Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy

Abstract

Background: Elevated immune activation persists during treated human immunodeficiency virus (HIV) infection and is associated with blunted CD4 recovery and premature mortality, but its causes remain incompletely characterized. We hypothesized that asymptomatic cytomegalovirus (CMV) replication might contribute to immune activation in this setting.

Methods: Thirty antiretroviral therapy-treated HIV-infected CMV-seropositive participants with CD4 counts <350 cells/mm(3) were randomized to receive valganciclovir 900 mg daily or placebo for 8 weeks, followed by an additional 4-week observation period. The primary outcome was the week 8 change in percentage of activated (CD38(+) HLA-DR(+)) CD8(+) T cells.

Results: Fourteen participants were randomized to valganciclovir and 16 to placebo. Most participants (21 [70%] of 30) had plasma HIV RNA levels <75 copies/mL. The median CD4 count was 190 (IQR: 134-232) cells/mm(3), and 12 (40%) of 30 had detectable CMV DNA in saliva, plasma, or semen at baseline. CMV DNA continued to be detectable at weeks 4-12 in 7 (44%) of 16 placebo-treated participants, but in none of the valganciclovir-treated participants (P = .007). Valganciclovir-treated participants had significantly greater reductions in CD8 activation at weeks 8 (P = .03) and 12 (P = .02) than did placebo-treated participants. These trends were significant even among those with undetectable plasma HIV RNA levels.

Conclusions: 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.

Clinical trials registration: NCT00264290.

Figure 1.

Screening and enrollment status. The disposition of all screened subjects is outlined. Of 60 screened subjects, 27 were excluded for the reasons noted, 3 refused participation, and 30 were enrolled. Randomization was stratified by plasma human immunodeficiency virus (HIV) RNA level (<75 or ≥75 copies/mL) in block sizes of 2. All 14 participants randomized to valganciclovir completed the trial, whereas 1 of the 16 placebo-treated participants discontinued study medication prematurely (congestive heart failure exacerbation). ANC, absolute neutrophil count; CMV, cytomegalovirus; VL, virus level.

Figure 2.

Changes in herpesvirus DNA levels in saliva and semen with valganciclovir therapy. Herpesvirus DNA levels were assessed by polymerase chain reaction (lower limit of detection, 150 copies/mL) on saliva (at weeks 0, 4, 8, and 12) and seminal plasma (at weeks 0 and 8 only). The proportion of participants with a positive herpesvirus DNA level result is plotted for both valganciclovir and placebo groups in saliva and seminal plasma for cytomegalovirus (CMV) (A and E), Epstein-Barr virus (EBV) (B and F), human herpesvirus (HHV) type 8 (C and G), and HHV type 6 (D and H). Plotted P values test whether the proportion of participants with a positive DNA level result changes over time within each treatment group (Cochran Q test). The proportion of participants with positive CMV and EBV DNA levels in saliva declined significantly with valganciclovir therapy but not with placebo. The proportion of participants with detectable salivary CMV DNA levels remained suppressed 4 weeks after study drug discontinuation, whereas the proportion with detectable EBV levels rebounded to pretreatment levels. Whereas 2 (29%) of 7 valganciclovir-treated participants had detectable CMV DNA plasma at baseline, none had it at week 8.

Figure 3.

Changes in T cell activation and C reactive protein (CRP) levels with valganciclovir therapy. The percentage of activated (CD38⁺ HLA-DR⁺) CD8⁺ T cells, percentage of activated CD4⁺ T cells, and plasma CRP levels were assessed over time in both placebo-treated (A, D, G) and valganciclovir-treated participants (B, E, H) with generalized estimating equations. The thin gray lines (A, B, D, E, G, H) indicate individual participant changes, and the thick lines represent the estimated mean changes at each time point within each treatment arm. Mean changes from baseline at each time point were also plotted and compared between placebo- and valganciclovir-treated participants with generalized estimating equations (C, F, I), with P values referring to differences in the change from baseline between treatment arms at each time point. Whereas there was no evidence for a change from baseline in the percentage of activated CD8⁺ T cells at any time point for placebo-treated participants (A), valganciclovir-treated participants experienced a mean decline of 4% activated CD8⁺ T cells by week 8 (P = .01) and continued to have a mean 4.1% fewer activated CD8⁺ T cells than baseline at week 12 (P = .01, B). Compared with placebo-treated participants, those receiving valganciclovir experienced a greater decline in CD8⁺ T cell activation from baseline at week 8 (P = .03) and from baseline to week 12 (P = .02, C). Whereas there was no evidence for a change in CD4⁺ T cell activation levels in the placebo arm (P > .36 for all time points, D), there were trends toward a decrease in CD4⁺ T cell activation levels at weeks 4 (P = .12) and 8 (P = .08) in the valganciclovir arm (E), but the differences between arms were not significant (P > .24 for all time points, F). Whereas there was no evidence for a change in the placebo arm (P > .43 for all time points, G), CRP levels declined significantly by week 8 in the valganciclovir arm (P = .01, H), but the difference in CRP changes between arms was not significant (P ≥ .13 for all time points, I).

Figure 4.

Changes in plasma human immunodeficiency virus (HIV) RNA levels and CD4 counts during valganciclovir therapy. Changes in plasma HIV RNA levels (A) and CD4⁺ T cell counts (B) were assessed over time in valganciclovir- and placebo-treated participants. Each line represents an individual participant's trajectory. Dark thick lines in panel B represent the estimated mean changes over time within each treatment group from a linear mixed model. There was no evidence for changes over time in either plasma HIV RNA levels or CD4⁺ T cell counts in either treatment group.