Background
Cryptococcus is the most common cause of HIV-associated meningitis globally, accounting for 19% of all AIDS-related deaths. Case fatality is 24-45%, even in the context of clinical trials. Co-prevalent infections – including Cytomegalovirus (CMV) and Epstein–Barr virus (EBV) – may contribute to poor outcomes.
Methods
We measured CMV and EBV viral load by qPCR in baseline plasma and CSF samples collected prospectively as part of AMBITION-CM, a multi-site, randomized trial which investigated the use of single high dose liposomal amphotericin B for the treatment of HIV-associated cryptococcal meningitis. The AMBITION-CM trial was conducted in Uganda, Botswana, South Africa, Malawi and Zimbabwe. We described the prevalence of CMV- and EBV-viraemia (in plasma), and CNS co-infections (CSF qPCR positivity), and associations of any detectable CMV- or EBV-viremia or viremia >1000 IU/ml with 2- and 10-week mortality using logistic regression modelling.
Results
825 AMBITION-CM participants were included: 61% male, median age 37 years (IQR 32-43), median baseline CD4 count 33 cells/μL (IQR 12-67). EBV plasma viraemia was present in 73% (600/825), and CMV viraemia in 49% (418/825). CNS co-infections were less common; 27% had detectable EBV in CSF, and 5% had detectable CMV. CMV plasma viraemia was significantly associated with lower CD4 counts, less CSF inflammation, and higher CSF fungal burdens. Conversely, EBV plasma viraemia was positively associated with higher CD4 counts and more CSF inflammation. CMV plasma viraemia (>1000IU/ml) was associated with double the odds of both 2-week (aOR 1.98 95%CI 1.01-3.88) and 10-week mortality (aOR 2.15, 95%CI 1.22-3.78) after adjustment for age, sex, CD4 count and study site. CMV CNS co-infection was associated with a non-significant increase in mortality. EBV viraemia, and EBV CNS co-infection, were weakly associated with improved survival (Table 1).
Conclusions
EBV co-infections were associated with a pro-inflammatory cryptococcal phenotype known to be associated with improved survival (suggesting that EBV is a probable by-stander infection), whilst CMV viraemia was associated with a pauci-inflammatory response, higher fungal burdens and increased mortality. CMV viremia >1000IU/ml represents a potentially modifiable risk factor to improve survival amongst adults with cryptococcal meningitis. Interventional trials are required to understand how treatment of CMV impacts immune-modulation in advanced HIV disease.
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