Transcript Powerpoint - Programme-at-a

Overview of WHO Guidelines on
management of Cryptococcal infection
Philippa Easterbrook
Department of HIV/AIDS
World Heath Organization
Outline
1. Background to development of Guidelines
•
Epidemiology
•
New evidence
•
Areas where lack of consensus in national guidelines
2. WHO Guidelines Development Process
3. Recommendations at a glance for adults
Why Crypto was priority OI for
guidelines development
 1. Magnitude of the problem (morbidity and mortality)
 2. Lack of guidance for resource limited settings
3. Wide variation in recommendations in national
guidelines
4. Poor access to optimal diagnostics and drugs and wide
variation in costs - opportunities for advocacy
5. New opportunities and evidence
1. Magnitude of the problem in SSA
• Commonest cause of adult meningitis (45% of cases) 1-3
• Estimated 720,000 cases and 624,700 deaths per year 1
• Case fatality rate remains unacceptably high at 30 -70% 1-3
• Accounts for up to 20% of all HIV-related deaths, and
major contributor to high early mortality in ART
programmes 1-3
Park AIDS 2009; Bicanic, CID 2007 & 2008; Lessells, SAMJ 2011; Kambugu, CID 2008
3. Areas where there is a lack of
consensus or gaps in recommendations
• Survey of recommendations in 33 national guidelines
on OI management from RLS (Abstract No. TAB0505)
– 15 from SSA, 11 Latin America, 7 Asia
• Wide variation in recommendations in:– Fluconazole induction and consolidation (dose and
duration)
• Too low and too short
– Timing of discontinuation of maintenance
– Lack of guidance on toxicity monitoring and management
5. Opportunities – new evidence
• Earlier diagnosis:
– New Point of Care assay for diagnosis CrAg Lateral Flow Assay
• Prevention of cryptococcus:
– 3 studies of cost-effectiveness of “Screen and treat”
with pre-emptive fluconazole in CrAg +ve.
• Effective treatment: Cheaper, less toxic oral regimens:
– RCT in Vietnam (Ampho + Flucytosine or Flucon vs. Ampho)
– RCT Oral regimens (High dose Flucon + Flucytosine vs. Flucon)
• Further reduction in case fatality rate:
– Pre-emptive hydration and electrolyte replacement with Ampho B
Objectives of WHO Guidelines
• To provide evidence-based recommendations on the prevention,
diagnosis and management of cryptococcal disease
– HIV-infected adults, adolescents (10-19 years) and children
(up to 10 years)
– Meningeal and non-meningeal disease
• Directed at:
– Resource limited settings
– Policy makers + National treatment advisory boards +
programme managers
– Clinicians providing in and outpatient care
• To identify gaps and prioritize areas where further clinical and
operational research or advocacy are required.
Guidelines in 10 key areas
1. Diagnosis of cryptococcal disease
7. Monitoring of treatment response
2. Prevention of cryptococcal disease
8. Diagnostic approach and
management of persistent or
recurrent symptoms
3. Induction, consolidation and
maintenance treatment
4. Prevention, monitoring and
management of ampho B toxicity
5. Timing of ART initiation
6. Discontinuation of maintenance
treatment
9. Management of raised intracranial
pressure
10. Management of cryptococcal IRIS
Critical outcomes:
Mortality•
Clinical and neurological outcome•
CSF fungal clearance•
Severe adverse events •
Other outcomes evaluated
Cost•
Azole drug resistance•
2. WHO Guidelines Development Process
Quality Evidence
(GRADE)
Preferences & Values
Feasibility & Cost
(Consultations)
(Appraisals & modeling exercises)
Major Steps in WHO guideline development process
Prioritize problems, formulate questions and relevant outcomes

Evidence retrieval and synthesis (Systematic review)

Evidence Profile (using GRADE)

Relative importance of outcomes and
Overall quality of evidence

Formulation of recommendations

GRADE
Strength of recommendation
Including explicit consideration of:
 Benefits and harms
 Values and preferences
 Feasibility and cost
 Research gaps and areas for advocacy

Implementation and evaluation of guidelines
Strong vs. conditional
recommendation using GRADE
Factors
Comments
Quality of the evidence
(GRADE)
Higher the quality of the evidence the more likely a
strong recommendation can be made
Balance between desirable
and undesirable effects
Larger the gap or gradient between these then more
likely a strong recommendation will be made
Values and preferences
(acceptability)
If there is a great deal of variability or strong reasons
that the recommended course of action is unlikely to
be accepted then it is more likely a conditional
recommendation will be made.
Costs/financial implications
(resource use)
Higher the cost both financial and in terms of
infrastructure, equipment or requirements, and more
resource intensive requirements, then less likely to
make a strong recommendation
Feasibility
Where the intervention is possible and practical in
settings most affected and greatest impact being
sought, a strong recommendation is more likely
Feasibility survey on access to cryptococcal
diagnostics and drugs
- Semi-structured telephone interview
- 30 Clinicians, Ministry of Health, lab managers, pharmacists
- In settings where >100 patients/year
- Africa (Botswana, Ethiopia, Kenya, Malawi, Mozambique, South
Africa, Tanzania, Uganda, Zimbabwe)
- Asia (Cambodia, China, India, Laos, Thailand, Vietnam,)
- Latin America (Argentina, Brazil)
Topics covered: local epidemiology, national guidelines diagnostic and treatment practices Access, costs, payment methods Barriers and priorities -
Wide variation in Access, Availability and
Funding source for drugs and diagnostics
• ACCESS to Ampho and CrAg assay limited
– Mainly in City hospitals, private sector and research settings
– Amphotericin stock-outs a problem
– Oral Fluconazole increasingly used as first line
• AVAILABILITY of generic Ampho B and 5FC
– 4 generic companies in India; Few or none in SSA
– 5FC not registered or available in SSA
• FUNDING source for Ampho and CrAg assay
– PEPFAR, Global Fund, NGOs, National government, Donation programmes,
Self-pay
Cost
• Sources
– Diagnostics: Telephone survey of labs and end-users
– Drug databases: International Drug Price Indicator Guide (IDPI) and
Global Price Reporting Mechanism (GPRM)
• Diagnostics
– CrAg assay (Latex agglutination):
– India Ink:
$3 – 16
$1 – 5
4. Recommendations at a glance
Need to prevent…….
Only modest impact of ART •
on incidence of cryptococcosis
20-30% of CM occurs •
post ART
Additional 58% developed •
CM while waiting to start ART
(Govender et al, GERMS 2010)
Jarvis, J Infect 2010, AIDS 2010, Bicanic CID 2007, Bisson JAIDS 2008
Need to diagnose and treat earlier
No change in in-hospital case •
fatality rate despite increasing
use of amphotericin
Why?
Patients continue to present with •
advanced disease and neurological
deficit.
Incident lab-confirmed cryptococcosis (n=9,498*) diagnosed
at GERMS-SA enhanced surveillance sites, South Africa,
Poor access to rapid diagnostics•
2005-2010
Poor access to LP for management •
of raised intracranial pressure
Management is labour and resource •
intensive
Need for safer ways of using ampho,
and drugs with less side effects …….
Potential contribution of •
amphotericin B toxicity to
mortality
Impact of introduction of routine K+
supplementation on AmB.
COAT Trial, Uganda. Source: Bahr et al,
ICCC 2011
Guiding principles
• Earlier HIV diagnosis and ART initiation is the most important preventive
strategy to reduce high incidence and mortality from cryptococcal
disease.
• Initiate ART at CD4 count of 350 cells, and before CD4 < 200.
• Early diagnosis of cryptococcal disease is key to improving mortality.
• Low threshold for suspecting cryptococcal meningitis.
• Countries should prioritise access to rapid diagnostic CrAg assays.
• Early initiation of optimal antifungal regimens that improve survival,
clinical outcome, and fungal clearance, while minimising drug related
toxicities.
• Prompt referral for HIV testing and care following diagnosis of
cryptococcal disease, to facilitate retention in care and early uptake of
1. Diagnose Crypto meningitis earlier …
• Prompt LP with measurement of CSF opening pressure and rapid CrAg
assay (either LA or LFA) or rapid serum CrAg (either LA or LFA) is
preferred diagnostic approach. (Strong recommendation, moderate
quality of evidence)
• Depending on programmatic considerations and level of facilities:
LP Available
No LP available or
contraindicated
Rapid CrAg available
CSF CrAg
Serum or plasma CrAg,
and refer
No rapid CrAg available
CSF India Ink
Rapid referral
(Strong recommendation, moderate quality of evidence)
2. Prevent cryptococcal meningitis…..
• Routine fluconazole prophylaxis in all patients with a CD4 count ≤ 100
cells, and CrAg negative or CrAg status unknown is not recommended,
unless prolonged delay in ART initiation likely. (Strong
recommendation, high quality of evidence)
• Routine serum or plasma CrAg screening (using LA or LFA with use of
pre-emptive fluconazole therapy if CrAg +ve* may be considered in
patients with a CD4 ≤ 100 cells and high prevalence of CrAg +ve (>3%).
(Conditional recommendation, moderate quality of evidence)
* LP and CSF CrAg to exclude active meningitis in patients with symptoms/signs
of crypto meningitis.
3. Improve treatment outcome….
Reduce toxic effects of Ampho with minimum
package of toxicity prevention, monitoring and
management
• Ampho B based regimen is preferred induction option, where
available, and when minimum package of pre-emptive hydration
+ electrolyte replacement + toxicity monitoring and management
can be provided.
(Strong recommendation, moderate quality of evidence)
Prevention
Pre-hydration + electrolyte
(K+) replacement
Monitoring
Management
Before each amphotericin
infusion
• IL N Saline
• I ampoule (20mmol) K+
• 1-2 tablets K+ twice daily
Baseline and
twice weekly
• Potassium
• Creatinine
If K+ <3.3 mmol/l
• 2 ampoules (40mmol)
K+
• 1-2 tablets K+ three
times daily
4. Improve treatment outcome….
Hierachy of treatment recommendations, depending
on evidence and programmatic considerations
Drugs available
Toxicity
prevention
package
Induction
(2 weeks)
Consolidation
(8 weeks)
Ampho ± Flucytosine
Available
• Ampho + Flucytosine
[Strong/High]
• Ampho + Fluconazole
[Strong/Moderate]
Fluconazole
400-800mg
[Strong/Low]
Ampho
Not
Available
• Ampho + Fluconazole
(short course)
[Conditional/Low]
Fluconazole
800mg
No Ampho
Not
Available
• Fluconazole ± Flucytosine
• Fluconazole 1200mg
[Conditional/Low]
Fluconazole
800mg
5. Timing of ART initiation
• Immediate ART initiation is not recommended in patients with CM due
to high risk of IRIS, which may be life-threatening. (Conditional
recommendation, low quality of evidence)
• Defer ART initiation until evidence of a sustained clinical response to
anti-fungal therapy AND after
Induction
regimen
Meningitis
Non-meningeal
Amphotericin
2-4 weeks
2 weeks
Fluconazole
4-6 weeks
4 weeks
(Conditional recommendation, low quality of evidence)
6. Timing of discontinuation of
maintenance treatment
• Discontinuation of maintenance treatment based on
following criteria:
• > 1 year stable and adherent to ART and anti-fungal
maintenance, and CD4 ≥200 cells (Strong recommendation,
low quality of evidence)
• > 1 year stable and adherent to ART and anti-fungal
maintenance, and CD4 ≥100 cells if viral load suppressed.
(Conditional recommendation, low quality of evidence)
7. Monitoring treatment response
• Opening pressure measurement at initial LP in all patients with
suspected CM to evaluate for raised ICP (Strong recommendation,
very low quality of evidence)
• Daily clinical assessment of clinical response during initial induction
therapy (Conditional recommendation, very low quality of evidence)
• In patients with normal ICP (<20 -25) at baselline and sustained clinical
response, we do not recommend routine follow-up LP to assess ICP or
mycologic response (CSF CRAG, or serum CRAG or CSF fungal culture).
(Conditional recommendation, low quality of evidence)
8. Diagnosis and management of
persistent or recurrent symptoms
• Diagnostic approach recommended
– LP with measurement of opening pressure and CSF examination
– Establish potential reasons for symptoms:
• Raised ICP
• Sub-optimal treatment (inadequate dose/duration, lack of adherence, drug
interaction)
• Drug resistance
• Cryptococcal IRIS
• Other concomitant illness
(Conditional recommendation, low quality of evidence)
• Paradoxical cryptococcal IRIS should be considered a diagnosis of
exclusion (Conditional recommendation, low quality of evidence)
9. Management of raised ICP (>20cm)
• Relieve pressure by draining volume sufficient to reduce CSF
pressure to <20 cm (not to exceed 30 cc on each occasion)
(Conditional recommendation, very low quality of evidence)
• Use of drugs (mannitol, acetazolamide, furosemide, etc) not
recommended (Conditional recommendation, low quality of
evidence)
10. Management of paradoxical
cryptococcal IRIS
Guiding principles:
Early management of raised ICP and Optimizing anti-fungal therapy
• Continuation of ART (Strong recommendation, very low quality
of evidence)
• If continued deterioration or life-threatening complications
(intracranial lesions or mass effect), consider short course of
steroids for at least one week or until clinical improvement.
(Strong recommendation, low quality of evidence)
Analysis of Major Recommendations in 6
key areas
Quality of
Evidence
Strong
Recommendation
s
Conditional
Recommendations
High
3
0
4
Moderate
7
1
8
Low
6
9
14
Very Low
Total
0
16
0
10
Total
0
26
RESEARCH GAPS
1. LFA performance for screening
in low/ high Crypto prevalence
2. Clinical trials:
Short course Ampho B vs. oralhigh dose Fluc ± 5FC
3. Optimal treatment of
asymptomatic serum CrAg +ve
4. Timing of ART (COAT trial)
FEASABILITY AND COST
RESEARCH GAPS
Evaluation in children .1
Diagnosis of non-meningeal disease .2
Discontinuation of maintenance in RLS .3
Impact and Cost effectiveness
analyses of "screen and treat"
Next Steps
• Online
http://www.who.int/hiv/pub
• Evidence map: http://cryptococcus.pbworks.com
• Full Guideline published in October 2012
– Monitoring of treatment response
– Diagnosis and management of treatment failure or relapse
– Management of complications of raised intracranial pressure
– Management of immune reconstitution inflammatory syndrome
• Advocacy Forum
– Increased access to rapid CrAg assays
– Improved treatment access (Ampho and 5FC generics and 5FC
registration)
Acknowledgements
Guideline Development Group WHO
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• Lulu Muhe
Graeme Meintjes, South Africa
Nagalingeswaran Kumarasamy, India • Marco Vittoria
Ploenchan Chetchotisakd, Thailand • Frank Lule (AFRO)
• Omar Sued (PAHO)
Tom Harrison, UK
Conrad Muzzora, Uganda
John Perfect, US
CDC
Tammy Meyers, South Africa
• Monika Roy
Saye Khoo, UK
Yazdanpanah Yazdan, France
28 Peer Review Group
George Rutherford, US
Ben Parks, US
Members
Neeraj Mohan, India
Papa Salif Sow, Senegal
Send comments to:
Nelesh Govender, South Africa
Philippa Easterbrook
Jon Kaplan, US
Lut Lynen, Belgium
[email protected]
Peter Pappas, US
Ryan Phelps, US