Transcript Document

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): 525-530, 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
Guidelines
(year of
publication)
1st Option
InductionConsolidation
Alternatives
IDSA
(2010)
• AmB 0.7-1mg/kg
or
• L-AmB 3-5mg/kg
QD
+ 5FC 25mg QID x
2w (min)
• L-AmB 3-5mg/kg
QD x 2w
• AmB+ Fluconazole
800mg x 2w
• Fluconazole 8001200mg +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
• AmB +Fluconazole
400-800mg QD
• L-AmB 4-6mg/kg
QD
• Fluconazole 400800mg +5FC
Start after 2w and neg
CSF culture
• Fluconazole 400mg x 8w
• traconazole
Consolidation
Secondary
Prophylaxis
Monitoring
• Fluconazole 200mg
or
• Itraconazole 200mg
or
• AmB 1mg/kg/w
• Intracranial Pressure
• AmB: (Renal function,
Electrolytes)
Current Recommendations
RLS
• AmB 1mg/kg QD
or
• AmB 0.7mg/kg +
Fluconazole 800mg
x 2w
CDC
(2009)
• AmB 0.7mg/kg
QD+ 5FC 25mgQID
x 2w (min)
MSF
(2010)
• AmB 0.5-1mg/kg x
2w + Fluconazole
400mg QD x 8w
WHO
EURO
(2007)
• AmB 0.7-1mg/kg
QD+ 5FC 25mgQID
x 2w (min)
until CD4>100 and
low HIV RNA x 3m
• Fluconazole 200mg
lifelong or after
immune
reconstitution on
ART
• Intracranial Pressure
• AmB ( Renal function,
Electrolytes)
• 5FC: ( blood levels,
BM, GI)
• Fluconazole ( LFT)
• FLuconazole
lifelong
• AmB 0.7-1mg/kg
QD+ 5FC 25mgQID
x 6-10w
• AmB 0.7-1mg/kg x
6-10w
• Fluconazole 400800mg 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
Areas of consensus and discrepancy
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, CD4 cell count and HIV RNA criteria)
National OI guidelines reviewed (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
Haiti
2008
West Africa (n=4)
Côte d'Ivoire
2005
Panama
2007
Liberia
2007
Paraguay
2007
Nigeria
2010
Venezuela
2009
Senegal
2003
Bhutan
2008
South Africa (n=4)
Asia (n=7)
Lesotho
2007
China
2005
Mozambique
2010
India
2007
Namibia
2010
Lao PDR
2007
Zambia
2010
Malaysia
2008
Myanmar
2007
Viet Nam
2005
Sources:
• In-house databases
• Key websites
• WHO regional and country
offices
• Other key informants
First-line induction drugs and dose
48%
AmB
36% (12)
AmB/5FC
AmB/Fluconazole
Fluconazole
Fluconazole/5FC
0%
6% (2)
(16)
Africa: Botswana, Côte d'Ivoire, Kenya, Madagascar,
Namibia, Rwanda, Senegal, Zambia,
Americas: Argentina, Dom Republic, Ecuador,
Guatemala, Panama, Paraguay, Venezuela,
Asia: Bhutan
Africa: Comoros, Ethiopia, Lesotho, Liberia, Tanzania
Americas: Guyana
Asia: China, India, Lao PDR, Malaysia, Myanmar, Vietnam
Cuba, El Salvador
• Recommended AmB dose varied (0.4,
0.6-1, 0.7, 0.7-1, 1 mg/kg/day)
6% (2)
3%
Mozambique, Haiti
• 3 countries recommended either <
standard dose or not per kg based
dosing
Nigeria
(1)
20%
40%
60%
Percentage of guidelines
80%
100%
All Alternative Regimens (n=33)
IV duration: 3d-10w (median=2w)
3% (1)
AmB/5FC
9% (3)
AmB/Fluconazole
0: n=7
1: n=18
2: n=6
5: n=1
24% (8)
AmB
L-AmB
12% (4)
Fluconazole/5FC
12%
(4)
Number of
Alternatives
Provided
PO duration: 2-12w (median=8w)
Fluconazole
45% (15)
3% (1)
Itraconazole
0%
20%
40%
60%
Percentage of guidelines
80%
100%
Fluconazole dose
Minimum induction Fluconazole dose and
duration (n=15)
1200mg
0%
Mozambique, Cuba, Ecuador
20% (3)
800mg
Duration: 3d (n=1); 4w (n=1); 6w (n=1)
400mg
67% (10)
Africa: Botswana, Côte d'Ivoire,
Ethiopia, Kenya, Lesotho,
Senegal, Tanzania
Americas: Argentina, El Salvador,
Haiti
Duration: 2w (n=2); 4-6w (n=2); 8-10w (n=3); 12w (n=2); lifelong (n=1)
200mg
13% (2)
Guatemala, Paraguay
Duration: 8-10w (n=1); lifelong (n=1)
0%
20%
40%
60%
Percentage of guidelines
80%
100%
Consolidation Fluconazole dose and
duration(n=26)
200mg
3.8% (1)
>10w
Senegal
Africa: Botswana, Comoros, Ethiopia,,
Kenya, Lesotho, Liberia, Madagascar,
Mozambique, Namibia, Rwanda,
Tanzania
Americas: Argentina, Ecuador
Guatemala, Guyana, Paraguay,
Venezuela
Asia: Bhutan, India, Myanmar,
Vietnam
Duration
400mg
3.8% (1)
10w
Cuba
84.6% (22)
8w
7.7% (2)
6w
0%
20%
Côte d'Ivoire, Malaysia
40%
60%
Percentage of guidelines
80%
100%
Treatment Monitoring
Recommendations (n=33)
Africa: Madagascar, Namibia,
Nigeria, Rwanda, Senegal
Americas: Panama, Paraguay,
Venezuela
25% (8)
ABSENT
PARTIAL/
UNSPECIFIC
COMPLETE
0%
72% (23)
6% (2)
20%
Botswana, Kenya
40%
60%
80%
100%
Percentage of guidelines
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)
Focus of Monitoring (n=33)
18% (6)
Hematologic
33% (11)
Infusion Reactions
36% (12)
CNS
21% (7)
Electrolytes
30% (10)
Renal
21% (7)
Liver
0%
10%
20%
30%
Percentage of Guidelines
40%
50%
Secondary prophylaxis (drug and
duration) (n=29)
88%
FLU
(29)
200mg (n=29)
21%
AmB
Africa: Côte d'Ivoire, Rwanda
Americas: Dom. Republic, Panama, Paraguay, Venezuela
Asia: China
(7)
0.5mg QW (n=2); 0.6mg QW (n=2) 1mg QW (n=3)
12%
Itraconazole
(4)
Argentina, Panama, Ecuador, Venezuela
Duration
200mg (n=2); 400mg (n=2)
0%
20%
40%
60%
80%
100%
•
•
•
77%: did not specify
15%: indefinite
8%: until CD4 >100200 cells/mm3 on ART
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