Cryptococcosis: Treatment outcome Síle Molloy, PhD Centre for Global Health, Institute of Infection and Immunity St. George’s, University of London

Intended Learning Outcomes To be aware of the 10 week and 1 year survival on antifungal therapy To be aware of the predictors of poor prognosis in cryptococcal meningitis To appreciate the role of maintenance fluconazole therapy in preventing relapses

Deaths from Cryptococcal meningitis by region Global: 181,100 (119,400-234,300) Sub-Saharan Africa: 135,900 (75%) Asia and Pacific: 39,700 (22%) Latin America: 2,400 (1.3%) North Africa & Middle East: 1,900 (1.1%) Europe: 1,800 (1.0%) Caribbean: 700 (0.4%) North America: 700 (0.4%) Rajasingham et al., Lancet Infect Dis, 2017; 17 (8): 873-881

10-weeks and 1 year mortality on antifungal therapy Treatment outcome 10-weeks and 1 year mortality on antifungal therapy BEST: Clinical trial setting 35-40% 10 weeks mortality 2 weeks Amphotericin B-based therapy USUAL REALITY: Malawi: Fluconazole: 10 wk mortality >50% One year 22% survival on fluconazole Jarvis et al., Clin Infect Dis. 2014;58(5):736-45 Zambia: 2 wk AmB routine use 39% in hospital mortality Rothe et al . The solid line shows estimated proportion of survivors and the dotted lines show 95% confidence intervals. Amongst the 47 patients who did not survive on fluconazole to 52 weeks, two had positive CSF cultures at 10 weeks and were switched to fluconazole. The remaining 45 died Siddiqi et al. Clin Infect Dis. 2014;58(12):1771-7. Rothe et al. PLoS ONE. 2013; 8(6): e67311.

Predictors of poor prognosis (10-week mortality) Altered mental status (GCS <15) High fungal burden Older age (>50 years) Low body weight Anaemia (haemoglobin <7.5 g/dL) High peripheral white cell count Serial measurement of cryptococcal antigen titers to gauge treatment response does not have any proven benefit Jarvis et al., Clin Infect Dis, 2014, 58 (5) 736-45

Relapse following optimal treatment for acute cryptococcal meningitis 30-40% of patients before introduction of consolidation and maintenance strategies Consolidation schedule Fluconazole 800mg from end of induction therapy till start ART, followed by Fluconazole 400-800mg Maintenance schedule Reduce to Fluconazole 200mg from 10 weeks Bozzette et al N Engl J Med 1991;324;580-4

Relapse following optimal treatment for acute cryptococcal meningitis To diagnose relapse a patient MUST have :- New clinical signs and symptoms consistent with cryptococcosis after an initial clinical improvement AND Positive cultures after initial CSF sterilisation Surrogate markers like India ink, CrAg titres, and biochemical markers are insufficient to diagnose relapse. Maziarz & Perfect. Infect Dis Clin N Am. 2016; 30: 179-206

Persistent Cryptococcal meningitis Persistent cryptococcal disease is defined as persistently positive CSF cultures after 1 month of antifungal therapy Like relapse, surrogate markers like India ink, CrAg titres, and biochemical markers are insufficient to diagnose persistent disease Maziarz & Perfect. Infect Dis Clin N Am. 2016; 30: 179-206

Management of relapsed and persistent disease Both persistent and relapsed infections must be distinguished from c-IRIS and raised intracranial pressure Relapse and persistence is rare except where Fluconazole monotherapy is used for induction therapy Management Re-initiation of induction therapy (Amphotericin B) Until CSF sterilisation Antifungal susceptibility testing (where available) Checks for changes in minimum inhibitory concentration (MIC) from the original isolate Perfect et al. Clin Infect Dis. 2010;50(3):291-322

Summary Most CM deaths are in sub-Saharan Africa where 10-week mortality in routine setting is >50% Fungal burden and altered mental status are important prognostic indicators Long-term maintenance antifungal therapy reduces the rate of relapse from >50% to less than 5% Culture is required to diagnose relapse or persistent disease Re-initiation of induction therapy at a higher dose and longer duration is recommended Antifungal susceptibility testing on all relapse isolates

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