Determinants of two-year mortality among HIV positive patients with Cryptococcal meningitis initiating standard antifungal treatment with or without adjunctive dexamethasone in Uganda

Abstract

Globally, early initiation of antiretroviral therapy for HIV led to a reduction in the estimated mortality from cryptococcal meningitis (CCM) from 624,700 in 2009 to 181,100 in 2014. However, CCM remains one of the leading causes of mortality among HIV infected patients especially in sub-Saharan Africa where 75% of the deaths occur. Most of the studies evaluating mortality have reported short-term mortality (at or before 10 weeks of therapy). We determined mortality and associated factors among patients treated for CCM in the CryptoDex trial (ISRCTN59144167) in Uganda, and the effect of dexamethasone adjunctive therapy on mortality at two years. We conducted a retrospective cohort study between May 2017 and July 2017 to determine the long term survival (up to 2 years post-randomization) of all patients who had been enrolled into the CryptoDex trial in Uganda. The CryptoDex trial recruited between April 2013 and February 2015. We estimated mortality rates and determined factors affecting mortality at two years using Cox regression. The study followed up 211 participants, 127 (60.2%) of whom were male. Sixteen participants (7.58%) were diagnosed with HIV at the same admission when CCM was diagnosed. By two years following randomization 127 (60%) participants had died, a mortality rate of 67 deaths per 100 person-years. Mortality was associated with Glasgow coma score (GCS) below 15 (adjusted Hazard ratio (aHR) 1.77, 95% CI: 1.02–2.44), p = 0.040; weight (aHR 0.97, per 1 Kg increase; 95% CI: 0.94–0.99), p = 0.003; and presence of convulsions (aHR 2.31, 95% CI: 1.32–4.04), p = 0.004, while dexamethasone use and fungal burden had no effect. Long-term mortality in CCM patients remains high even among patients receiving recommended therapy. Strategies to improve long-term survival in CCM patients are urgently needed, especially targeting those with reduced GCS, low weight, and convulsions.

Poor long-term outcomes despite improved hospital survival for patients with cryptococcal meningitis in rural, Northern Uganda

“…difference in mortality between males and females, similar to an earlier study conducted in Uganda [28]. Even in the interventional CryptoDex trial in Uganda and Asia, a similar trend of sub-optimal long-term survival was observed, with mortality of 60% at 2 years among HIV patients with CM [29,30]. Conversely, an earlier study in Uganda observed a 5-year survival rate of 42% among 189 CM patients which is higher compared to our study [11].…”

Prevalence of cryptococcal meningitis among people living with human immuno-deficiency virus and predictors of mortality in adults on induction therapy in Africa: A systematic review and meta-analysis

“…This study found that low GCS (< 15/15), focal neurological signs, delay in CM diagnosis, and FLU monotherapy were significant predictors of mortality for CM in PLWH. Low GCS, defined as a score < 15/15 or a reduced level of consciousness, was supported as a mortality predictor by studies looking at both short-term and long-term mortality predictors which applied cox regression models to establish associations ( 57 , 63 ). Another study done in Uganda linked low GCS to seizure occurrence and these were associated with higher 10-week mortality ( 64 ).…”

Lack of an atypical PDR transporter generates an immunogenicCryptococcus neoformansstrain that drives a dysregulated and lethal immune response in murine lungs

“…Mechanistically, these anti-inflammatory drugs function by suppressing the migration of neutrophils and decreasing lymphocyte colony proliferation (27). The potential of dexamethasone as a treatment strategy during cryptococcal infection was investigated in a clinical trial but was prematurely concluded because of adverse effects and increased mortality (28, 29); however, corticosteroids have been used successfully to treat CME-associated inflammatory disorders such as postinfectious inflammatory response syndrome and immune reconstitution inflammatory syndrome (21). Given the robust pro-inflammatory immune response observed in the pdr6 Δ-infected mice, we hypothesized dexamethasone treatment would dampen or knock down the aggressive Th1 response resulting in fungal clearance and improved survival.…”