Date post: | 12-Mar-2018 |
Category: |
Documents |
Upload: | trinhhuong |
View: | 215 times |
Download: | 2 times |
What did we learn about HIV and IGRA
Pernille Ravn,MD, PhD,
Big Island
Hawaii 2012
Associate ProfessorUniversity Hospital Odense
Disclosure: Patent on the use of IP10 for diagosis of TB infection. Cellestis Invited speaker and rceived kit for research, Support from Schering Plough, MSD, Abbott,
Natural course of HIV infection
4
Pulmonary TB
Disseminated TB
IGRA and HIV ?
• Diagnosing active TB in TB suspect• Diagnosing active TB in TB-suspect
• Screening for active TB before starting IPT
S i f LTBI t t ti TB• Screening for LTBI to prevent active TB
• Low CD 4 cell count and IGRA
IGRA for diagnosing active TB in HIV+ ve
• 590 HIV+ ve• 844 HIV-ve• 27 studies (17 QFT-IT, 10 T-SPOT.TB)
Sensitivity HIV +ve HIV-ve
More indeterminate results 15% (9-21) vs 4% (1-7)
John Metcalfe
IGRA for diagnosing active TB in HIV+ve
Lower sensitivity
More indeterminate results
Neither better nor worse than TST (few studies)
No real differences between the two IGRAs (3 studies, 37 pt)
Metcalfe et al. JID 2011
Additional studies confirm these statements(Ling et al, ERJ 2011, Rangaka et al., ERJ, 2011)
Eur Inf Dis 2010
Focus on commercially available tests (20/30 studies)
Sensitivity in active TB, positivity and indeterminate rates
and the influence of low CD4 cell count
Active TB- Effect of HIV on IGRA Commercially available IGRAs – up to 2010
% No No of Positivity tested studies
TST 43 236 6
QFT-IT 66 290 6
T-SPOT 72 77 4
Hoffmann and Ravn, Eur Inf Dis 2010
Overall effect of HIV on indeterminate ratescommercially available IGRA - anno 2010
LTBI Active TB
% Inde-terminate
n(# studies)
% Inde-terminate
n(# studie)
QFT 3 550(3)
13 90(2)
QFT IT 4 2151 16 5 290QFT-IT 4 2151(5)
16,5 290(6 )
T-SPOT 7,5 908(6)
9,5 64(3)
Hoffmann and Ravn, Eur Inf Dis 2010
Effect of indeterminate rate on sensitivityCommercially available IGRAs – up to 2010
% Indeter- Sensitivity
Sensitivityexcluding
No tested
No of studiesIndeter
minateSensitivity excluding
indeterminatetested studies
TST na 43 Na 236 6
QFT Excluded - 65 26 2
QFT-IT 16,5 66 79 290 6
T-SPOT 9,5 72 82 77 4*
Hoffmann and Ravn, Eur Inf Dis 2010* 1 study excluded indeterminate
Screening for active TB before IPT and HAART
779 HIV + ve in South Africa
Could QFT improve the performance of a clinical algorithm? – not being on ART – weight less than 60 kg – no history of prior TB– any one positive TB symptom/sign (cough ≥ 2 weeks) – CD4+ count less than 250 cells/mm
Result:No discriminatory value of IGRA
Molebogeng X Rangaka in ERJ 2011
CountryStudy subjects
HIV + ve Sensitivity Ref
Combined biomarker approach
using CXCL10/ IP-10
Country HIV + ve Sensitivity Ref
India28 confirmed TB
39% with CD4 cell count<200IP-10 test: 86% QFT-IT: 61%
Goletti et al. PLoS One 2010
Tanzania65 confirmed TB
median CD4 cells count 272 IP-10 test: 63% QFT-IT: 63%
Combining: 71%.
Aabye et al. ERJ 2010
50 confirmed TB patients IP-10 test+ :86% Kabeer et al. AIDS
India50 confirmed TB patients
median CD4 cell count 86 IP 10 test :86%QFT-IT +: 70% 2010
India170 screened for LTBI
22% with CD4 cell count<200IP-10 test+: 45%QFT-IT+: 38%
Combining: 48%
Kabeer et al. Diagn Microbiol Infect Dis 2011
Ruhwald, Aabye and Ravn, ,Exp Review Mol Diagn 2012
Active TB
IGRAs have no value for the diagnosis of active TB in the context of HIV
Prevention is better!
Who are at risk?
What lessons can be learned
from using TSTfrom using TST
Risk of TB according to TST and IPT
Elzi et al, CID 2007
IPT reduces risk of TB in TST+veRelative Risk
Overall
TST +ve
TST -ve
overall
reduction in TB = 33%
reduction inTST+ve
Akolo, Cochrane Review 2010 (11 randomised trials with 8,130 HIV+ ve participants)
TST+ve= 64%
Effect of HAART and IPT on TB incidence
IRR (per 100 PYs) 95% CIs
No IPT, no HAART 7.1 6.2-8.2HAART, no IPT 4.6 3.4-6.2
IPT before HAART 5.2 3.4-7.8HAART and IPT 1.1 0.02-7.60
Golub et al, AIDS 2009. 2778 patients and 4287 PY
50% Reduction with HAART alone80% Reduction with HAART and IPT
South Africa
Take Home Message
WHO now recommends
Isonizid 6 months to all HIV+ve without active TB
TST/IGRA not required
X ray not required
Isonizid 36 month in TST +veIsonizid 36 month in TST +ve
IGRA and screening for LTBI
Several studies on IGRAs and TST in HIV+ve cohortes without TB (i.e. reviewed Cattamanchi J AIDS,
2011, Hoffmann and Ravn, Eur Inf Dis 2010)
Few detailed studies on the effect of CD4
Few studies on prognostic value in HIV +ve (Clarck, Elliot, Jonnalagadda, Aichelburg, and Ravn unpublished)
Prognostic value of IGRA in HIV+ve
• 590 HIV+ve from Denmark590 HIV ve from Denmark• QFT-IT screened (Brock et al, Resp Research 2006)
• Active TB• 2/28 positive PPV = 7%• 1/542 negative NPV = 99 8%1/542 negative NPV 99,8%• 0/29 Indeterminate
Ravn, Søborg, Ruhvald et al, unpubliished
% indeterminate in HIV +ve screened for LTBI
Cattamanch A et al., J AIDS 2011
• ”Variable effect on proportion of positive and indeterminate results of CD4 < 200 cells/ul”
Cattamanch A et al., J AIDS 2011
Hoffmann and Ravn 2010, Eur Inf Dis
QFT-IT
TSPOT
Effect of immunosuppression on IGRA results in patients with active TB
65 HIV infected TB patients from Tanzania65 HIV infected TB patients from Tanzania
32Aabye et al PlosONE 2009
100
Effect of immunosuppression on IGRA -Mitogen response
IU/ml
1
10
0-99
100-1
99
200-3
00>3
00
0.1
CD4 ll t ( ll / i lit )
Brock et al. Respiratory Research,
2006P<0.0001
Effect of immunosuppression ? Lessons from TST
Elzi CID 2007
Are IGRA less effected than the TST
247 HIV+ve from Senegal
T-SPOT.TB
TST
35Karam et al PlosONE 2008
Need for more differentiated meta-analysis with detailed sub-analysis of the impact of low CD4
1
Positive re
sult
Indeterminate
36
immunosuppression
Ruhwald 2011
Need for more differentiated meta-analysis with detailed sub-analysis of the impact of low CD4
1 2 Po
sitive re
sult
Indeterminate
37
immunosuppression
Ruhwald 2011
Need for more differentiated meta-analysis with detailed sub-analysis of the impact of low CD4
1 2 3
Positive re
sult
Indeterminate
38
immunosuppression
Ruhwald 2011
Summary 1
• Low PPV
• High NPV in low endemic regions
• Variable NPV in high endemic regions
Summary 2• Reduced sensitivity compared to HIV-ve
• More indeterminate compared to HIV-ve
• Correlation between CD4 cell count and IGRA performance
Still to be determined
• The effect of targeted IPT• The effect of targeted IPT
• Differences between IGRAs
Eff t f t d di CD4 ll• Effect of current and nadir CD4 cell count/viral load and comorbidity, low BMI..
Need for more differentiated meta-analysis with detailed sub-analysis of the impact of low CD4
1 2 3
Positive re
sult
Indeterminatecut off
42
immunosuppression
Ruhwald 2011
Thank you!Hvidovre HospitalDep. of Infectious DiseasesClinical Research CentreM t R h ld MD PhD
Statens Serum InstituteInt. Reference Lab. of MycobacteriologyVibeke Østergaard ThomsenTh Sti HMorten Ruhwald, MD, PhD
Martine Aabye, MDLine L HolmAnne Marie Werlinrud
National Institute for Medical ResearchMwanza Medical Research CentreGeorge PrayGod, MD, PhDKidola Jeremiah, MDJohn Changalucha, DScOswald Kaswamila
Thomas Stig Hermansen
University Hospital OdenseDep. of Infectious DiseasesAase B. Andersen, MD, DMSc
Muhimbili Medical Research CentreNyagosya Range, DSc, PhD
contact: [email protected]