2. Dr Mpho Tlali

17‐Jun‐14
Sensitivity of urine LAM vs. sputum TB culture in ambulant HIV+ patients: the TB Fast Track study
Mpho Tlali
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Background
• TB diagnosis difficult in HIV + people
• Existing diagnostic tests for TB serve HIV+ Existing diagnostic tests for TB serve HIV+
patients poorly
– sputum smear negative TB common
– sputum culture, long turn around times – CXR often not available on site
• Xpert MTB/RIF challenges remain
MTB/RIF challenges remain
– suboptimal sensitivity
– relatively complex – patients often sputum scarce/ EPTB
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17‐Jun‐14
New TB diagnostics
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Urine lipoarabinomannan
Urine
lipoarabinomannan (LAM): (LAM):
• major lipopolysaccharide component of the mycobacterial cell wall
• PoC tests ideal resource limited settings
– simple, affordable & rapid
– no requirement for sputum
• sensitivity low in general population
• higher sensitivity with HIV & advanced disease
TB Fast Track: rationale
• Designed for primary care clinics with no on‐
site lab facilities
• Nurses responsible for most care but
– can't start TB treatment unless smear or culture (or Xpert) positive
– cannot order CXR
– usually cannot start empirical TB treatment without a doctor's authorityy
• How can we help nurses to identify HIV+ people at high TB risk, so they can start TB treatment immediately?
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17‐Jun‐14
TB Fast Track
• Open, cluster‐randomised trial
• Clusters are 24 primary health clinics in South Africa
Clusters are 24 primary health clinics in South Africa
– Limpopo, Gauteng, North West provinces
• Adults with HIV and CD4 ≤150 presenting for ART are eligible
• Tests an intervention aiming to identify HIV+ people at high risk of TB – to
to start TB treatment immediately, followed by ART
start TB treatment immediately followed by ART
– the intervention is a novel algorithm based on TB symptom screen, LAM, BMI & Hb
• Primary outcome: all‐cause mortality at 6m
LAM evaluation sub study: Aim
Among TB Fast Track study participants enrolled t th i t
to the intervention arm:
ti
• To estimate the sensitivity of PoC LAM compared to the gold standard of sputum culture positive for M tb
culture positive for M.tb
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17‐Jun‐14
Methods • Inclusion criteria:
– Enrolled into TB Fast Track study intervention arm before 1 March 2014
– Have LAM and sputum culture result available
LAM Test
• PoC urine LAM on all intervention arm participants –
ti i
t Determine
D t
i TM TB LAM test
TB LAM t t
– Performed on site by trained research nurses
– On fresh urine samples – Results read by single reader within 25‐35 minutes
– Positive result: any visible band 1
Positive result: any visible band 1+ to 5
to 5+ 4
17‐Jun‐14
Gold standard sputum culture
• Single spot sputum collected from participants i i t
in intervention arm
ti
• Sputum collected on site by research nurses
– MGIT culture on all samples
– HAIN DR plus for species ID LAM sensitivity
• LAM sensitivity is calculated as: a/(a+c)
– Numerator = total LAM pos plus culture pos (a)
– Denominator Denominator = total sputum culture pos
total sputum culture pos M.tb (a+c)
`
MTB positive
MTB negative
LAM +
a (TP)
b (FP)
a+b
LAM ‐
c (FN)
d (TN)
c+d
a+c
b+d
• LAM specificity not evaluated as part of study
– a single sputum culture results not adequate to exclude TB
• High risk population for active TB
• High likelihood of extra pulmonary TB
• All LAM + start TB treatment
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17‐Jun‐14
Results
Intervention participant N=838
Invalid LAM n=1
LAM results valid l
ld
n=837
Unable to produce sputum n=276
Sputum collected n=561
Culture result available
Outstanding results Outstanding
results
n=20
contaminated n=11
n=530
Demographic data • For 530 participants with valid sputum and LAM test
Parameter
Age : median (IQR)
Gender : female (%)
CD4 : median (IQR)
d ( )
Hb : median (IQR)
BMI : median (IQR)
N=530
38 (32‐44) 269 (50.8%) 76.5 (35‐112) 76
5 (35 112)
11.0 (9.6‐12.7)
20.8 (18.7‐24.3) IQR: interquartile range
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17‐Jun‐14
LAM results, n=530
• 13.2% (70/530) LAM positive = any band visible • 5.5% (29/530) LAM positive = grade ≥ 2+
5 5% (29/530) LAM
iti
d ≥2
Sputum mycobacterial culture results, n=530
• Overall 12% (62/530) culture positive for M.tb
Overall 12% (62/530) culture positive for M tb
– additional 7% (48/530) culture positive for NTM
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17‐Jun‐14
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Sensitivity of LAM
100%
90%
positive = any band visible
80%
Sensitivity (95% CI)
70%
positive = ≥ 2+ 60%
50%
40%
30%
20%
45%
10%
23%
0%
Overall
Overall 2+
n/N: 28/62 14/62
22.6% , (14/62), Sensitivity using cut off of 2+ 95% CI: 12.9%, 35.0%
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17‐Jun‐14
Sensitivity of LAM
100%
90%
Sensitivity (95% CI)
80%
70%
60%
50%
40%
30%
20%
60%
56%
52%
45%
41%
38%
37%
10%
0%
Overall
CD4<50
CD4 50‐150
BMI<18.5 BMI>=18.5
N: 62 20 42 23 39 Hb <=10
Hb >10
27 35
Sensitivity increased with high risk markers; CD4<50, BMI <18.5 & Hb ≤10
Limitations
• This is a pragmatic study
– no estimate of specificity
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17‐Jun‐14
Conclusion
• LAM sensitivity moderate in high risk group (CD4 ≤150)
(CD4 ≤150)
• Higher sensitivity in sub groups with poor prognostic indicators • As a single test, proportion LAM + is low, so unlikely to be useful in isolation in this ambulatory population b l t
l ti
• LAM may be more useful in combination with other tests
The TB Fast Track participants
Acknowledgement
TB Fast Track team
Funders
Parktown: Aaron Karat, Tshifhiwa Muravha, Nelisiwe Xaba, Pule Global Health Trials (UK Dept for International Development / Seatlanyane, Rachel Mukora, Kholofelo Rasethe, Deborah Pako, Skhumbuzo Wellcome Trust / Medical Research Council)
Xaba, Bongani Nkaqa, Zanele Nthebe, Sefalane Monkwe, Monde Phasha, Nwabisa Sosibo, Neema Minja, Xoliswa Mbanjwa,
TB Fast Track investigators
Tshwane: Dalene Blom, Mafa Motloutsi, Miriam Gigqini, Rebecca Modau, London School of Hygiene & Tropical Medicine:
Jacob Jabari, Kwena Sekele, Suzan Kunene, Ivy Sithole, Lolo Ngwenya, Alison Grant – Principal Investigator
Marichen Matlou, Tshepo Motsatsi, Dorothy Mafafo, Tshepo Segala, Betty Katherine Fieldingg
Nthit V
Nthite, Veronica Sekala, Emily Lekitlane, Phanuel
i S k l E il L kitl
Ph
l Nemukombane, Muriel N
k b
M i l
Anna Vassall
Mokgehle
Aurum Institute:
Ekhurhuleni: Tsholofelo Pitso‐Pule, Solani Mthimunye, Makhanana Mawila, Salome Charalambous – Principal Investigator Mpho Tlali
Fikile Khoza
Gavin Churchyard
North West: Puleng Mokoena, Aaron Tshikombedze, Matshidiso
Johns Hopkins University:
Motswaledi
Chris Hoffman
Limpopo: Thulile Mathenjwa, Modjadji Maribeng, Lebogang Matonyane, Susan Dorman
Raymond Magolego, Violet Masenya, Cynthia Masemola, William Foundation for Professional Development: Magolego
Suzanne Johnson
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17‐Jun‐14
TB Fast Track algorithm
TB symptom screen;
urine LAM; BMI; Hb
High probability TB
LAM +, Hb<10;
BMI<18.5
[or smear/xpert pos]
Medium probability TB
symptomatic;
LAM negative; Hb>10,
BMI>18.5
Low probability TB
no TB symptoms,
LAM negative;
Hb>10; BMI>18.5
Further
investigation
Start TB
treatment,
then ART
Start ART
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