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