screen-and-treat a new strategy to prevent cryptococcal deaths
TRANSCRIPT
Screen-and-TreatA new strategy to prevent cryptococcal deaths
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
High, early mortality among HIV-infected adults on ART in sub-Saharan
Africa
Lawn S, et al. AIDS. 2008
Three-pillared strategy to reduce deaths
EarlierHIV
diagnosis
Prevent and treat
opportunistic infections
Earlierantiretroviral
treatment
Lawn S, et al. AIDS. 2008
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
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
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 survival1
• RCT from Uganda: Fluconazole prevented cryptococcal disease among patients without evidence of cryptococcal infection2
1. Chetchotisakd et al., HIV Medicine 2004; 2. Parkes-Ratanshi et al., Lancet 2011
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
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/mm3, 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.
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
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
Estimated causes of death in sub-Saharan Africa, excluding HIV, 2009
Death from Cryptococcus in sub-Saharan Africa
Lateral flow assay as a screening tool
Immunoassay Format
Serotype sensitivity (ng Crag/ml)
A B C D
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
Pre-emptive treatment with fluconazole
Meya D, et al. Clin Infect Dis. 2010
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 $2062
• Uganda: $190 to prevent one CM case; $266 to prevent one death1
1. Meya et al., CID 2010; 2. Jarvis et al., CID 2010. *In areas where fluconazole is free of cost
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
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
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
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
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
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
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
Working towards screen-and-treat
• Understand the costs of no change vs. screen-and-treat
Number of cases of cryptococcal
meningitis per year7,204
XCost 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
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
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)
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
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
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
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
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
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
NHLS CD4 lab footprint
Pelonomi CD4 Lab Clinic Sites
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
Integration with routine HIV and TB care
Health care worker training
Patient education
Materials developed by the technical group for the South African screening programme
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 meningitis4. Number of CrAg+ patients given pre-emptive fluconazole 5. Number of fluconazole tablets used6. Proportion of HIV+ patients with CD4 < 100 screened for
CrAg7. 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-up9. Incidence of cryptococcal meningitis10. Overall 6 & 12 month mortality in patients initiating ART
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
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
Questions
Nelesh Govender MBBCh, F C Path, M Med, DTM&H, Dip HIV Man
Centre for Opportunistic, Tropical and Hospital InfectionsNATIONAL INSTITUTE FOR COMMUNICABLE DISEASESTel: 011 555 0353Email: [email protected]