Diagnosis and management of cryptococcal meningitis in HIV-infected adults

Abstract

Cryptococcal meningitis is a leading cause of morbidity and mortality globally, especially in people with advanced HIV disease. Cryptococcal meningitis is responsible for nearly 20% of all deaths related to advanced HIV disease, with the burden of disease predominantly experienced by people in resource-limited countries. Major advancements in diagnostics have introduced low-cost, easy-to-use antigen tests with remarkably high sensitivity and specificity. These tests have led to improved diagnostic accuracy and are essential for screening campaigns to reduce the burden of cryptococcosis. In the last 5 years, several high-quality, multisite clinical trials have led to innovations in therapeutics that have allowed for simplified regimens, which are better tolerated and result in less intensive monitoring and management of medication adverse effects. One trial found that a shorter, 7-day course of deoxycholate amphotericin B is as effective as the longer 14-day course and that flucytosine is an essential partner drug for reducing mortality in the acute phase of disease. Single-dose liposomal amphotericin B has also been found to be as effective as a 7-day course of deoxycholate amphotericin B. These findings have allowed for simpler and safer treatment regimens that also reduce the burden on the healthcare system. This review provides a detailed discussion of the latest evidence guiding the clinical management and special circumstances that make cryptococcal meningitis uniquely difficult to treat.

Keywords: HIV/AIDS; amphotericin; antiretroviral therapy; cryptococcal antigen; cryptococcal meningitis; fluconazole; flucytosine; lumbar puncture.

Fig 1

Instructions for cryptococcal antigen lateral flow assay (CrAg LFA) screening that can be completed at the bedside or as near-patient testing. (Courtesy of Immy, Inc., reproduced with permission.)

Fig 2

Survival in CrAg-positive persons by quantitative plasma cryptococcal antigen (CrAg) LFA titer. (Modified from reference .)

Fig 3

Plasma CrAg titer predicts CSF cryptococcal antigen (CrAg) titer positivity in symptomatic and asymptomatic individuals. Over 60% of persons with plasma titers ≥1:640 will have positive CSF titer. 19% of asymptomatic persons with plasma CrAg titer ≥1:2,560 will have positive CSF CrAg titer. (Based on data from reference .)

Fig 4

10-week mortality by antifungal regimen for cryptococcal meningitis from the clinical trial by Molloy et al. in top section (separated by red line) and Jarvis et al. in bottom section (27, 28). Proportions dying by 10 weeks for each group are represented by diamonds and 95% CI is represented by error bars.

Fig 5

2022 WHO antifungal treatment recommendations for cryptococcal meningitis. Single-dose liposomal amphotericin is preferred when available; otherwise, amphotericin B deoxycholate for 7 days is an acceptable alternative. Therapeutic lumbar punctures and electrolyte supplementation are critical during the first 2-week period.

Fig 6

Cumulative survival in Ugandan and South African individuals with cryptococcal meningitis who did or did not receive a therapeutic lumbar puncture. The adjusted relative risk of mortality in those who received a therapeutic lumbar puncture was 0.31 (95% CI: 0.12–0.82), implying a 69% relative risk of mortality reduction with a lumbar puncture conducted in the first week (94). The median time to the second lumbar puncture was ~2 days (IQR: 1–4). (Based on data from reference .)