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Ending Cryptococcal Meningitis Deaths by 2030
A Strategic Framework
Nelesh Govender
National Institute for Communicable Diseases, South Africa
Conflicts of interest
Current research grants from the National Institutes of Health, Centers
for Disease Control and Prevention, UK Medical Research Council,
Gates Foundation, National Health Laboratory Service Research Trust
No other conflicts of interest
Connection to other global initiatives
The main infectious causes of AIDS deaths
= AIDS
Connection to other global initiatives
Ending AIDS deaths
Cryptococcal meningitis (CM)
Rajasingham R, et al. Lancet Infect Dis 2017
Globally, cryptococcal
meningitis was responsible for 15% of
AIDS-related deaths (95% CI 10–19)
The global scale of AIDS deaths
AIDS-related deaths have been reduced by 64% since the peak in
2004 and by 47% since 2010
https://www.unaids.org/en/resources/fact-sheet
Cryptococcal meningitis
Rajasingham R, et al. Unpublished estimates for 2020
Treatment of cryptococcal meningitis
Molloy SF, et al. N Engl J Med 2018;378:1004-17.
ACTA trial
Treatment of cryptococcal meningitis
Induction
• 1 week: AmB + 5-FC, then 1
week high-dose fluconazole
• (2 weeks: fluconazole + 5-FC)
Consolidation
• 8 weeks: fluconazole
Maintenance
• Minimum 12 months:
fluconazole
World Health Organization, March 2018
http://apps.who.int/
Treatment of cryptococcal meningitis
Prespecified Non-inferiority Margin
-15 -10 -5 0 5 10 15
Better than control Worse than control
ITT population
Unadjusted
Adjusted
PP population
Unadjusted
Adjusted
Primary outcome: All-cause mortality at 10 weeks (non-inferiority)
Control arm (WHO standard)
1 mg/kg AmB for 7 days
AND
5FC 100 mg/kg/day for 7 days
THEN
FLU 1200 mg/day for 7 days
AmBisome arm
10 mg/kg LAmB single dose
AND
5FC 100 mg/kg/day for 14 days
AND
FLU 1200 mg/day for 14 days
Lawrence D, et al. IAS July 2021
Critical antifungal agents for meningitis
A feasible and effective screen-and-treat
intervention for cryptococcal disease is now being
implemented globally
Screening for cryptococcal antigen in blood
1. Cryptococcal antigen can be found in the bloodstream weeks before symptoms of meningitis
2. People with advanced HIV are tested early for cryptococcal disease
3. Patients who test positive for blood cryptococcal antigen are screened for meningitis (LP) and prescribed
appropriate antifungal medicines
4. Antifungal medicines treats meningitis in those who have it, and can prevent meningitis in those who do not
What are the main gaps?
CD4 tests
Cryptococcal antigen
tests for screening
and meningitis
diagnosis
Lumbar puncture
availability,
consumables
Critical antifungal
medicines for
meningitis
What are the main gaps?
CD4 tests
Cryptococcal antigen
tests for screening
and meningitis
diagnosis
Lumbar puncture
availability,
consumables
Critical antifungal
medicines for
meningitis
CrAg test availability in Africa
Amphotericin B registration in Africa
Flucytosine registration in Africa
Missed opportunities in CrAg screening & treatment
Aiming for zero cryptococcal meningitis deaths
Undiagnosed, cryptococcal meningitis is always fatal
Diagnosis with fluconazole monotherapy improves survival marginally
Deferring ART to the appropriate time and therapeutic LPs improves survival further
Adding flucytosine to a fluconazole induction regimen improves survival even more
WHO standard of amphotericin B + flucytosine improves survival to 70%
Liposomal AmB-based induction regimen non-inferior to WHO standard and less toxic
Zero deaths
Address the gaps in CrAg screening
South Africa’s
National Reflex CrAg
Screening Programme
Feb ‘17 – Sep’21
CrAg reflex tests run: 1 238 237 (98.9%)
Positive reflex CrAg tests: 76 085 (6.1%)
Eligible patients screened: 1 012 493 (99.1%)
CrAg+ patients identified: 64 310 (6.0%)
Address the gaps in diagnosis of
meningitis
Increase access to lumbar
puncture and CSF CrAg testing for
people with a positive screening
blood CrAg test and those with
symptoms of meningitis
Address the gaps in access to key
medicines
Ensure availability
Register and procure
Ensure availability
Reduce costs
Research and development
• Diagnostic needs
− POC diagnostics for multiple OIs in people with AHD
− POC diagnostics to reliably establish cryptococcal meningitis cure
− CrAg diagnostics to predict progression of disease
• Treatment needs
− Test more effective pre-emptive antifungal regimen for antigenaemia in trials
− Test less toxic and/or oral formulations of amphotericin B in trials
− Develop a modified slow-release flucytosine for less frequent dosing
− Bring novel antifungals into phase I, II and III clinical trials
High-level targets
Acknowledgements

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Professor Nelesh govender

  • 1. Ending Cryptococcal Meningitis Deaths by 2030 A Strategic Framework Nelesh Govender National Institute for Communicable Diseases, South Africa
  • 2. Conflicts of interest Current research grants from the National Institutes of Health, Centers for Disease Control and Prevention, UK Medical Research Council, Gates Foundation, National Health Laboratory Service Research Trust No other conflicts of interest
  • 3. Connection to other global initiatives
  • 4. The main infectious causes of AIDS deaths = AIDS
  • 5. Connection to other global initiatives Ending AIDS deaths
  • 6. Cryptococcal meningitis (CM) Rajasingham R, et al. Lancet Infect Dis 2017 Globally, cryptococcal meningitis was responsible for 15% of AIDS-related deaths (95% CI 10–19)
  • 7. The global scale of AIDS deaths AIDS-related deaths have been reduced by 64% since the peak in 2004 and by 47% since 2010 https://www.unaids.org/en/resources/fact-sheet
  • 8. Cryptococcal meningitis Rajasingham R, et al. Unpublished estimates for 2020
  • 9. Treatment of cryptococcal meningitis Molloy SF, et al. N Engl J Med 2018;378:1004-17. ACTA trial
  • 10. Treatment of cryptococcal meningitis Induction • 1 week: AmB + 5-FC, then 1 week high-dose fluconazole • (2 weeks: fluconazole + 5-FC) Consolidation • 8 weeks: fluconazole Maintenance • Minimum 12 months: fluconazole World Health Organization, March 2018 http://apps.who.int/
  • 11. Treatment of cryptococcal meningitis Prespecified Non-inferiority Margin -15 -10 -5 0 5 10 15 Better than control Worse than control ITT population Unadjusted Adjusted PP population Unadjusted Adjusted Primary outcome: All-cause mortality at 10 weeks (non-inferiority) Control arm (WHO standard) 1 mg/kg AmB for 7 days AND 5FC 100 mg/kg/day for 7 days THEN FLU 1200 mg/day for 7 days AmBisome arm 10 mg/kg LAmB single dose AND 5FC 100 mg/kg/day for 14 days AND FLU 1200 mg/day for 14 days Lawrence D, et al. IAS July 2021
  • 12. Critical antifungal agents for meningitis
  • 13. A feasible and effective screen-and-treat intervention for cryptococcal disease is now being implemented globally
  • 14. Screening for cryptococcal antigen in blood 1. Cryptococcal antigen can be found in the bloodstream weeks before symptoms of meningitis 2. People with advanced HIV are tested early for cryptococcal disease 3. Patients who test positive for blood cryptococcal antigen are screened for meningitis (LP) and prescribed appropriate antifungal medicines 4. Antifungal medicines treats meningitis in those who have it, and can prevent meningitis in those who do not
  • 15. What are the main gaps? CD4 tests Cryptococcal antigen tests for screening and meningitis diagnosis Lumbar puncture availability, consumables Critical antifungal medicines for meningitis
  • 16. What are the main gaps? CD4 tests Cryptococcal antigen tests for screening and meningitis diagnosis Lumbar puncture availability, consumables Critical antifungal medicines for meningitis
  • 20. Missed opportunities in CrAg screening & treatment
  • 21. Aiming for zero cryptococcal meningitis deaths Undiagnosed, cryptococcal meningitis is always fatal Diagnosis with fluconazole monotherapy improves survival marginally Deferring ART to the appropriate time and therapeutic LPs improves survival further Adding flucytosine to a fluconazole induction regimen improves survival even more WHO standard of amphotericin B + flucytosine improves survival to 70% Liposomal AmB-based induction regimen non-inferior to WHO standard and less toxic Zero deaths
  • 22. Address the gaps in CrAg screening
  • 23. South Africa’s National Reflex CrAg Screening Programme Feb ‘17 – Sep’21 CrAg reflex tests run: 1 238 237 (98.9%) Positive reflex CrAg tests: 76 085 (6.1%) Eligible patients screened: 1 012 493 (99.1%) CrAg+ patients identified: 64 310 (6.0%)
  • 24. Address the gaps in diagnosis of meningitis Increase access to lumbar puncture and CSF CrAg testing for people with a positive screening blood CrAg test and those with symptoms of meningitis
  • 25. Address the gaps in access to key medicines Ensure availability Register and procure Ensure availability Reduce costs
  • 26. Research and development • Diagnostic needs − POC diagnostics for multiple OIs in people with AHD − POC diagnostics to reliably establish cryptococcal meningitis cure − CrAg diagnostics to predict progression of disease • Treatment needs − Test more effective pre-emptive antifungal regimen for antigenaemia in trials − Test less toxic and/or oral formulations of amphotericin B in trials − Develop a modified slow-release flucytosine for less frequent dosing − Bring novel antifungals into phase I, II and III clinical trials
  • 28.