Cryptococcal Meningitis (CM): Review of Treatment Guidance in Resource-Limited Settings (RLS) G. Gavriilidis, P. Easterbrook, L. Muhe, M. Vitoria Department of HIV/AIDS World Heath Organization

Estimated global burden of HIV-associated cryptococcosis Park, B et al. AIDS 23 (4): , 2009

Estimated deaths in Sub-Saharan Africa from cryptococcosis and other infectious diseases

Cryptoccocal meningitis case fatality remains unacceptably high in SSA Rural Kwazulu-Natal – 41% in-hospital mortality(Lessells, SAMJ 2011) Cape Town – 24-37% 10 week mortality (Bicanic, CID 2007 & 2008) Kambugu, Clin Infect Dis 2008

Objectives To assess the extent to which a sample of national guidelines from resource-limited countries conform to the best current international recommendations on management of cryptococcal disease. To identify the main areas of discrepancy between guidelines.

Methods Identified national guidelines on management of opportunistic infections from low/middle income, high/moderate HIV burden countries through:-  in-house databases,  key websites (eg. Ministries of Health, USAID)  contacts with key informants.

Methods Evaluated recommendations for adults and children in 4 key areas:  First-line and second-line induction regimens (drug, dose and duration)  Consolidation regimens (drug, dose and duration)  Monitoring for drug toxicities  Timing of discontinuation of maintenance treatment

Current Recommendations Guidelines (year of publication) 1 st Option Induction- Consolidation AlternativesConsolidationSecondary Prophylaxis Monitoring IDSA (2010) AmB 0.7-1mg/kg or L-AmB 3-5mg/kg QD + 5FC 25mg QID x 2w (min) RLS AmB 1mg/kg QD or AmB 0.7mg/kg + Fluconazole 800mg x 2w L-AmB 3-5mg/kg QD x 2w AmB+ Fluconazole 800mg x 2w Fluconazole mg +5FC x 6w Fluconazole 1.2-2g QD x 12w Itraconazole 400mg QD x 12w Fluconazole 400x 8w Itraconazole Fluconazole 800mg when induction with Fluconazole Fluconazole 200mg or Itraconazole 200mg or AmB 1mg/kg/w until CD4>100 and low HIV RNA x 3m Intracranial Pressure AmB: (Renal function, Electrolytes) CDC (2009) AmB 0.7mg/kg QD+ 5FC 25mgQID x 2w (min) AmB +Fluconazole mg QD L-AmB 4-6mg/kg QD Fluconazole mg +5FC Start after 2w and neg CSF culture Fluconazole 400mg x 8w traconazole Fluconazole 200mg lifelong or after immune reconstitution on ART Intracranial Pressure AmB ( Renal function, Electrolytes) 5FC: ( blood levels, BM, GI) Fluconazole ( LFT) MSF (2010) AmB 0.5-1mg/kg x 2w + Fluconazole 400mg QD x 8w FLuconazole lifelong WHO EURO (2007) AmB 0.7-1mg/kg QD+ 5FC 25mgQID x 2w (min) AmB 0.7-1mg/kg QD+ 5FC 25mgQID x 6-10w AmB 0.7-1mg/kg x 6-10w Fluconazole mg x 10-12w (mild cases) Fluconazole 400mg x 10w FLuconazole 200mg lifelong Itraconazole 200mg lifelong Electrolytes Liver function Renal function time full blood count, differential, platelets

Consensus: A)Amphotericin B + 5FC as first line in high income countries and AmB + Fluconazole in RLS (IDSA and MSF) B)Lack of specific monitoring and toxicity management guidance Discrepancy: A)Dose of Amphotericin B (0.5-1, 0.7-1,1 mg/kg) B)Fluconazole induction dose (400mg, mg, 800mg, mg, 1.2-2g) and consolidation dose (400mg, 800mg), and duration. C)Criteria for discontinuation of secondary prophylaxis (Lifelong, Immune reconstitution on ART, CD4 cell count and HIV RNA criteria) Areas of consensus and discrepancy

National OI guidelines reviewed (n=33) East Africa (n=7)Latin America/ Caribbean (n=11) Botswana2008Argentina2002 Comoros2007Cuba2009 Ethiopia2008Dom. Republic2004 Kenya2008Ecuador2010 Madagascar2009El Salvador2005 Rwanda2007Guatemala2006 Tanzania2009Guyana2006 West Africa (n=4)Haiti2008 Côte d'Ivoire2005Panama2007 Liberia2007Paraguay2007 Nigeria2010Venezuela2009 Senegal2003Asia (n=7) South Africa (n=4)Bhutan2008 Lesotho2007China2005 Mozambique2010India2007 Namibia2010Lao PDR2007 Zambia2010Malaysia2008 Myanmar2007 Viet Nam2005 Sources: In-house databases Key websites WHO regional and country offices Other key informants Sources: In-house databases Key websites WHO regional and country offices Other key informants

First-line induction drugs and dose (2) (1) (12) (16) (2) Africa: Comoros, Ethiopia, Lesotho, Liberia, Tanzania Americas: Guyana Asia: China, India, Lao PDR, Malaysia, Myanmar, Vietnam Africa: Botswana, Côte d'Ivoire, Kenya, Madagascar, Namibia, Rwanda, Senegal, Zambia, Americas: Argentina, Dom Republic, Ecuador, Guatemala, Panama, Paraguay, Venezuela, Asia: Bhutan Cuba, El Salvador Mozambique, Haiti Nigeria Recommended AmB dose varied (0.4, 0.6-1, 0.7, 0.7-1, 1 mg/kg/day) 3 countries recommended either < standard dose or not per kg based dosing

All Alternative Regimens (n=33) (1) (3) (4) (8) (15) (1) Number of Alternatives Provided 0: n=7 1: n=18 2: n=6 5: n=1 IV duration: 3d-10w (median=2w) PO duration: 2-12w (median=8w) 3% 45% 12% 24% 9% 3% 0%20%40%60%80%100% Itraconazole Fluconazole Fluconazole/5FC L-AmB AmB AmB/Fluconazole AmB/5FC Percentage of guidelines

(2) (10) (3) Duration: 8-10w (n=1); lifelong (n=1) Duration: 2w (n=2); 4-6w (n=2); 8-10w (n=3); 12w (n=2); lifelong (n=1) Duration: 3d (n=1); 4w (n=1); 6w (n=1) Africa: Botswana, Côte d'Ivoire, Ethiopia, Kenya, Lesotho, Senegal, Tanzania Americas: Argentina, El Salvador, Haiti Guatemala, Paraguay Mozambique, Cuba, Ecuador Minimum induction Fluconazole dose and duration (n=15)

Consolidation Fluconazole dose and duration(n=26) (2) (1) (22) Africa: Botswana, Comoros, Ethiopia,, Kenya, Lesotho, Liberia, Madagascar, Mozambique, Namibia, Rwanda, Tanzania Americas: Argentina, Ecuador Guatemala, Guyana, Paraguay, Venezuela Asia: Bhutan, India, Myanmar, Vietnam 200mg 400mg Senegal Cuba Côte d'Ivoire, Malaysia

Treatment Monitoring Recommendations (n=33) Complete: Guidelines that cover neurological, renal, liver, blood and electrolyte monitoring and frequency for CM Partial/Unspecific: Guidelines that omit one or more of the above, or give general instructions for patient follow-up (not specific to CM treatment) (8) (2) (23) Botswana, Kenya Africa: Madagascar, Namibia, Nigeria, Rwanda, Senegal Americas: Panama, Paraguay, Venezuela

Focus of Monitoring (n=33) (6) (11) (12) ( 10 ) (7)

Secondary prophylaxis (drug and duration) (n=29) Duration 77%: did not specify 15%: indefinite 8%: until CD4 > cells/mm3 on ART Duration 77%: did not specify 15%: indefinite 8%: until CD4 > cells/mm3 on ART 200mg (n=29) 200mg (n=2); 400mg (n=2) 0.5mg QW (n=2); 0.6mg QW (n=2) 1mg QW (n=3) (4) (7) (29) Africa: Côte d'Ivoire, Rwanda Americas: Dom. Republic, Panama, Paraguay, Venezuela Asia: China Argentina, Panama, Ecuador, Venezuela

Conclusions Many RLS have adopted combination induction therapy for CM, but a significant proportion propose single drug, including inadequate dose fluconazole-only regimens Still wide variation in drug, dose and duration of initial and alternative treatment regimens Specific areas of concern e.g.: – Too low a dose (or too short a duration) of oral fluconazole regimens for induction and consolidation – Use of amphotericin B as maintenance

Conclusions The duration of secondary prophylaxis not explicitly stated in many or lifelong treatment was recommended. Few national guidelines include explicit, complete and detailed instructions for monitoring and management of toxicities Minimal paediatric guidance

WHO Rapid Advice 2011 Diagnosis Prevention Induction, consolidation and maintenance regimens Prevention, monitoring and management of toxicities Timing of ART Timing of discontinuation of maintenance treatment