What did we learn about HIV and IGRA

Pernille Ravn,MD, PhD,

Big Island

Hawaii 2012

Associate ProfessorUniversity Hospital Odense

peravn@gmail.com

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: Peravn@gmail.com