Baseline Cytomegalovirus Viremia at Cryptococcal Meningitis Diagnosis Is Associated With Long-term Increased Incident TB Disease and Mortality in a Prospective Cohort of Ugandan Adults With HIV

Jayne Ellis; Ananta S Bangdiwala; Caleb P Skipper; Lillian Tugume; Laura Nsangi; John Matovu; Katelyn A Pastick; Kenneth Ssebambulidde; Bozena M Morawski; Abdu K Musubire; Mark R Schleiss; David A J Moore; Joseph N Jarvis; David R Boulware; David B Meya; Barbara Castelnuovo

doi:10.1093/ofid/ofad449

Baseline Cytomegalovirus Viremia at Cryptococcal Meningitis Diagnosis Is Associated With Long-term Increased Incident TB Disease and Mortality in a Prospective Cohort of Ugandan Adults With HIV

Open Forum Infect Dis. 2023 Sep 19;10(9):ofad449. doi: 10.1093/ofid/ofad449. eCollection 2023 Sep.

Authors

Jayne Ellis^{1

2}, Ananta S Bangdiwala³, Caleb P Skipper³, Lillian Tugume¹, Laura Nsangi¹, John Matovu¹, Katelyn A Pastick³, Kenneth Ssebambulidde¹, Bozena M Morawski³, Abdu K Musubire¹, Mark R Schleiss³, David A J Moore², Joseph N Jarvis^{2

4}, David R Boulware³, David B Meya^{1

3}, Barbara Castelnuovo¹

Affiliations

¹ Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda.
² Clinical Research Department, London School of Hygiene and Tropical Medicine, London, UK.
³ University of Minnesota, Minneapolis, Minnesota, USA.
⁴ Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.

Abstract

Background: Adults with HIV-associated cryptococcal meningitis have overlapping burdens of cytomegalovirus (CMV) and tuberculosis (TB) coinfections. CMV infection/reactivation is strongly associated with CMV-specific memory T-cell activation and upregulation of type 1 interferons, which may lead to increased risk of TB disease and poor outcomes.

Methods: We conducted a cohort study of 2-week survivors of cryptococcal meningitis during 2010-2021 to determine TB incidence and all-cause mortality over time stratified by baseline CMV status.

Results: We followed 497 Ugandans with HIV-associated cryptococcal meningitis for a median (interquartile range) of 4.6 (2.6-53.9) months. Overall, 42% (210/497) developed incident TB disease or died. One-fifth (98/497, 19.7%) developed incident TB disease, and 29% (142/497) of participants died during follow-up. Of 259 participants with CMV viral load measured at baseline, 37% (96/259) had concurrent CMV viremia (defined as anyone with detectable CMV DNA in plasma/serum by qualitative polymerase chain reaction [PCR] detection). Of 59 with measured CMV immunoglobulin G (IgG), 100% had positive CMV IgG antibody serology (≥10 enzyme-linked immunosorbent assay units/mL). CMV viremia was positively associated with higher HIV viral load (196 667 vs 73 295 copies/mL; P = .002) and higher cerebrospinal fluid fungal burden (68 500 vs 14 000 cfu/mL; P = .002) compared with those without. Participants with high-level CMV viremia (defined as CMV viral load ≥1000 IU/mL) had twice the risk of incident TB (subdistribution adjusted hazard ratio [aHR], 2.18; 95% CI, 1.11-4.27) and death (aHR, 1.99; 95% CI, 1.14-3.49) compared with participants with no or low-level CMV viremia. There was no association between the CMV IgG index and the incidence of TB/death (P = .75).

Conclusions: CMV viremia >1000 IU/mL at meningitis diagnosis was associated with increased incident TB disease and mortality during long-term follow-up. Future studies to determine the causal relationship and potential for therapeutic intervention are warranted.

Keywords: Cryptococcus; advanced HIV disease; cytomegalovirus; meningitis; tuberculosis.

Grants and funding

T35 AI118620/AI/NIAID NIH HHS/United States