CMV viremia is associated with poor fungal clearance from cerebrospinal fluid in adult patients with HIV-associated cryptococcal meningitis

Abstract Background Cryptococcosis remains a leading cause of HIV-associated mortality globally. Cytomegalovirus (CMV) viremia is common in advanced HIV disease and is associated with excess mortality through unclear mechanisms. We assessed if CMV viremia is associated with slower rates of Cryptococcus clearance from cerebrospinal fluid (CSF) in persons being treated for HIV-associated cryptococcal meningitis. Methods We quantified baseline CMV DNA using PCR from cryopreserved plasma in adults with cryptococcal meningitis in Uganda from 2010 to 2024. The early fungicidal activity (EFA) was calculated as the negative slope of log10 Cryptococcus colony-forming units (CFU)/mL CSF/day over 18 days. We compared fungal burden, EFA, proportions achieving CSF sterility, and 18-week mortality by CMV status. Results Among 508 participants, 37% had detectable CMV viremia. Median EFA was lower in those with CMV viremia (0.31 vs 0.35 log10 CFU/mL/day; p=0.03), with a greater proportion having EFA <0.20 CFU/mL/day (30.5% vs 22.4%; p=0.04) and with fewer achieving CSF sterility by day 18 (36% vs 54%; p<0.001) than those without CMV viremia. Mortality at 18 weeks was higher in CMV viremic participants (43% vs 26%; p<0.001). Participants with both CMV viremia and EFA <0.20 had 2.5-fold increased hazard of death compared with those without CMV viremia and with EFA >0.20 (adjusted Hazard Ratio = 2.48 [95%CI, 1.52–4.06]). No interaction with antifungal treatment was observed. Conclusions CMV viremia is associated with impaired CSF fungal clearance and increased mortality in HIV-associated cryptococcal meningitis—potentially supporting an immunomodulatory role. Further investigation into the underlying immune response in HIV-CMV co-infection is warranted.