Should IGRAs replace the TST?

Transcription

1 Should IGRAs replace the TST? Jim Rothel Melbourne, Australia Disclaimer: I am a consultant to Cellestis, a QIAGEN company

2 Presentation Outline Comparative performance of QFT and the TST Is the TST / QFT dual strategy useful? Should IGRAs replace the TST? Conclusions 2

3 Peer reviewed IGRA publications over time: Still rapidly growing - As of March 2013, > 800 on QFT 800 Total Source: PubMed

4 Performance of IGRAs and the TST Clear consensus from developed country studies: IGRAs are more specific than the TST Unaffected by BCG and most NTM IGRAs are more sensitive for active TB IGRA results are more closely related to measures of LTBI risk IGRAs are less affected by immunosuppression QFT is more cost-effective in almost all settings (in developed countries) However, one area of superior performance is still debated by some Progression to Active TB

5 Progression to Active TB Is it sensible to require QFT to have a high PPV for progression before being widely used? That s what s being expected by some But, QFT is a measure of MTB infection A necessity for progression, not a cause The requirement for a high PPV seems misconceived Progression to active TB is dependent on many factors: Being infected with MTB Time since infection Infectious dose Immune status Nutritional status Co-morbidities Etc. Etc. But despite the inappropriate expectation does QFT detect those who will progress?

6 6 Predictive value of interferon-gamma release assays and tuberculin skin testing for predicting progression from latent TB infection to disease state: a meta-analysis. Diel R, Loddenkemper R, Nienhaus A. Chest. 2012

7 7 (N = 6,385) PPV= 1.5% Diel R, Loddenkemper R, Nienhaus A. Chest

8 8 (N = 3,391) PPV= 2.4% Diel R, Loddenkemper R, Nienhaus A. Chest. 2012

9 9 Progression to Active TB (N = 5,194) PPV= 2.7% Diel R, Loddenkemper R, Nienhaus A. Chest. 2012

10 10 (N = 1,436) PPV= 6.8% Diel R, Loddenkemper R, Nienhaus A. Chest. 2012

11 Progression to Active TB IGRA TST p All studies PPV 2.7% 1.5% < High risk populations PPV 6.8% 2.4% <0.0001

12 Progression to Active TB NPV= 99.7% n=12,154 Diel R, Loddenkemper R, Nienhaus A. Chest

13 13 NPV= 99.4% n=8,618 Diel R, Loddenkemper R, Nienhaus A. Chest. 2012

14 Progression to Active TB IGRA TST p All studies PPV 2.7% 1.5% < High risk populations PPV 6.8% 2.4% < All studies NPV 99.7% 99.4% <0.01

15 Progression to Active TB What can we learn from predictive studies? IGRAs (QFT) have a very high NPV for progression o In most populations, a negative result can be trusted IGRAs (and the TST) alone are not predictors of progression to active TB o They tell us if a person is infected - a needed condition for progression Progression is related to risk factors o Perhaps the most important being recent infection, immune status and comorbidities In those with these risk factors (e.g. recent contacts) the rate of progression if IGRA positive is high (much higher than if TST positive) o In those with older ( remote ) infection the rate of progression is much lower With QFT we have a test that detects those truly infected we now have to work out how to best use it Targeted testing

16 Role of QFT for TB control Targeted testing and treatment for LTBI is the key Priority targets should include: Close contacts Immunosuppressed Major medical co-morbidities At risk HCWs Immigrant screening

17 How does QFT compare with TST in these target groups?

18 Comparative performance of QFT and TST Probably the best way to compare performance is to use estimates from independent meta-analyses SENSITIVITY Meta-analyses QFT TST Diel et al Chest 2010 Developed country 84.5% 71.5% Sester et al ERJ % 68% NOTE: This is sensitivity for ACTIVE TB, sensitivity for LTBI likely much higher SPECIFICITY Meta-analyses QFT TST Diel et al Chest % ND Pai et al 2008 (BCG vaccinated) ND 59% Pai et al 2008 (not vaccinated) ND 97% US CDC Guidelines 99% 86% Diel et al ERJ % 88.7%

19 Comparative performance of QFT and TST For the European setting, let us assume the following estimates: QFT Sensitivity for active TB 83.0% Specificity 99.4% TST Sensitivity for active TB 71.5% Specificity 78%* (* TST specificity based o a 50% BCG vaccination rate) What does this mean for test accuracy?

20 How does QFT and TST compare in accuracy? QFT Se. 83%, Sp. 99.4%. TST Se. 71.5%, Sp. given Prevalence TEST PPV (%) NPV (%) Accuracy (%) 1% QFT 58.3% 99.8% 99.2% TST 3.2% 99.6% 77.9% 5% QFT 87.9% 99.1% 98.6% TST 14.6% 98.1% 77.7% 25% QFT 97.9% 94.6% 95.3% TST 52.0% 89.1% 76.4% 50% QFT 99.3% 85.4% 91.2% TST 76.5% 73.2% 74.8%

21 How does QFT and TST compare in accuracy? QFT Se. 83%, Sp. 99.4%. TST Se. 71.5%, Sp. given Prevalence TEST PPV (%) NPV (%) Accuracy (%) 1% QFT 58.3% 99.8% 99.2% TST 3.2% 99.6% 77.9% 5% QFT 87.9% 99.1% 98.6% TST 14.6% 98.1% 77.7% 25% QFT 97.9% 94.6% 95.3% TST 52.0% 89.1% 76.4% 50% QFT 99.3% 85.4% 91.2% TST 76.5% 73.2% 74.8%

22 How does QFT and TST compare in accuracy? QFT Se. 83%, Sp. 99.4%. TST Se. 71.5%, Sp. given Prevalence TEST PPV (%) NPV (%) Accuracy (%) 1% QFT 58.3% 99.8% 99.2% TST 3.2% 99.6% 77.9% 5% QFT 87.9% 99.1% 98.6% TST 14.6% 98.1% 77.7% 25% QFT 97.9% 94.6% 95.3% TST 52.0% 89.1% 76.4% 50% QFT 99.3% 85.4% 91.2% TST 76.5% 73.2% 74.8%

23 How does QFT and TST compare in accuracy? QFT Se. 83%, Sp. 99.4%. TST Se. 71.5%, Sp. given Prevalence TEST PPV (%) NPV (%) Accuracy (%) 1% QFT 58.3% 99.8% 99.2% TST 3.2% 99.6% 77.9% 5% QFT 87.9% 99.1% 98.6% TST 14.6% 98.1% 77.7% 25% QFT 97.9% 94.6% 95.3% TST 52.0% 89.1% 76.4% 50% QFT 99.3% 85.4% 91.2% TST 76.5% 73.2% 74.8%

24 Cost-effectiveness of IGRAs, TST and chest x-ray for TB screening A number of papers have been published investigating the cost-effectiveness of TB screening methods. Key populations studied are: Contacts Mol Diagn Ther. 2008;12: Healthcare workers Hosp Infect. 2011;78: Prisons Epidemiol Infect. 2013; 3:1-11. [Epub] Hemodialysis patients Nephrol Dial Transplant [Epub] School students Mol Diagn Ther. 2012;16: Employees Am J Infect Control. 2011;39:e67-72 Rheumatoid arthritis patients Mol Diagn Ther. 2010;14: Elderly Mol Diagn Ther. 2010;14: In almost every situation, QFT has been shown as the most efficient screening method from both a health and a cost perspective Some studies have reported the TST/QFT dual strategy as the most cost effective, but these papers have used debatable estimates of sensitivity and specificity in their analysis. NOTE: The UK s NICE guidelines now report QFT alone as the most cost effective

25 Is the TST / QFT dual strategy useful?

26 Is the TST / QFT dual strategy useful? Interest in using the TST as the initial test and confirming positives using QFT was first raised by the UK s NICE guidelines They found this process was slightly less expensive than using QFT alone This guideline was NOT based on health-effectiveness The updated NICE guidelines now recommend IGRA only Largely based on updated performance data and practical issues with running two tests Identified QFT alone as the least expensive method A small number of published cost-effectiveness studies find TST/QFT strategy slightly cheaper than QFT alone Due to different models and or different performance estimates? But cost is not the only parameter to consider what about diagnostic accuracy?

27 IGRAs versus TST in serial testing of HWs Nienhaus et al. Expert Rev. Anti Infect. Ther. 11(1), (2013) Routine TB screening is a cornerstone in preventing TB in hospitals Clear advantage to using IGRAs for pre-employment screening Serial TB screening should be risk-based. Proposes 3 groups regarding frequency of screening High risk: regular contact with infectious TB or infectious material screen annually, bi or tri-annually Medium Risk: regular contact with patients not known to have TB screen routinely or only when exposed Low risk: no regular contact with patients no routine screening

28 Nienhaus et al. Expert Rev. Anti Infect. Ther. 11(1), (2013) Missed by QFT? Unlikely BCG false positive more likely Missed by TST

29 Effect of introducing IGRAs in HCW TB screening Less positives: reduction in number of CXRs and preventive treatment Low-intermediate incidence countries: 32 cross sectional studies and all but one noted lower prevalence of positive IGRA than +TST However, significant number of QFT+ / TST - results Conclusion: TST followed by IGRA confirmation should not be done in low/intermediate incidence countries

30 Predictive power of QFT for development of active TB Diel, Loddenkemper et al., AJRCCM, 27 August close contacts 198 QFT-positive 756 QFT-negative 142 QFT-positive/ TST-positive 5 QFT-positive TST-negative 51 QFT-positive (49 TST-positive) 413 TST positive 343 TST negative Not treated Not treated Chemoprophylaxis RIF and/or INH Not treated TST / QFT strategy would have missed these two TB cases Not treated 17 developed active TB 2 developed active TB No active TB No active TB No active TB Mean follow-up >3.5 yr

31 Is the TST / QFT dual strategy useful? Some studies suggest it might be slightly cheaper However, sensitivity will be reduced compared with QFT alone Two different testing methods will have to be maintained What does the clinician do with someone TST positive / QFT negative? The US CDC specifically recommend against using the dual strategy UK NICE guidelines no longer recommend TST/QFT strategy

32 Should IGRAs replace the TST?

33 Should IGRAs replace the TST? Some Facts: QFT is significantly more specific than TST, unaffected by BCG QFT is more sensitive in detecting active TB QFT results are closely related to measures of infection risk TST results are often not associated QFT has significantly higher PPV and NPV for progression than the TST QFT is less affected by immunosuppression QFT is objective, whereas TST interpretation is subjective QFT is more cost-effective in almost all developed country settings Given the above, it s hard to think of any situation where QFT should not be preferentially used

34 CONCLUSIONS Tackling LTBI is likely to provide the biggest gains in enhancing TB control The TST has been useful, but has many performance problems New tools now exist that have and should continue to improve TB control Development of enhanced IGRAs is already happening Development of new drug regimens that simplify LTBI treatment (Rifapentene/INH) make testing for LTBI more practical The benefit of LTBI screening and treatment lies in targeted use (testing of highest-risk groups)

35 Many thanks for your attention

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39 HSIA - ARTHRITIS & RHEUMATISM 2012

40 HSIA - ARTHRITIS & RHEUMATISM different multicentre/multinational studies were conducted with Golimumab (J&J) 2,228 patients with RA, PsA or AS 34% BCG vaccinated 67% taking corticosteroids (prednisolone), 43% at time of testing All screened with TST (different cut-offs), QFT and chest x-ray Multivariate regression analysis looked at the variables: Methotrexate use Corticosteroid use Age (>65 years vs < 65 years) World region (Asia, Nth America, East Europe, West Europe, Latin America)

41 HSIA - ARTHRITIS & RHEUMATISM 2012 Limited agreement between QFT and TST Low rate of QFT indeterminate results - 1.8%

42 HSIA - ARTHRITIS & RHEUMATISM 2012 Agreement between positive TST and QFT results TST cut-off varied according to local country guidelines. Test Positive % TST 7.0 QFT 9.4 Agreement between QFT and TST fair (kappa coefficient of 0.22).

43 HSIA - ARTHRITIS & RHEUMATISM 2012 BCG vaccination explained some of the TST positive discordance 781 (34.2%) out of the 2,282 BCG vaccinated BCG vaccinated Non-BCG vaccinated Test Positive % TST 15.2 QFT 9.1 Test Positive % TST 5.0 QFT 5.8 Supports TST being significantly affected by BCG vaccination

44 HSIA - ARTHRITIS & RHEUMATISM 2012 Screening results by geographic region and prior BCG vaccination Region Positive % %BCG North America Western Europe Eastern Europe Latin America Asia

45 HSIA - ARTHRITIS & RHEUMATISM 2012 Multivariate analysis of factors associated with LTBI QFT positive results associated with indicators of TB risk Age > 65 years TB rate in region of origin TST results less strongly associated with region of origin but also with BCG vaccination MTX or corticosteroid use did not have an effect on QFT or TST result Small trend for higher positive rate with QFT

46 HSIA - ARTHRITIS & RHEUMATISM 2012 Key messages: QFT positivity correlated with TB risk factors more so than the TST Suggests higher sensitivity than TST in immunosuppressed MTX (10mg/day) or corticosteroids did not effect test result TST confounded by BCG vaccination Very low number of indeterminate results (1.8%) Authors conclusion: In the absence of a true gold standard for latent TB infection, results of this comparison ( ) suggest that the IGRA provides greater specificity and possibly greater sensitivity than the TST.

47 Renal dialysis patients

48 Rogerson et al. Am J Kidney Dis :33-43 Analyzed published studies employing IGRAs in ESRD patients 9 studies were identified 3 TST vs QFT (n=347) 2 TST vs T-Spot (n=418) 4 3-way studies (n=361) Results compared to TST by risk association: Positive QFT more strongly associated with clinical risk than TST Radiologic evidence of past TB (OR 4.29, p=0.001) Contact to TB (OR 3.36, p=0.001) Negative QFT associated with BCG (OR.30 p=0.002) - Protective? T-Spot: no statistical differences for any clinical risk factor

49 QFT versus TST in renal dialysis patients

50 Rogerson et al. Am J Kidney Dis :33-43 Major conclusions ELISA-IGRA likely to be a more accurate diagnostic tool for LTBI in ESRD Consistent with previous systematic reviews of general population showing QFT results are better correlated with TB exposure and independent from prior BCG Propose that the ELISA-IGRA should be the test of choice

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52 KOBASHI INTERNAL MEDICINE 2012 There are differing opinions in the medical community regarding use of IGRAs to aid active TB diagnosis Most studies saying not to use IGRAS are from developing countries This study looked at differential diagnosis of active TB in Japan: 66 patients who required clinical differentiation of pulmonary TB 22 diagnosed with TB based on culture 44 had other pulmonary infections confirmed Compared TST, QFT-2G, QFT-3G and T-Spot.TB

53 KOBASHI INTERNAL MEDICINE 2012

54 KOBASHI INTERNAL MEDICINE 2012 The 3 patients without TB and QFT positive, were also T-Spot positive Two of these had M. kansasii confirmed and would be expected positive T-Spot was presumably false-positive in 3 patients without TB

55 KOBASHI INTERNAL MEDICINE 2012 QFT had good sensitivity and specificity for diagnosing active TB in this study HOWEVER: This was a developed country study, with assumed low rate of LTBI In a high prevalence setting would expect poor specificity MANY of the 22 patients with TB would have been easily diagnosed without IGRA No need for IGRA in most cases of active TB diagnosis CONCLUSIONS: QFT can aid diagnosis of active TB, when conventional methods are inconclusive Use of IGRAs for active TB should be selective QFT (or any IGRA) should not be used as a routine diagnostic for active TB Especially in moderate to high prevalence settings