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 available No LP available or contraindicated

Rapid CrAg available CSF CrAg Serum or plasma CrAg, and refer

No rapid CrAg available

CSF India Ink Rapid 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 available Toxicity prevention package

Induction(2 weeks)

Consolidation(8 weeks)

Ampho B ± flucytosine

Available • Ampho + flucytosine[Strong/High]• Ampho + fluconazole[Strong/Moderate]

Fluconazole 400-800 mg[Strong/Low]

Ampho B Not Available • Ampho + fluconazole(short course)[Conditional/Low]

Fluconazole 800 mg

No ampho B Not 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]

Monitoring Management

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

Meningitis Non-meningeal

Amphotericin 4 weeks 2 weeksFluconazole 4-6 weeks 4 weeks

(Boulware D, et al. COAT Trial. N Engl J Med 2014;370:2487-98)

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