HIV-associated Cryptococcal Meningitis in sub-Saharan Africa: Factors affecting short and long-term survival

Abstract

Cryptococcal meningitis (CM) is a wide-spread, yet under-recognized, fungal opportunistic infection occurring primarily among people living with advanced HIV/AIDS. While vast advances in understanding the pathogenesis and treatment options for CM have reduced mortality, major gaps remain in understanding factors that contribute to mortality rates of 12-20% in the first two weeks. The intent of this dissertation was to contribute towards the efforts to address these gaps and provide evidence that could further improve short and long-term recovery from HIV-associated CM in sub-Saharan Africa. The first paper was focused on mortality in the days after CM diagnosis and understanding whether lumbar punctures (LPs) to reduce intracranial pressure also reduce mortality. Raised intracranial pressure is common in CM patients and contributes to many of the disease's signs and symptoms. Two hundred forty-eight HIV-positive, CM patients from Uganda and South Africa were evaluated for the occurrence of therapeutic LPs and mortality within 11 days of CM diagnosis. Analysis was conducted using a marginal structure model, with time-varying exposure. The results suggest that undergoing at least one repeat LP reduced 11-day mortality by 69% (95% CI: 18% to 88%), adjusted for heart rate, CSF fungal burden and altered mental status. This beneficial effect was independent of the baseline CSF opening pressure, demonstrating that increases in intracranial pressure may be common among all CM patients and that all patients may benefit from an additional LP during initial therapy. The second paper was aimed at investigating baseline demographic and clinical features predictive of CM treatment success. The recommended initial treatment regimen for CM rapidly reduces infection; however, nearly 50% of CM patients will continue to have viable fungus in their central nervous system at the end of therapy. Being able to predict patientutcomes has many advantages including optimizing treatment for each patient and reducing drug toxicities. One hundred seventy-seven HIV-positive, CM patients undergoing 2 weeks of antifungal treatment, including amphotericin B and fluconazole, were evaluated for sterility of a CSF culture by the end of therapy. The baseline CSF quantitative fungal burden was a strong and practical predictor of achieving CSF sterility, along with the rate of fungal clearance over the first week of treatment, and the baseline hemoglobin. Information on the baseline burden of infection could be used to tailor the duration of treatment, thus avoiding unnecessary toxicity and treatment costs for individuals with a lower burden of infection and potentially shifting resources to allow for more aggressive treatment of high-risk patients. The third paper aimed to understand the consequence of residual fungal infection at the end of initial antifungal therapy in terms of mortality in the first weeks and months after 2-week therapy ends. Among 154 HIV-positive individuals surviving the initial 2-week phase of therapy, there was no evidence that either the presence or the amount of residual cryptococcal infection in the CSF had an association with mortality in the following 3 weeks or 6 months. It is possible that a higher dose of fluconazole used at the end of amphotericin therapy in the present cohort may have contributed to the lack of association. The objective of this dissertation was to expand the understanding of CM treatment and recovery in resource-limited settings. The results suggest that additional benefits could be gained from the use of therapeutic lumbar punctures during the acute phase of treatment, the possibility of customizing therapy to further reduce treatment toxicities, and, finally, describing the relationship between residual infection and CM mortality with indirect support for higher doses of fluconazole during subsequent phases of CM therapy.