovir must be balanced against the potential for clinical benefit if such trials are to be conducted.
In summary, this randomized controlled trial of valganciclovir revealed that CMV and/or other herpesvirus replication is a significant cause of persistent T cell activation in patients with treated HIV infection. 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 [15
]. Furthermore, given persistent functional T cell defects and immunosenescence even in treated HIV-infected individuals with optimal CD4+
T cell recovery [50
], and the clear associations between CMV and immunosenescence in HIV-uninfected individuals [30
], a larger trial of anti-CMV therapy for treated HIV-infected patients is clearly warranted.