Background
People with HIV (PWH) and CMV face an increased risk of frailty and aging-related outcomes, yet the causal role of CMV remains untested.
Methods
A randomized trial assessed whether 48 weeks of letermovir, a CMV terminase inhibitor, reduced plasma sTNFR2 levels (primary endpoint) and other immunologic and functional aging-related outcomes in PWH seropositive for CMV on suppressive ART, compared to ART alone. Randomization was stratified by CD4 count (50% with <350 cells/mm³) and sex at birth (>30% female identity). A planned futility analysis was conducted after 40 participants (of a planned 180) reached week 8. Linear mixed models evaluated continuous outcome changes between arms.
Results
As previously reported, the trial stopped early as the futility analysis showed unexpected increases in sTNFR2 at week 8 in the letermovir arm (n=18) compared to the control arm (n=21). However, from weeks 8 to 48, sTNFR2 levels declined significantly in the letermovir arm (P=0.001), such that the reduction from baseline at week 48 was nominally greater in the letermovir than control arm (diff: -9%, P=0.20). IL-6 also transiently increased at week 8 (+27%, P=0.02) then declined by week 48 (-28%, P=0.003) in the letermovir arm. IL-6R and IL1b levels declined to a greater degree in the letermovir arm throughout the treatment period (diff: -10%, P<0.001 and -29%, P=0.005). At week 48, the letermovir arm had greater declines in CMV-specific IgG titers (-28%,P<0.001) and CD8 counts (-119 cells/mm3,P=0.024), and greater CD4/CD8 ratio increases (+14%,P=0.008,Panel A). By week 48, chair rise time improved by a mean -1.7 seconds (-15%) in the letermovir arm (P=0.002) and to a greater degree than the control arm (P=0.02, Panel B). Improved chair rise performance at week 48 was associated with reductions in IL1b (ρ=0.45, P=0.023) and IL6R (ρ=0.44, P=0.026), and increases in the CD4/CD8 ratio (ρ=-0.67, P<0.001). Although not statistically significant, other functional outcomes like grip strength, gait speed, and Fried frailty classification showed trends favoring letermovir.
Conclusions
Letermovir initially increased some inflammatory markers but ultimately resulted in sustained reductions in inflammation, improved CD4/CD8 ratios, and enhanced physical function/leg strength in PWH with CMV on suppressive ART. These findings suggest that suppression of asymptomatic CMV with a CMV-specific inhibitor may improve aging-related outcomes. Larger studies are needed to establish the clinical significance of these results.