• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Confronting cryptococcal meningitis in Africa
 

Confronting cryptococcal meningitis in Africa

on

  • 1,009 views

Professor Tom Harrison's presentation at Meningitis Research Foundation's 2013 conference, Meningitis & Septicaemia in Children & Adults

Professor Tom Harrison's presentation at Meningitis Research Foundation's 2013 conference, Meningitis & Septicaemia in Children & Adults

Statistics

Views

Total Views
1,009
Views on SlideShare
493
Embed Views
516

Actions

Likes
0
Downloads
9
Comments
0

2 Embeds 516

http://www.meningitis.org 515
http://translate.googleusercontent.com 1

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • Thank you Arturo <br /> Happy to start off this mornings session focused on crypto dis <br /> I wanted to give brief overview epidemiology ongoing burden of crypto dis <br /> Causes mortality, <br /> Discuss developments diagnostics <br /> And in use current antifungals – point out lack novel anti CM drugs in clinical devlopment <br /> Work recently completed and ongoing to try to reduce mortality and burden <br /> AIM To provide current clinical context for discussion crypto dis this am - and discussion some novel approaches to development antifungal therapies later this am, and throughout the mycoses sessions <br />
  • Efforts to reduce that disease burden thro.. <br /> And finally talk bit about lab based work on pathogen diversity and host defense and immunotherapy, and hope convince you of power of linking such lab studies to clinically based studies and detailed patient outcome data <br />
  • ART coverage has climbed steeply since 2004 – almost 2 M in 2012 for entire SA <br /> Incidence of cryptococcal meningitis although declining slowly, still remains high and above pre-ART incidence levels <br /> Median CD4 at initiation ART 210 (2013) – partly because Cd4 threshold has shifted; large proportion start &lt;200 <br />
  • being adopted in South Africa <br /> potential to prevent HIV-associated cases that present after diagnosis of HIV <br />
  • As suggested by original animal model work Bob Larsen <br />
  • As suggested by original animal model work Bob Larsen <br />
  • So issue is 30% reduction seen at 10 weeks in trial powered at 80% for 45% reduction in Mortality at 10 weeks – so that size effect altho important, v unlikely to be significant <br /> Interesting to combine Pappas and Day data – I know Graeme has estimated <br />
  • Also incidentally chosen DB and JD/DL as background regimens in their respective ART timing and Steroid trials <br />
  • So data Ive shown data that forms basis of IDSA and WHO guidance in settings where 2 wks safe amb currently not possible – ie 1 wk better than none and flucon1200 / 5fc optimal oral regimen <br />
  • And I think important in monitoring trial to look at the Art naïve and experienced patients separately <br /> Which we hope may then take advantgae Giead openess to considering trying to make ambisome mreo available for crypto Rx, and define how it may be best used in CM <br />
  • And I think important in monitoring trial to look at the Art naïve and experienced patients separately <br /> Which we hope may then take advantgae Giead openess to considering trying to make ambisome mreo available for crypto Rx, and define how it may be best used in CM <br />

Confronting cryptococcal meningitis in Africa Confronting cryptococcal meningitis in Africa Presentation Transcript

  • Confronting Cryptococcal meningitis in Africa: New diagnostic, prevention and treatment strategies to reduce disease burden Tom Harrison Meningitis Research Foundation November 5th, 2013
  • Plan: • Epidemiology • ongoing burden HIV-associated CM (non HIV CM) • Diagnostics • New LF point-of-care dipstick test for CrAg • Use in screening, early diagnosis • Therapy • Current options: • Developed and Resource-limited settings • Ongoing and future studies • [Mnx of complications: CM-IRIS, timing ART (COAT study), raised CSF pressure. Immunology of HIV-CM, virulence & evolution C. neoformans]
  • HIV-associated cryptococcal infection: • Accounts majority global burden of CM • Cryptococcal meningitis: common in late stage HIV • Treatment is poor – > 50% 10 wk mortality in Africa • Common cause of death in HIV cohorts - around 15% all HIV deaths S/E Africa • At least 100,000 deaths/yr in SSA: CDC – CID 2009; 23:525 • Not decreasing yet with ART in most centres • But ART means good long term prognosis if survive acute infection
  • Aetiology of Adult Meningitis in S/E Africa Cape Town, South Africa Jarvis J et al. BMC Inf Dis 2010 Kampala, Uganda Durski K et al. JAIDS 2013
  • S Africa: high CM burden despite ART rollout Source: National Institute for Communicable Diseases, Johannesburg, SA
  • Bicanic et al CROI 2011 P-150, Submitted
  • • Problem: Late presentation. Need: Earlier Diagnosis • Early features – headache, fever v. non specific – patients often not referred immediately to hospital for LP – by which time may be too late for effective Rx • Need Point-of-Care diagnostic test • Polysaccharide capsule - major virulence factor but also ?Achilles heel of Cryptococcus basis specific, early (subclinical stage) diagnostic test (Latex agglutination assay CrAg) • POC format Immuno-Mycologics (Sean Baumann, CEO), Tom Kozel (Univ. of Nevada at Reno):
  • LFI dipstick for GXM. LFI was constructed using a cocktail of mAbs F12D2 and 339 KOZEL LAB. The assay has a sensitivity of 2-5 ng/ml for serotype A GXM: Jarvis et al CID 2011; 53:1019 Table 3. Sensitivity limits of a prototype LFI assay (constructed by IMMY) for GXM of serotypes A, B, C and D compared with commercially available latex agglutination assaysa Immunoassay Serotype Ab Serotype B Serotype C Serotype D CN6 MU-1 184 409 2406 6 KC 298 9375 127 Prototype LFI assay 2.4 5.0 4.6 3.0 16 7.0 10 5.1 Commercial latex agglutinationc 250 500 500 250 8,000 4,000 1000 250
  • Crag Lateral Flow Assay
  • CrAg LFA test for serum, CSF (samples already approved for latex agglutination test) approved in Europe, and now by FDA But, ideally need test using non-invasive sample, with no processing Urine Drop whole blood
  • 106 Serum vs. plasma 104 Plasma vs. urine 104 105 103 103 104 102 Serum vs. urine 102 103 104 105 Serum (ng/ml) 106 R = 0.97 P < 0.0001 Slope = 0.097 101 100 100 10 1 10 2 10 3 10 4 Plasma (ng/ml) 10 5 Urine (ng/ml) 102 102 Urine (ng/ml) R = 0.997 P < 0.0001 Slope = 0.85 103 10 6 R = 0.98 P < 0.0001 Slope = 0.083 101 100 100 101 102 103 Serum (ng/ml) Concentration of GXM in paired serum, plasma and urine from 25 subjects. Blood and urine were collected from 25 patients in Cape Town with culture proven cryptococcosis. Serum, plasma and urine were evaluated by quantitative ELISA to assess concentrations of GXM. Jarvis et al CID 2011; 53:1019 104 105 106
  • Sensitivity of Urine vs Plasma/Serum LFA in culture-confirmed cases CM - Cape Town Retrospective Study: Cryptococcus culture-confirmed paired serum, plasma and urine specimens from 62 South African patients in Cape Town Serum Plasma Urine Crag LFA (+) 61 61 61 Crag LFA (+/-) 1 1 0 Crag LFA (-) 0 0 1 Crag LFA Sensitivity 95% CI Serum Plasma Urine 100% 100% 98% 94-100% 94-100% 91-100% Jarvis et al CID 2011; 53:1019
  • • POC could be used: • Facilitate earlier diagnosis (in primary care settings) and treatment all symptomatic cases • Prevention clinical CM by screening for subclinical infection and pre-emptive treatment • Targeted use pre-emptive fluconazole therapy for patients with CD4<100 who are CrAg positive, after HIV diagnosis and prior to starting ART: an alternative strategy to primary “across-the-board” fluconazole prophylaxis Jarvis et al: Clin Infect Dis 2009; 48:856
  • • In South Africa • 20-33% of cases now present after initiation of ART • Over 70% present after a diagnosis of HIV Bicanic CID 2007; 45:76 Jarvis CID 2010; 51:1463 • All these cases are potentially preventable • Screening identifies those patients at risk : Jarvis et al: Clin Infect Dis 2009; 48:856 Serum Antigen positive (approx 5-10% of CD4<100) 28% developed meningitis Serum Antigen negative (90%+ of CD4<100) 0/660 patients developed meningitis
  • Current Gold Standard Therapy: Amphotericin B plus Flucytosine IDSA Perfect et al CID 2010 50:291-322, WHO Rapid advice guideline, WHO November, 2011: 2 wks: AmB 0.7-1 mg/kg/d plus flucytosine (5-FC) 100 mg/kg/d Based on..Van der Horst et al NEJM 1997; 337:15 Supported by…Brouwer et al: Lancet 2004; 363:1764-67 Nailed by….Day et al NEJM 2013; 368:1291-302
  • • Vietnam trial, Day et al Induction with: • AmB 1 mg/kg/d alone, 4 weeks • Vs AmB 1 mg/kg/d alone plus 5FC 100 mg/kg/d, 2 weeks • Vs AmB 1 mg/kg/d alone plus fluconazole 800 mg/d, 2 weeks • To clinical endpoints [n=300] • Results presented ICAAC last year, NEJM April 2013
  • Vietnam trial, Jeremy Day et al [ISRCTN95123928] AmB+5FC AmB +flucon AmB alone Day J et al ICAAC 2011
  • Amphotericin B combinations Given availability (low or no cost), safety fluconazole, but current lack access 5FC Important question for high burden countries in Africa in particular is: Is AmB plus fluconazole preferable to AmB alone?
  • Vietnam trial, Jeremy Day et al Day J et al N Engl J Med 2013;368:1291-302
  • Southern African J HIV Med 2013; 14:76 Vietnam trial plus Pappas et al: CID 2009; 48 1775-83 in the absence of 5FC… AmB 1 mg/kg/d plus fluconazole 800 mg/d
  • Antifungal therapy: New Paradigms in resource-restricted settings Problem 1. accepted gold standard 2 wks AmB+5FC not available, feasible in many African centres 2. currently widely-used and available alternative oral fluconazole - inadequate
  • F S C Fluconazole 400 mg/d l m / U F C Log CFU/ml CSF 7 6 5 4 3 g 2 o L 1 0 0 2 4 6 8 Day 10 12 14 Amphotericin B 1 mg/kg/d 7 6 5 4 3 2 1 0 0 2 4 6 8 Day Bicanic T et al, Clin Infect Dis 2007; 45:76-80. 10 12 14
  • Fluconazole 800 EFA -0.08 logCFU/d Log CFU/ml CSF 7 No increased toxicity observed – small numbers 6 5 4 Longley, Muzoora, et al Clin Infect Dis 2008; 47 1556-61 3 2 1 2 4 6 10 12 14 16 Day Fluconazole 1200 EFA -0.18 logCFU/d 7 Log CFU/ml CSF 8 6 5 0.5 Patients from Cape Town 0.0 4 3 2 -0.5 1 0 Rate of clearance (log CFU/d) 0 2 4 6 8 10 12 14 16 Day 400 800 1200 Fluconazole dose (mg/d)
  • Nussbaum et al. Clin Infect Dis 2010; 50:338-44 UNC Project, Lilongwe, Malawi
  • 1 .0 0 0 .8 0 s u r v iv a l p r o b a b ilit y 0 .6 0 0 .4 0 0 .2 0 0 .0 0 F lu c o n a z o le m o n o t h e r a p y F lu c o n a z o le / 5 F C c o m b in a t io n 0 2 4 6 8 n u m b e r o f w e e k s f o l lo w - u p 2 week mortality: HR 0.24 (0.05-1.16) p=0.05 Nussbaum et al. Clin Infect Dis 2010; 50:338-44 10
  • Alternative, resource-restricted centres: Add Short course AmB (5-7 days) Cohorts in Mbarara, Uganda (5 d) and Lilongwe, Malawi (7d) (Muzoora et al J.Infect 2012, Jackson et al, AIDS 2012) •Very large gain: Tolerability Feasibility, sustainability •?Would efficacy be compromised? Large initial reduction in organism load Carries on through second week - with no flattening ?long half life AmB Follow up therapy: high dose fluconazole
  • Muzoora et al: J Infect 2012; 64:76 30 patients Rx 1200 mg/d flucanozole plus AmB 1 mg/kg/d 5 days: EFA -0.30 log CFU/d over 2 weeks, -0.31 over 7 days
  • Gain in tolerability:: Muzoora et al Flu1200+ AmB1.0 5d Laboratory parameter Decrease in hemoglobin level, >2 g/d, (%) Decrease in hemoglobin level, % change, mean Creatinine level >2x baseline level (%) AmB 2 wks Bicanic CID 2008; 47:123 -30 Day 14 Day 14 AmB 0.7 AmB 1.0 Day 7 Day 14 17 10 50 71 8 6 16 25 4 4.5 13 32 no grade III/IV anemia, ↑ALT, no grade IV hypokalaemia, ↑creatinine Trends in mortality: ↓ compared earlier Mbarara cohorts: 2 and 10 wks: 23%, 28%
  • ACTA Trial: MRC funded: MLW Blantyre, UNC Lilongwe, UTH Lusaka; ANRS: Cameroon Strategy 1: Fluconazole 1200 mg /d plus flucytosine 25 mg/kg qds for 2weeks. Strategy 2: Amphotericin B (AmB) 1 mg/kg/d + fluconazole 1200 mg /d OR 5FC for 7 days Strategy 3: Amphotericin B (AmB) 1 mg/kg/d + fluconazole 1200 mg /d OR 5FC for 14 days
  • Potential Impact Strategies 1, 2, much more readily, safely sustained than 3. IF either shown to be as effective as 3, could result in a reduction in the 10-week mortality in resource-limited settings using fluconazole from around 50-60% to the 30-35% seen with 2 wk AmB-combination treatment. IF NOT as effective then substantial extra resources to SAFELY deliver 2 wks AmB-combination Rx are justified
  • Other ongoing studies Adjunctive Steroid study CRYPTODEX (Jeremy Day, David Lalloo and colleagues) ACTG 5225: Fluconazole dose escalation (1200g2000g/d) vs AmB. (Bob Larsen and colleagues)
  • Other planned / ongoing studies Phase II: 3rd Strategy building on high dose fluconazole backbone – adding Intermittent high dose Ambisome – 1, 2, or 3 doses, vs standard daily dosing Ambisome, with EFA endpoint. Joe Jarvis, et al. Mwanza Tanzania.
  • CMAG - cryptococcal meningitis action group Loyse A et al. Lancet Infect Dis. 2013 Jul;13(7):629-37 GAFFI – Global Action For Fungal Infections - David Denning and colleagues AmB and 5FC from 2013 on WHO essential medicines list
  • St. George’s Tihana Bicanic Joe Jarvis Angela Loyse Nicky Longley Sile Molloy Annemarie Brouwer Thailand Nick White, Nick Day Funders: Wellcome Trust MRC USAID DFID Malawi British Infection Society Lancet ANRS South Africa Graeme Meintjes, Linda-Gail Bekker, Robin Wood Mbarara, Uganda Conrad Muzoora, Kabanda Taseera Lilongwe Malawi, UNC Project Jesse Nussbaum, Charles Van der Horst, Dan Namarika, Mina Hosseinipour Blantyre, MLW, CoM: Rob Heyderman, David Lalloo, Kate Gaskell Lusaka UTH: Shabir Lakhi, Duncan Chanda Cameroon: Charles Kuouanfack, Elvis Temfack Pasteur Institute: Olivier Lortholary London School Hygiene Tropical Medicine Shabbar Jaffar, John Bradley University Nevada, Reno: Tom Kozel Immuno-Mycologics: Sean Baumann