1 / 33

Overview of WHO Guidelines on management of Cryptococcal infection

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

shalom
Download Presentation

Overview of WHO Guidelines on management of Cryptococcal infection

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Overview of WHO Guidelines onmanagement of Cryptococcal infection Philippa Easterbrook Department of HIV/AIDS World Heath Organization

  2. 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

  3. 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

  4. 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 programmes1-3 Park AIDS 2009; Bicanic, CID 2007 & 2008; Lessells, SAMJ 2011; Kambugu, CID 2008

  5. 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

  6. 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 AmphoB

  7. 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.

  8. Guidelines in 10 key areas 7. Monitoring of treatment response 1. Diagnosis of cryptococcal disease 8. Diagnostic approach and management of persistent or recurrent symptoms 2. Prevention of cryptococcal disease 3. Induction, consolidation and maintenance treatment 9. Management of raised intracranial pressure 4. Prevention, monitoring and management of ampho B toxicity 10. Management of cryptococcal IRIS • Critical outcomes: • Mortality • Clinical and neurological outcome • CSF fungal clearance • Severe adverse events • Other outcomes evaluated • Cost • Azoledrug resistance 5. Timing of ART initiation 6. Discontinuation of maintenance treatment

  9. 2. WHO Guidelines Development Process Quality Evidence (GRADE) Preferences & Values (Consultations) Feasibility & Cost (Appraisals & modeling exercises)

  10. Major Steps in WHO guideline developmentprocess GRADE

  11. Strong vs. conditional recommendation using GRADE

  12. 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

  13. 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

  14. 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

  15. 4. Recommendations at a glance

  16. 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, BicanicCID 2007, BissonJAIDS 2008

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

  18. 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

  19. 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.

  20. 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: (Strong recommendation, moderate quality of evidence)

  21. 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.

  22. 3. Improve treatment outcome….Reduce toxic effects of Ampho withminimum package of toxicity prevention, monitoring and management AmphoB 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)

  23. 4. Improve treatment outcome….Hierachy of treatment recommendations, depending on evidence and programmatic considerations

  24. 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 (Conditional recommendation, low quality of evidence)

  25. 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)

  26. 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)

  27. 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)

  28. 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)

  29. 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)

  30. Analysis of Major Recommendations in 6 key areas • RESEARCH GAPS • 1. LFA performance for screening • in 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 • Evaluation in children • Diagnosis of non-meningeal disease • Discontinuation of maintenance in RLS

  31. 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)

  32. Acknowledgements Guideline 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 Easterbrook easterbrookp@who.int

More Related