screen-and-treat a new strategy to prevent cryptococcal deaths

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: neleshg@nicd.ac.za