Tackling Public Enemy #2: Screening to Prevent Cryptococcal

1

Tackling Public Enemy #2:

Screening to Prevent Cryptococcal Deaths

Fighting a deadly fungus

A common, deadly

and costly disease

Weighing up strategies

to prevent deaths

Screening to prevent

deaths in South Africa

Case studies


A common, deadly

and costly disease


to prevent deaths



Case studies

54,4007,800 500 6,500 27,200

120,000

13,600 100

720,000

7,8000

100,000

200,000

300,000

400,000

500,000

600,000

700,000

800,000

North

America

Latin

America

Caribbean Western

and Central

Europe

North Africa

and Middle

East

Sub-Saharan

Africa

Eastern

Europe and

Central Asia

South and

Southeast

Asia

East Asia Oceania

Region

Est

ima

ted

ye

arl

y c

ase

s

Global burden of

HIV-associated cryptococcal meningitis

~1 million new cases per year

and ~ 625,000 deaths per year

Park BJ, et al. AIDS 2009;23:525-30.

Incidence of cryptococcosis (n=17,005*) vs. number of persons on

antiretroviral treatment (ART)** by year,

Gauteng Province, 2002-2010

0

5

10

15

20

25

2002:

n=1,194

2003:

n=1,511

2004:

n=1,539

2005:

n=2,000

2006:

n=2,253

2007:

n=2,109

2008:

n=2,141

2009:

n=2,141

2010:

n=2,117

Year

Incid

en

ce (

ca

se

s p

er

10

0,0

00

pe

rso

ns

0

50000

100000

150000

200000

250000

300000

Nu

mb

er o

f pe

rso

ns o

n

an

tiretro

vira

l treatm

en

t

Incidence

ART

High burden of cryptococcosis in

South Africa

*Complete surveillance audits were conducted throughout; **ASSA-2003 model

High, early mortality amongst

adults accessing ART in sub-Saharan Africa

Lawn S, et al. AIDS. 2008

2

3-pillared strategy

to reduce early mortality

Early

HIV

diagnosis

Prevent,

screen

& treat

OIs

Strong

links

to ART

Lawn S, et al. AIDS. 2008

Estimated causes of death in sub-Saharan Africa, excluding HIV, 2009

Death from Cryptococcus in

sub-Saharan Africa

High in-hospital mortality

Induction treatment with amphotericin B and in-hospital case-fatality ratio for cases of incident

lab-confirmed cryptococcosis (n=9,498*) diagnosed at GERMS-SA enhanced surveillance sites,

South Africa, 2005-2010

0

10

20

30

40

50

60

70

80

90

100

2005 2006 2007 2008 2009 2010

Year

Cases t

reate

d w

ith

am

ph

ote

ricin

B (

%)

0

5

10

15

20

25

30

35

40

Case-fa

tality

ratio

(%)

Amphotericin B Case-fatality ratio

*Only includes cases with a CRF; missing treatment data for 226 cases and missing outcome data for 85 cases

Admitted to hospital

during Mar-Nov

2002, and Jul-Sep

2003

(n = 1,089)

Death in hospital

(n = 316, 29%)

Discharged alive

(n = 721, 66%)

Disposition

unknown

(n = 52, 5%)

Follow-up available

(n = 256, 36%)

Lost to follow-up

(n = 465, 64%)

Last follow-up dead

(n = 154, 60%)

Last follow-up alive

(n = 102, 40%)

Died during readmission

to hospital (n = 86, 56%)

Died as outpatient

(n = 68, 44%)

Disposition known

(n = 1,037, 95%)

Post-discharge survival in the

pre-ART era• Eight hospitals in

Gauteng

• Follow-up post-discharge

– Pharmacy records

– Outpatient records

– Interviews

Park BJ, et al. Int J STD AIDS. 2011.

Admitted to hospital

from Jan 2008 to

Mar 2009

(n = 255)

Death in hospital

(n = 60, 28%)

Discharged alive

(n = 157, 72%)

Excluded

(n = 38, 15%)

Follow-up available

(n = 89, 57%)

Lost to follow-up

(n = 68, 43%)

Last follow-up dead

(n = 17, 19%)

Last follow-up alive

(n = 72, 81%)

Met inclusion criteria

(n = 217, 85%)

• One hospital in Gauteng

• Follow-up post-discharge

– Pharmacy records

– Outpatient records

– Interviews

Post-discharge survival in the

post-ART era

Number of cases of

cryptococcal

meningitis per year

8,330

XCost of

hospitalisation

R 20,080

= Estimated annual cost

R 167,266,400

GERMS-SA Surveillance 2009;

Haile et al. APHA Conference Atlanta, 2001

What does it cost annually to treat

patients in hospital?

3


A common, deadly

and costly disease


to prevent deaths



Case studies

Preventing deaths amongst patients with CD4 <100

WHY IS SCREENING AN ATTRACTIVE OPTION?

1 - Cryptococcal Antigen

• Detectable in serum, plasma (& urine) before

symptoms of meningitis develop

• Average of 22 days prior to symptom onset1

• Highly predictive of who is at risk for developing

cryptococcal disease

• In Cape Town, 13/46 CrAg+ and 0/661 CrAg- patients

developed meningitis2

• Prevalence of cryptococcal antigenemia ranges

from 3% to 21%

• Highest amongst patients with CD4 <100

1French et al. AIDS 2002; 2Jarvis et al. Clin Infect Dis 2009

Cryptococcal Antigenaemia Prevalence in Published Studies

Country Year Setting Serum CrAg

Prevalence

Notes

Zaire (Congo) 1989 Newly diagnosed HIV+ 12.2% (450) Includes symptomatic

Rwanda 1990 Laboratory serum tested

Cross sectional

4.2% (213)

South Africa

(Soweto)

2011 ART enrollment hospital

clinic

Prospective

3.0% (1033) No history of CM

CD4 <100

South Africa

(Cape Town)

2002-2005 Community clinic

Retrospective

7.0% (707) No history of CM

CD4 <100

Uganda 2003-2004 ART clinic

Retrospective

5.8 % (377) CD4 < 100

Uganda 2004-2006 ART enrollment

Prospective

8.2% (609) CD4 <200

Uganda 2000 In and out-patients

Prospective

10.7% (197) Stage III or IV

Uganda 1995-1999 Two community clinics

Cohort

5.6% (1372)

Cambodia 2004 ART enrollment

Cross-sectional

18.0% (327) Includes symptomatic

CD4 <50

Thailand 2008 Retrospective 9.2% (131) CD4 <100

2 - Missed opportunities for screening

Timeline

Prior

diagnosis of

HIV infection

Prior initiation

of antiretroviral

treatment

Admission to

hospital with

cryptococcal

meningitis

(n=1,468)Death in

hospital

Death post-

discharge

1,075/1,468

(73%)

368/1,075

(34%)

503/1,468

(35%)

>50% of

persons who

survive

admission

1 2

2 - Missed opportunities for screening

Antiretroviral treatment at time of diagnosis for cases of incident lab-confirmed

cryptococcosis (n=7,397) diagnosed at GERMS-SA enhanced surveillance sites, South

Africa, 2005-2010

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2005 (n=954) 2006 (n=1,034) 2007 (n=1,247) 2008 (n=1,651) 2009 (n=1,647) 2010 (n=1,075)

Year

Ca

ses

on

an

tire

tro

vir

al

tre

atm

en

t

On ART Not on ART

4

3 – development of a new test for

Cryptococcus

The new test (lateral flow

assay) is:

Simple and quickResults available in 10 minutes

Available and effectiveHighly sensitive and accurate (>95%)

Affordable$2/test

Lateral flow assay format

Analyte

Antibodies conjugated to tag(gold, latex, fluorophore, etc.)

Test line(antibodies)

Control line

(IgG antibodies)

Samplepad

Conjugatepad

Nitrocellulosemembrane

Wickingpad

Test line(positive)

Control line(valid test)

Backing

Capillary flow

LFA can detect tiny amounts of

antigen in body fluids

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 ELISA 28 23 >2000 770

mAbs F12D2 + 339 ELISA 0.6 0.8 5.0 0.6

IMMY LFA 1 1 9 8

LFA is very sensitive

Jarvis, et al. Clin Infect Dis. In press.

Comparison of LFA vs. EIA• Sets of samples from 62 patients with culture-proven cryptococcosis

• Samples assayed by quantitative EIA and by LFA

Serum

101 102 103 104 105 106

EIA

- C

rag

(ng

/ml)

101

102

103

104

105

106

Plasma

LFA titer

100 101 102 103 104 105 10610-1

100

101

102

103

104

105

106

Urine

10-1 100 101 102 103 104 10510-1

100

101

102

103

104

105

Correlation = 0.93P < 0.001



Serum Plasma Urine

CrAg LFA (+) 61 61 61

CrAg LFA (+/-) 1 1 0

CrAg LFA (-) 0 0 1

Serum Plasma Urine

Sensitivity 100% 100% 98%

95% CI 94-100% 94-100% 91-100%

4 - An intervention exists…

Meya D, et al. Clin Infect Dis. 2010

5

5 - Screening costs vs. cost of amphotericin B(based on prevalence of cryptococcal antigenemia)

Meya D, et al. Clin Infect Dis. 2010

Preventing deaths amongst patients with CD4 <100


A common, deadly

and costly disease


to prevent deaths



Case studies

Lab-driven screening strategyReflex testing of remnant CD4 plasma

CD4 <100

National Screening Programme Cost Evaluation

Number of CD4

specimens <100

per year1

(636,000)

XCost of crypto LFA

test2

(R 21)=

Estimated annual cost of

national screening programme

R 13,356,000

Number of CM

cases per year3

(8,330)

XCost of

hospitalisation for

CM4

(R 20,080)

=

Estimated annual cost of

current CM management

R 167,266,400

Number of

preventable CM

cases per year5

(4800)

XCost of

hospitalization for

CM

(R 20,080)

=Estimated annual savings from

national screening programme

R 96,384,000

1. NHLS Data Warehouse

2. Preliminary NHLS estimate

3. GERMS Surveillance 2009

4. Haile et al. APHA Conference Atlanta, 2001

5. Based on 3% CrAg+ positivity (Govender et al, unpublished) , 28% CM development among CrAg+ (Jarvis et al. Clin Infect Dis 2009), & 10% unpreventable deaths

in pts presenting with overt CM (Meintjes, personal communication).

Cryptococcal Screening Programme

Objectives

1.Identify patients at risk (CD4 <100)

2.Test for cryptococcal antigen

3.Treat with oral fluconazole

4.Prevent cryptococcal meningitis deaths

6

Proposed Cryptococcal Screening Algorithm for HIV+ Patients

† A lumbar puncture may considered in asymptomatic patients. Pregnant women, children, and those with liver failure may require special attention.

* Initiate ART if not already started

Screening Fits into Routine HIV Care

Patient referred to HIV clinic

for ART initiation

Intake visit by nurse:

CD4 & reflex CrAg

(if CD4 <100)

Cryptococcal Screening Algorithm:

Antifungal treatment

No antifungal

treatment

CRAG+ CRAG -

Return visit to initiate

ART at 1-2 weeks

Decrease dose of

fluconazole

Role of lumbar puncture

• Three options for

asymptomatic patients

• Offer lumbar puncture to

all CrAg+ patients

• Offer lumbar puncture if

CrAg titre greater than

cutoff value

• Treat empirically with

fluconazole, no lumbar

puncture


Jarvis et al. Clin Infect Dis. 2009

P=0.03


• Three options for

asymptomatic patients

• Offer lumbar puncture to

all CrAg+ patients

• Offer lumbar puncture if

CrAg titre greater than

cutoff value

• Treat empirically with

fluconazole, no lumbar

puncture

• SA HIV Clinicians’ Society Guidelines: 2 to 4 weeks

post-diagnosis

• IDSA Guidelines: 2 to 10 weeks post-diagnosis

• Zolopa1: supportive of 2 weeks

• Makadzange2: <3 days not recommended

• Boulware: ongoing, NIH-funded, multicentre RCT

Timing of ART initiation

1Zolopa et al ACTG A5164 PLOS One; 2Makadzange et. al. Clin Infect Dis 2010

7

Screening in the real world:

Soweto, 2009-2010

Patient referred after hospital

discharge (with AIDS-defining

illness) or from outpatient

provider

Intake visit by clinic nurse:

reviewed CD4 count and clinical

history to determine ARV

eligibility (CD4 <250 or WHO

Stage IV)

Patient sent for baseline labs

(including CrAg) and given clinic

appointment in 2 weeks

Some patients lost to

follow up

CrAg results

available to

clinician

Patient scheduled

for earlier visit

Patient keeps

regularly

scheduled

appointment

Patient came to

ART initiation

clinic visit

Assessed by

physician

Needs LP or is ill No LP and is well

Sent to hospital for

LP +/- admission. No

clinic chart started.

No ART yet

Started on

fluconazole &

started on ART

within 2 weeks

How did screening work in practice?

• CrAg results provided to clinicians within 1 week

• Prevalence of incident antigenaemia = 3%

• Approximately half of CrAg+ patients had previous history of CM

• Median CD4 count of patients with incident CrAg+ was extremely low (19)

How did screening work in practice?

• Almost one-third (30%) of incident CrAg+ patients never returned to ART clinic for follow-up

• Almost half (45%) refused an LP when offered

• Only three-quarters (73%) were prescribed an antifungal drug

• Three incident antigenaemic patients developed meningitis post-screening (no fluconazole)

Programme Implementation

• Three initial implementation sites, 2011• 3 NHLS CD4 testing labs in Gauteng and Free State

• Chosen for convenience

• Intensive laboratory and clinician training

• Monitoring and programme evaluation• Identify operational issues

• Define magnitude of benefit of screening strategy

• Long-term goal: Nationwide implementation


A common, deadly

and costly disease


to prevent deaths



Case studies

Case 1

• 40-year old man was seen at primary health care clinic in Cape Town

– New diagnosis of HIV infection, CD4 count = 9

– Diarrhoea for 1 month and significant weight loss

– No headache, fever, photophobia or vomiting

• Unkempt, lived alone in an informal settlement

• Significant alcohol history

All cases courtesy of Nicky Longley, Cape Town

8

Case 1

• CRAG screening test was performed

• Urgently worked up for initiation of ARVs and asked

to return for ARVs in 2 weeks

• Patient defaulted - did not return to clinic and could

not be contacted

• CrAg screening test done at clinic was positive

Case 1

• 3 months later

– Admitted to GF Jooste Hospital with a 2-week history of

headache, neck stiffness and confusion

– Still not on ARVs

– LP: India ink positive, serum CrAg positive, opening

pressure 45cm water

– Had therapeutic tap and subsequent daily LPs

– Started on amphotericin B 1 mg/kg/day

• Patient died on day 5 post-admission

Discussion points

• Delay in presentation → severe disease

• Early detection of antigenaemia and pre-

emptive treatment could have averted fatal

disease

• Role of point-of-care testing

Case 2

• 40-year old man

• Referred to primary health care clinic for ARVs from GF JoosteHospital

– New HIV diagnosis, CD4 count = 11

– Recent admission with PCP: treated with cotrimoxazole & steroids→good recovery

• At clinic– Well-looking man

– No headache, fever, confusion or neck stiffness

– Severe oral candidiasis

– Single KS lesion on back

– Peripheral neuropathy

• Urgently worked up for ART

Case 2

• CrAg test positive

• Patient called back to clinic

– Still well, no CNS symptoms

– Agreed to have an LP

• 3 attempts at LP failed - very large man (98kg)

• As patient apparently well, did not persist.

– Blood culture sent instead

– Patient started on fluconazole 800 mg per day

– Plan to follow up in 2 weeks to start ART

– Given phone numbers if problems

Case 2

• Day 10 of fluconazole (Thursday)

– Lab called - Cryptococcus neoformans cultured from blood.

– Spoke to patient - still felt well, taking fluconazole, no headache,

– Did not want to come to hospital until next Monday but was convinced to go to GF Jooste the next day

• GF Jooste– New small umbilicated lesion on left forearm - cutaneous

cryptococcosis

– LP: CrAg positive, India ink positive, opening pressure 21 cm H20

– Patient started on amphotericin B 1 mg/kg/day with pre-hydration

9

Case 2

• GF Jooste

– Day 4 amphotericin B - creatinine increased from 84 to 176

– Fluids increased and amphotericin B dose reduced to 0.7mg/kg

– Completed 16 days amphotericin B

– Had one subsequent LP with normal opening pressure

– Developed amphotericin B-induced thrombophlebitis

• Post-discharge follow-up at clinic

– Fluconazole 400 mg/day, doing well

– Started on ART (AZT, 3TC, EFZ) in view of high creatinine and peripheral neuropathy, Hb = 9.6

Discussion points

• If patient had been screened when diagnosed with PCP at GF Jooste, he may have been diagnosed before developing meningitis and been successfully treated with fluconazole

• Insidious onset of cryptococcosis - if he had not been screened, he would not have presented to hospital for some time

• Toxicity of amphotericin B and benefits of detecting cryptococcal disease early

• Late-stage patients often have multiple pathologies – need high index of suspicion

Case 3

• 35-year old man

• Referred for ARVs from TB clinic

– Diagnosed with sputum smear-positive TB 4 weeks prior to clinic appointment

– Started on regimen 1

– Pulmonary symptoms improving

– Patient felt well otherwise, no headache, fever and neck stiffness

– CD4 count = 50; other screening bloods normal.

• CrAg positive

• Started on fluconazole 1200 mg per day for 2 weeks

• Reviewed at 2 weeks to start ART: EFZ, 3TC, TDF

Discussion points

• 30% of patients with CD4 count <100 will have concomitant TB

• Rifampicin induces cytochrome p450 enzymes → need to increase dose of fluconazole by 50%

• Fluconazole and rifampicin are both hepatotoxic→ watch out for signs of liver toxicity

• High-dose fluconazole & TB meds can often cause nausea/GI disturbance

– May help to split fluconazole dose to twice daily

– If severe nausea, give antiemetic 30 minutes before

Thank you to all participating Thank you to all participating

patients, laboratory, clinical and patients, laboratory, clinical and

administrative staff for submitting administrative staff for submitting

case reports and isolatescase reports and isolates

NICDNICD

RMPRU:RMPRU: Ruth Mpembe, Olga Hattingh, Happy Skosana, Azola Fali, Ruth Mpembe, Olga Hattingh, Happy Skosana, Azola Fali, MabathoMabatho

Moerane, Mignon du Plessis, Nicole Wolter, Kedibone Mothibeli, VMoerane, Mignon du Plessis, Nicole Wolter, Kedibone Mothibeli, Victoria Magomani, ictoria Magomani,

Chivonne Moodley, Maimuna Carrim, Akhona Tshangela, Prabha NaidoChivonne Moodley, Maimuna Carrim, Akhona Tshangela, Prabha Naidoo, Grandee o, Grandee

Shirindza, Shirindza, FahimaFahima MoosaMoosa, Thabo , Thabo MohaleMohale, , LifuoLifuo MakheleMakhele

EDRU:EDRU: Florah Mnyameni, Mimmy Ngomane, Anthony Smith, Husna Florah Mnyameni, Mimmy Ngomane, Anthony Smith, Husna IsmaelIsmael, Nomsa , Nomsa

Tau, Mzikazi Dickmolo, Rosah Kganakga, Tshilidzi Mazibuko, Jack Tau, Mzikazi Dickmolo, Rosah Kganakga, Tshilidzi Mazibuko, Jack KekanaKekana, ,

ThandubuhleThandubuhle GonoseGonose, Rachel Modiba, Vashnee , Rachel Modiba, Vashnee MoonallalMoonallal

MRU:MRU: ThokoThoko Zulu, Brian Nemukula, Sonto Mavasa, Nthabiseng Matjomane, Zulu, Brian Nemukula, Sonto Mavasa, Nthabiseng Matjomane,

Marelize van Wyk Marelize van Wyk

PRU:PRU: Rita van Deventer, Benjamin Mogoye, Ramona Moodley , David SoloRita van Deventer, Benjamin Mogoye, Ramona Moodley , David Solomonmon

NMSU:NMSU: Portia Mogale, Thembi Mthembu, Dumisani Mlotshwa, Emily DloboyiPortia Mogale, Thembi Mthembu, Dumisani Mlotshwa, Emily Dloboyi, ,

Bulelwa Zigana, Dumisani Sithole, Gugu Moyo, Nondumiso Sithole, Bulelwa Zigana, Dumisani Sithole, Gugu Moyo, Nondumiso Sithole, Judith TshabalalaJudith Tshabalala

AMRRU:AMRRU: Vivian Fensham,Vivian Fensham, Ashika Singh, Marshagne Smith, Rebecca Landsberg, Ashika Singh, Marshagne Smith, Rebecca Landsberg,

Elias Khomane, Yoliswa QuluElias Khomane, Yoliswa Qulu , Zazi Tshabalala, Crystal Zazi Tshabalala, Crystal ViljoenViljoen

Surveillance officers: Sandisiwe Joyi (EC); Khasiane

Mawasha (FS); Rachel Nare, Hazel Mzolo, Busi Mbatha,

Joy Appolis, Molly Morapeli, Mokupi Manaka, Sylvia

Nkomo, Ophthia Kaoho, Zodwa Kgaphola, Anna Motsi,

Fiona Timber, Vusi Ndlovu, Venesa Kok (GA); Khuthaza

Mazibuko, Nokuthula Nzuza, Cordelia Mazamo, Michelle

Moodley, Indran Naidoo, Ulenta Chetty (KZN); Maria

Mokwena (LP); Sunnieboy Njikho (MP); Lorato Moapese

(NC); Mmakgomo Rakhudu (NW); Cecilia Miller, Nazila

Shalabi, Priscilla Mouton, Cheryl Mentor (WC)

GERMSGERMS--SASA: : Sandeep Vasaikar, Dania Perez (EC); Gene Elliott, Ute Sandeep Vasaikar, Dania Perez (EC); Gene Elliott, Ute HallbauerHallbauer (FS); Charles Feldman, Trusha (FS); Charles Feldman, Trusha

Nana, Charlotte Sriruttan, Norma Bosman, Sheba Varughese, AdrianNana, Charlotte Sriruttan, Norma Bosman, Sheba Varughese, Adrian Duse, Warren Lowman, Alan Karstaedt, Duse, Warren Lowman, Alan Karstaedt,

David Moore, Sharona Seetharam, Jeanette Wadula, David Moore, MaDavid Moore, Sharona Seetharam, Jeanette Wadula, David Moore, Maphoshane Nchabeleng, Bonnie phoshane Nchabeleng, Bonnie

Maloba, Maloba, MoamokgethiMoamokgethi Moshe, Anwar Hoosen, Kamaldeen Baba, Ruth Lekalakala, Kathy LinMoshe, Anwar Hoosen, Kamaldeen Baba, Ruth Lekalakala, Kathy Lindeque, deque, TheunsTheuns

Avenant, Nicolette du Plessis, Gary Reubenson, Ranmini KularatneAvenant, Nicolette du Plessis, Gary Reubenson, Ranmini Kularatne (GA); Yacoob Coovadia, Moherndran (GA); Yacoob Coovadia, Moherndran

Archary, Prasha Mahabeer, Ramola Naidoo, Archary, Prasha Mahabeer, Ramola Naidoo, KhatijaKhatija Dawood, Halima Dawood, Dawood, Halima Dawood, SummayaSummaya HaffajeeHaffajee, Fathima , Fathima

NabyNaby, Khine Sweswe, Prathna Bhola (KZN); Takalani Muditambi, Ken Ham, Khine Sweswe, Prathna Bhola (KZN); Takalani Muditambi, Ken Hamese (LP); Greta Hoyland, Jacob ese (LP); Greta Hoyland, Jacob

Lebudi, Barry Spies (MP); Stan Harvey, Pieter Jooste, Eunice WeLebudi, Barry Spies (MP); Stan Harvey, Pieter Jooste, Eunice Weenink (NC); Andrew Rampe, enink (NC); Andrew Rampe, LinaLina SonoSono (NW); (NW);

Andrew Whitelaw, Brian Eley, James Andrew Whitelaw, Brian Eley, James NuttalNuttal, Preneshni Naicker, Elizabeth Wasserman, Louise Cooke, Heather, Preneshni Naicker, Elizabeth Wasserman, Louise Cooke, Heather

Finlayson, Helena Finlayson, Helena RabieRabie, Colleen Bamford, Heidi Orth, Mark Nicol, Rena Hoffmann, Steve , Colleen Bamford, Heidi Orth, Mark Nicol, Rena Hoffmann, Steve Oliver (WC); Oliver (WC); Keshree Keshree

Pillay, Chetna Govind (LANCET); Adrian Brink, Maria Botha, PeterPillay, Chetna Govind (LANCET); Adrian Brink, Maria Botha, Peter Smith, Inge Zietsman, Suzy Budavari, Xoliswa Smith, Inge Zietsman, Suzy Budavari, Xoliswa

Poswa (Ampath); Marthinus Senekal (Poswa (Ampath); Marthinus Senekal (PathCarePathCare); Anne Schuchat (CDC), Stephanie Schrag (CDC); Keith ); Anne Schuchat (CDC), Stephanie Schrag (CDC); Keith

Klugman (Emory); Anne von Gottberg, Linda de Gouveia, Karen KeddKlugman (Emory); Anne von Gottberg, Linda de Gouveia, Karen Keddy, Arvinda Sooka, John Frean, Bhavani y, Arvinda Sooka, John Frean, Bhavani

Poonsamy, Desiree du Plessis, Olga Perovic, Nelesh Govender, VanPoonsamy, Desiree du Plessis, Olga Perovic, Nelesh Govender, Vanessa Quan, Cheryl Cohen, Susan Meiring, essa Quan, Cheryl Cohen, Susan Meiring,

Penny Crowther, Jaymati Patel, Melony Penny Crowther, Jaymati Patel, Melony FortuinFortuin––de Smidt, Mohlamme John Mathabathe, Relebohile Ncha, de Smidt, Mohlamme John Mathabathe, Relebohile Ncha,

Claire von Mollendorf, Nireshni Naidoo, Vusi Nokeri, Babatyi KgClaire von Mollendorf, Nireshni Naidoo, Vusi Nokeri, Babatyi Kgokong, Jabulani Ncayiyana (NICD)okong, Jabulani Ncayiyana (NICD)

This work has been supported by the NICD/ NHLS & in part by coopThis work has been supported by the NICD/ NHLS & in part by cooperative agreements from the Centers for erative agreements from the Centers for

Disease Control and Prevention.Disease Control and Prevention.

Acknowledgements

NICD/ NHLS

• Centre for Opportunistic, Tropical and Hospital Infections

NHLS

• Sagie Pillay

• Wendy Stevens

• NPP Unit

Chris Hani Baragwanath

• Alan Karstaedt

• Jacqui Mendes

CDC

• Jeff Klausner

• Monika Roy

• Tom Chiller

USAID-South Africa

• Melinda Wilson

NDOH

• Margaret Ntlangula

• Thobile Mbengashe

• Yogan Pillay

Cape Town/ London

• Tom Harrison

• Graeme Meintjes

• Joseph Jarvis

• Nicky Longley

• Tihana Bicanic

Uganda/USA

• David Meya

• David Boulware

Immy

• Sean Bauman

PEPFAR partners

Documents

Tackling Public Enemy #2: Screening to Prevent Cryptococcal