1. G. Gavriilidis, PJ. Easterbrook, L. Muhe, M. Vitoria World Health Organization, HIV Department (ATC) Geneva, Switzerland July 2011 What are US, European and National Guidelines from Resource Limited Settings (RLS) Recommending?

2. 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 800- 1200mg +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 400-800mg QD L-AmB 4-6mg/kg QD Fluconazole 400- 800mg +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 400- 800mg 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

3. 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, 400-800mg, 800mg, 800-1200 mg, 1.2-2g) and consolidation dose (400mg, 800mg), and duration. C)Criteria for discontinuation of secondary prophylaxis (Lifelong, Immune reconstitution on ART, CD4cell count and HIV RNA criteria) D)Role of Itraconazole (alternative induction, consolidation or maintenance) Areas of consensus and discrepancy

4. Survey of National OI Guidelines in RLS (n=33) East Africa (n=7)Latin America/ Caribbean (n=11) Botswana2008Argentina2002 Comoros2007Cuba2009 Ethiopia2008Dom. Republic2004 Kenya2008Ecuador2010 Madagascar2009El Salvador2005 Rwanda2007Guatemala2006 Tanzania2009Guyana2006 West Africa (n=5)Haiti2008 Côte d'Ivoire2005Panama2007 Liberia2007Paraguay2007 Mozambique2010Venezuela2009 Nigeria2010Asia (n=7) Senegal2003Bhutan2008 South Africa (n=3)China2005 Lesotho2007India2007 Namibia2010Malaysia2008 Zambia2010Myanmar2007 Viet Nam2005 Lao PDR2007 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

5. 1 st Line Induction (n=33) (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) Two countries recommended either lower than the standard dose of AmB (Mozambique and Malaysia, 0.4mg/kg) or not per kg based dosing (China, 30-40mg QD)

6. 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)

7. (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 (n=15)

8. Consolidation Fluconazole dose (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

9. 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

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

11. Secondary prophylaxis (n=29) Duration 77%: did not specify 15%: indefinite 8%: until CD4 >100- 200 cells/mm3 on ART Duration 77%: did not specify 15%: indefinite 8%: until CD4 >100- 200 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

12. Conclusions 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 Few national guidelines include explicit, complete and detailed instructions for monitoring and management of toxicities Minimal paediatric guidance