1. Screen-and-Treat A new strategy to prevent cryptococcal deaths

2. Preventing cryptococcal deaths Assembling a customised screen-and- treat toolbox Working towards implementation of screening in your setting Weighing up strategies to prevent cryptococcal deaths

3. High, early mortality among HIV-infected adults on ART in sub-Saharan Africa Lawn S, et al. AIDS. 2008

4. Three-pillared strategy to reduce deaths Earlier HIV diagnosis Prevent and treat opportunistic infections Earlier antiretroviral treatment Lawn S, et al. AIDS. 2008

5. Prevent cryptococcal deaths Antiretroviral treatment Antifungal drugs Diagnostic tests Up-to-date guidelines for clinical management of meningitis Public health surveillance Screen-and-treat Primary prophylaxis

6. How does screening compare to primary prophylaxis? Primary prophylaxis – Treat all HIV/AIDS patients with CD4 <100 with fluconazole – Mixed evidence on whether this improves survival Screen-and-treat (pre-emptive treatment) – HIV/AIDS patients with CD4 <100 are screened to detect early asymptomatic disease → treatment of disease with fluconazole

7. What are the data for and against prophylaxis? Studies from USA, Europe have not shown survival benefit from primary prophylaxis Randomised controlled trial (RCT) from Thailand suggested improved survival 1 RCT from Uganda: Fluconazole prevented cryptococcal disease among patients without evidence of cryptococcal infection 2 1. Chetchotisakd et al., HIV Medicine 2004; 2. Parkes-Ratanshi et al., Lancet 2011

8. Why do the benefits of targeted screening outweigh those of prophylaxis? Treat approximately 10% (vs. 100%) of HIV/AIDS patients with CD4 <100 Minimise unnecessary drug exposure – Adverse events (and concern about fluconazole use during pregnancy) – Drug interactions (TB meds and fluconazole) Minimise azole resistance Potentially more cost-effective

9. WHO Rapid Advice “The use of routine serum or plasma CrAg screening in ART-naïve adults, followed by pre-emptive antifungal therapy if CrAg-positive, to reduce the development of cryptococcal disease, may be considered prior to ART initiation in patients with a CD4 count less than 100 cells/mm 3, and where this population also has a high prevalence of cryptococcal antigenaemia.” “In settings where screening for unrecognised cryptococcal infection is currently undertaken or being considered, a serum or plasma CrAg assay (LA or LFA) is recommended. “ WHO Rapid Advice, December 2011.

10. What makes a good screening programme?  Disease should be an important public health issue  Need an appropriate screening test  Early treatment (of asymptomatic disease) should be more effective than treatment of symptomatic disease  Screening should be cost-effective

11. What makes a good screening programme?  Disease should be an important public health issue  Need an appropriate screening test  Early treatment (of asymptomatic disease) should be more effective than treatment of symptomatic disease  Screening should be cost-effective

12. Estimated causes of death in sub-Saharan Africa, excluding HIV, 2009 Death from Cryptococcus in sub-Saharan Africa

13. Lateral flow assay as a screening tool ImmunoassayFormat Serotype sensitivity (ng Crag/ml) ABCD IMMY LA 28 47 380 62 Meridian CALAS LA 19 37 940 54 Inverness LA 38 64 1600 50 Meridian Premier EIA 28 23 >2000 770 IMMY LFA 1 1 9 8

14. Pre-emptive treatment with fluconazole Meya D, et al. Clin Infect Dis. 2010

15. Cost-effectiveness of screening Depends on the prevalence of antigenaemia and is likely to be cost-effective* in populations where the prevalence of antigenaemia is greater than 3% 1 South Africa: 98 patients screened to identify 1 CrAg-positive patient at a cost of $206 2 Uganda: $190 to prevent one CM case; $266 to prevent one death 1 1. Meya et al., CID 2010; 2. Jarvis et al., CID 2010. *In areas where fluconazole is free of cost

16. Preventing cryptococcal deaths Assembling a customised screen-and- treat toolbox Working towards implementation of screening in your setting Weighing up strategies to prevent cryptococcal deaths

17. How screen-and treat works Identify HIV-infected patients at highest risk for disease Test for cryptococcal antigenaemia before symptom onset Treat with oral fluconazole Prevent cryptococcal meningitis and deaths Pre-emptive fluconazole CrAg+ No symptoms Cryptococcal meningitis

18. Case 40-year old man referred to HIV clinic for ART initiation Recent 2-week hospitalisation – Pneumocystis pneumonia → treated with cotrimoxazole and steroids with a good recovery – Newly-diagnosed HIV infection Severe oral candidiasis, Kaposi’s sarcoma (KS) and peripheral neuropathy No headache, fever, confusion or neck stiffness

19. Case Reflex screening for CrAg with baseline CD4 count Cryptococcal antigen test positive Patient offered LP but procedure not successful despite repeated attempts Blood culture sent in view of positive CrAg result Prescribed – Fluconazole 400 mg daily – Cotrimoxazole Patient was asked to return to the clinic in 1-2 weeks to begin ART

20. Case On day 10 of fluconazole, the patient still felt well but his blood cultures grew Cryptococcus neoformans Admitted to hospital the following day – New skin lesion on his left forearm (cutaneous cryptococcosis) – LP: Cryptococcus; raised intracranial pressure – Treated with amphotericin B for 2 weeks and discharged on fluconazole 400 mg daily Post-hospital discharge clinic visit: patient well and no headache – Continued on fluconazole 400 mg daily for 8 weeks – Started on ART

21. Case If the patient had been screened for cryptococcal antigenaemia at time of HIV diagnosis in hospital, he could have been treated with fluconazole in the month before developing meningitis Upon initial presentation to the clinic, the patient did not have symptoms of cryptococcal meningitis. If not screened, he would not have presented to hospital for some time, and would have had more severe disease and a greater risk of dying

22. Working towards screen-and-treat Understand the baseline epidemiology of cryptococcal disease in your setting – Incidence of meningitis – Prevalence of antigenaemia – Case-fatality ratio Why? – Prioritise screening as a public health intervention – Attract resources for implementation – Estimate effectiveness of screening programme

23. Working towards screen-and-treat Understand the costs of no change vs. screen- and-treat

24. Number of cases of cryptococcal meningitis per year 7,204 X Cost of hospitalisation R 20,080 ($ 2,450) = Estimated annual cost R 144 million ($ 17.5 million) GERMS-SA Surveillance 2010 Haile et al. APHA Conference Atlanta, 2001 Annual cost of hospital treatment in South Africa

25. Working towards screen-and-treat Find a champion Why? – Highlight potential benefits of screen-and-treat – Advocate to policy makers – Advocate for local access to drugs and diagnostic tests – Coordinate the implementation efforts – Work around the operational challenges of implementation

26. Working towards screen-and-treat Identify the major stakeholders Ensure political buy-in Integrate programme into strategic plans at facility, district, province and national levels (depending on the scale of screen-and-treat programme)

28. Pfizer’s Diflucan Partnership Program (DPP) Countries with HIV prevalence >1% may be eligible Since 2000, present in 63 countries in Africa, Asia, Latin America, and the Caribbean Provides fluconazole free of cost to governments and non-governmental organizations Indications: cryptococcal meningitis and oesophageal candidiasis

29. Preventing cryptococcal deaths Assembling a customised screen-and- treat toolbox Working towards implementation of screening in your setting Weighing up strategies to prevent cryptococcal deaths

30. Assembling a customised screen-and-treat toolbox Who should be screened and where? Develop guidelines for clinical management Integrate screening into ART and TB programmes Train personnel Educate patients Perform monitoring and evaluation

31. Who should be screened? All HIV/AIDS patients HIV/AIDS patients starting ART HIV/AIDS patients with a particular CD4 count – CD4 < 200 – CD4 < 150 – CD4 < 100

32. Where should patients be screened? Laboratory – Test done automatically by the laboratory (reflex) – Test ordered by health care provider Point-of-care – Using point-of-care CD4 test to identify high-risk patients – Using WHO stage to identify high-risk patients

33. Reflex laboratory-driven screening strategy CD4 <100 Advantages: minimises extra blood draws, not provider- initiated, test results received with CD4 count, quality assurance processes easier to manage Disadvantage: delays in receiving CD4 result would result in delay of CrAg test result

34. NHLS CD4 lab footprint

35. Pelonomi CD4 Lab Clinic Sites

36. What about a point-of-care (POC) screening strategy? POC crypto screening will only be possible when the new CrAg test has been validated for use in whole blood and/or urine Could occur in combination with POC CD4 testing or with WHO stage of HIV infection in settings where POC CD4 testing is not available Advantage: minimises patient loss to follow-up and treatment delays Disadvantage: lack of quality control

38. Integration with routine HIV and TB care

39. Health care worker training

40. Patient education Materials developed by the technical group for the South African screening programme

41. Indicators for monitoring and evaluation 1.Number of laboratory workers, ART health care providers, pharmacists, and counsellors trained 2.Number of CrAg tests performed on samples with CD4 < 100 3.Incidence of cryptococcal meningitis 4.Number of CrAg+ patients given pre-emptive fluconazole 5.Number of fluconazole tablets used 6.Proportion of HIV+ patients with CD4 < 100 screened for CrAg 7.Proportion of CrAg+ patients given fluconazole 8.Proportion of CrAg+ patients who developed CM or death at 30 days, 3 months & 6 months of follow-up 9.Incidence of cryptococcal meningitis 10.Overall 6 & 12 month mortality in patients initiating ART

42. Expect challenges along the way Integration of HIV, TB and cryptococcal management Tracing CrAg+ patients (loss to follow-up) Up-referral of symptomatic CrAg+ patients Consent for lumbar puncture Supply of fluconazole and amphotericin B Determination of patient outcomes as part of programme monitoring and evaluation

45. Acknowledgements South African Government NICD NHLS PEPFAR CDC USAID Expert clinician group SA HIV Clinicians’ Society Foundation for Professional Development Right to Care Wits Reproductive and HIV Research Institute Aurum Health Systems Trust ANOVA BroadReach

46. Questions Nelesh Govender MBBCh, F C Path, M Med, DTM&H, Dip HIV Man Centre for Opportunistic, Tropical and Hospital Infections NATIONAL INSTITUTE FOR COMMUNICABLE DISEASES Tel: 011 555 0353 Email: neleshg@nicd.ac.za