Overview of WHO Guidelines onmanagement of Cryptococcal infection

Philippa EasterbrookDepartment 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

• 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

1 .Magnitude of the problem in SSA

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

Critical outcomes:• Mortality

• Clinical and neurological outcome• CSF fungal clearance

• Severe adverse events Other outcomes evaluated

• Cost• Azole drug resistance

1 .Diagnosis of cryptococcal disease

2 .Prevention of cryptococcal disease

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

7 .Monitoring of treatment response

8 .Diagnostic approach and management of persistent or recurrent symptoms

9 .Management of raised intracranial pressure

10 .Management of cryptococcal IRIS

2. WHO Guidelines Development Process

Quality Evidence(GRADE)

Feasibility & Cost(Appraisals & modeling exercises)

Preferences & Values(Consultations)

Major Steps in WHO guideline development processPrioritize 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

Strength of recommendationIncluding explicit consideration of:

Benefits and harms Values and preferences

Feasibility and cost Research gaps and areas for advocacy

Implementation and evaluation of guidelines

GRADE

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): $3 – 16– India Ink: $1 – 5

4. Recommendations at a glance

• 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 )

Need to prevent.……

Jarvis, J Infect 2010, AIDS 2010, Bicanic CID 2007, Bisson JAIDS 2008

Incident lab-confirmed cryptococcosis (n=9,498*) diagnosed at GERMS-SA enhanced surveillance sites, South Africa, 2005-2010

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.

• Poor access to rapid diagnostics• Poor access to LP for management

of raised intracranial pressure• Management is labour and resource

intensive

Impact of introduction of routine K+ supplementation on AmB.

COAT Trial, Uganda. Source: Bahr et al, ICCC 2011

Need for safer ways of using ampho, and drugs with less side effects.……

• Potential contribution of amphotericin B toxicity to mortality

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 ART.

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 Recommendations

Conditional Recommendations

Total

High 3 0 4

Moderate 7 1 8

Low 6 9 14

Very Low 0 0 0

Total 16 10 26

RESEARCH GAPS

1 .LFA performance for screeningin low/ high Crypto prevalence

2 .Clinical trials :-Short course Ampho B vs. oral

high dose Fluc ± 5FC

3 .Optimal treatment of asymptomatic serum CrAg +ve

4 .Timing of ART (COAT trial)

FEASABILITY AND COST

Impact and Cost effectiveness analyses of "screen and treat"

RESEARCH GAPS

.1Evaluation in children.2Diagnosis of non-meningeal disease

.3Discontinuation of maintenance in RLS

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)

AcknowledgementsGuideline Development Group• Graeme Meintjes, South Africa• Nagalingeswaran Kumarasamy, India• Ploenchan Chetchotisakd, Thailand• Tom Harrison, UK• Conrad Muzzora, Uganda • John Perfect, US• Tammy Meyers, South Africa• Saye Khoo, UK• Yazdanpanah Yazdan, France• George Rutherford, US• Ben Parks, US• Neeraj Mohan, India• Papa Salif Sow, Senegal• Nelesh Govender, South Africa• Jon Kaplan, US• Lut Lynen, Belgium• Peter Pappas, US• Ryan Phelps, US

WHO • Lulu Muhe• Marco Vittoria• Frank Lule (AFRO)• Omar Sued (PAHO)

CDC• Monika Roy

28 Peer Review Group Members

Send comments to:Philippa Easterbrookeasterbrookp@who.int