Excellent healthcare – locally delivered What’s new in the diagnosis, prevention and management of HIV-related cryptococcal disease Nelesh Govender (on behalf of the WHO Guidelines Development Group) National Institute for Communicable Diseases, South Africa

Why crypto disease was a priority OI for guidelines development Magnitude of the problem (morbidity and mortality) Poor access to optimal drugs and diagnostics - opportunities for advocacy New evidence and opportunities Lack of guidance for resource-limited settings, or wide variation in recommendations in national guidelines

Objectives of guidelines To provide evidence-based recommendations on the prevention, diagnosis and management of cryptococcal disease – HIV-infected adults, adolescents and children – Meningeal and non-meningeal disease Directed at: – Resource-limited settings – Programme managers + National treatment panels – Clinicians providing in and outpatient care To identify gaps and prioritize areas where further clinical and operational research or advocacy are required.

Guiding principles Earlier HIV diagnosis and ART initiation - most important preventive strategy to reduce high CM incidence and mortality – Initiate ART CD4 <500 cells, and before < 200. – Prompt HIV testing following diagnosis of CM Early diagnosis of CM - key to improving mortality – Low threshold for suspecting CM – Prioritise access to rapid diagnostic CrAg assays. Early initiation of optimal antifungal regimens while minimising drug-related toxicities

1. Diagnose crypto meningitis earlier (Strong recommendation, moderate quality of evidence) LP availableNo LP available or contraindicated Rapid CrAg availableCSF CrAgSerum or plasma CrAg, and refer No rapid CrAg available CSF India InkRapid referral Depending on programmatic considerations and level of facilities:

2. Prevent cryptococcal meningitis Routine serum or plasma CrAg screening with pre- emptive fluconazole therapy if CrAg +ve* may be considered in patients with a CD4 ≤ 100 cells and high prevalence of CrAg +ve (>3%) (Conditional recommendation, moderate quality of evidence) *LP and CSF CrAg to exclude active meningitis in patients with symptoms/signs of meningitis

3. Improve treatment outcomes Agents availableToxicity prevention package Induction (2 weeks) Consolidation (8 weeks) Ampho B ± flucytosine Available Ampho + flucytosine [Strong/High] Ampho + fluconazole [Strong/Moderate] Fluconazole mg [Strong/Low] Ampho BNot Available Ampho + fluconazole (short course) [Conditional/Low] Fluconazole 800 mg No ampho BNot Available Fluconazole ± flucytosine Fluconazole 1200 mg [Conditional/Low] Fluconazole 800 mg

4. Improve treatment outcomes: amphotericin B toxicity Amphotericin B-based regimen is preferred induction option, where available, and when minimum package of pre-emptive hydration + electrolyte replacement + toxicity monitoring and management can be provided. (Strong recommendation, moderate quality of evidence) Prevention [pre-hydration + electrolyte replacement] MonitoringManagement Before each infusion: 1 L normal saline 1 ampoule (20 mmol) K+ 1-2 tablets K+ twice daily Baseline and twice weekly: Potassium Creatinine If K+ <3.3 mmol/L: 2 ampoules (40 mmol) K+ 1-2 tablets K+ three times daily

5. Timing of ART initiation Immediate ART initiation is not recommended in patients with CM due to high risk of IRIS, which may be life-threatening Defer ART initiation until evidence of a sustained clinical response to anti- fungal therapy AND after: Induction regimen backbone MeningitisNon-meningeal Amphotericin4 weeks2 weeks Fluconazole4-6 weeks4 weeks (Boulware D, et al. COAT Trial. N Engl J Med 2014;370: )

6. Timing of discontinuation of maintenance treatment Discontinuation* of maintenance treatment if > 1 year stable and adherent to ART and anti-fungal maintenance, and CD4 ≥200 cells (Strong recommendation, low quality of evidence) *Continue maintenance treatment among children aged < 2 years

Non-GRADED PICOT topics Monitoring treatment response Diagnostic approach and management of persistent or recurrent symptoms – Raised intracranial pressure – Treatment failure – Cryptococcal IRIS (immune reconstitution inflammatory syndrome)

Next steps Improving access to crypto diagnostics – CrAg lateral flow assay validation and forecasting demand Improving antifungal medicines access, supply and registration – WHO Essential Medicines List – Price reduction and generic manufacturing, pooled procurement of amphotericin B and oral 5FC – Harmonization of drug registration – Improved supply and distribution – Improved estimation of disease burden and drug forecasting Dissemination of guidelines

Acknowledgements Guideline Development Group Graeme Meintjes, South Africa Nagalingeswaran Kumarasamy, India Ploenchan Chetchotisakd, Thailand Tom Harrison, UK Conrad Muzzora, Uganda John Perfect, US Tammy Meyers, South Africa Saye Khoo, UK Yazdanpanah Yazdan, France George Rutherford, US Ben Park, US Neeraj Mohan, India Papa Salif Sow, Senegal Nelesh Govender, South Africa Jon Kaplan, US Lut Lynen, Belgium Peter Pappas, US Ryan Phelps, US WHO – Philippa Easterbrook – Lulu Muhe – Marco Vittoria – Frank Lule (AFRO) – Omar Sued (PAHO) CDC – Monika Roy – Tom Chiller – Joel Chehab 28 peer review group members