G. Gavriilidis, PJ. Easterbrook, L. Muhe, M. VitoriaWorld Health Organization, HIV Department (ATC)
Geneva, Switzerland July 2011
What are US, European and National Guidelines from Resource Limited Settings (RLS) Recommending?
Current Recommendations
Guidelines (year of
publication)
1st Option Induction-
Consolidation
Alternatives Consolidation Secondary 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
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:
C) Dose of Amphotericin B (0.5-1, 0.7-1,1 mg/kg)
D) Fluconazole induction dose (400mg, 400-800mg, 800mg, 800-1200 mg, 1.2-2g) and consolidation dose (400mg, 800mg), and duration.
E) Criteria for discontinuation of secondary prophylaxis (Lifelong, Immune reconstitution on ART, CD4cell count and HIV RNA criteria)
F) Role of Itraconazole (alternative induction, consolidation or maintenance)
Areas of consensus and discrepancy
Survey of National OI Guidelines in RLS (n=33)
East Africa (n=7) Latin America/ Caribbean (n=11)
Botswana 2008 Argentina 2002
Comoros 2007 Cuba 2009
Ethiopia 2008 Dom. Republic 2004
Kenya 2008 Ecuador 2010
Madagascar 2009 El Salvador 2005
Rwanda 2007 Guatemala 2006
Tanzania 2009 Guyana 2006
West Africa (n=5) Haiti 2008
Côte d'Ivoire 2005 Panama 2007
Liberia 2007 Paraguay 2007
Mozambique 2010 Venezuela 2009
Nigeria 2010 Asia (n=7)
Senegal 2003 Bhutan 2008
South Africa (n=3) China 2005
Lesotho 2007 India 2007
Namibia 2010 Malaysia 2008
Zambia 2010 Myanmar 2007
Viet Nam 2005
Lao PDR 2007
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
1st Line Induction (n=33)
(2)
(1)
(12)
(16)
(2)
Africa: Comoros, Ethiopia, Lesotho, Liberia, TanzaniaAmericas: GuyanaAsia: 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)
All Alternative Regimens (n=33)
(1)
(3)
(4)
(4)
(8)
(15)
(1)
Number of Alternatives Provided
0: n=71: n=182: n=65: n=1
IV duration: 3d-10w (median=2w)
PO duration: 2-12w (median=8w)
(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)
Consolidation Fluconazole dose (n=26)
(2)
(1)
(1)
(22)
Africa: Botswana, Comoros, Ethiopia,, Kenya, Lesotho, Liberia, Madagascar, Mozambique, Namibia, Rwanda, TanzaniaAmericas: Argentina, Ecuador Guatemala, Guyana, Paraguay, VenezuelaAsia: 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 CMPartial/Unspecific: Guidelines that omit one or more of the above, or give general instructions for patient follow-up (not specific to CM treatment)
6%
72%
25%
0% 20% 40% 60% 80% 100%
COMPLETE
PARTIAL/UNSPECIFIC
ABSENT
Percentage of guidelines
(8)
(2)
(23)
Botswana, Kenya
Africa: Madagascar, Namibia, Nigeria, Rwanda, SenegalAmericas: Panama, Paraguay, Venezuela
Focus of Monitoring (n=33)
(6)
(11)
(12)
(10)
(7)
(7)
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, RwandaAmericas: Dom. Republic, Panama, Paraguay, VenezuelaAsia: China
Argentina, Panama, Ecuador, Venezuela
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