HEALTH TECHNOLOGY ASSESSMENT SECTION MEDICAL DEVELOPMENT DIVISION

Transcription

1 QUANTIFERON -TB GOLD HEALTH TECHNOLOGY ASSESSMENT SECTION MEDICAL DEVELOPMENT DIVISION MINISTRY OF HEALTH i MALAYSIA 13/2013

2 DISCLAIMER Technology review is a brief report, prepared on an urgent basis, which draws on restricted reviews from analysis of pertinent literature, on expert opinion and / or regulatory status where appropriate. It has not been subjected to an external review process. While effort has been made to do so, this document may not fully reflect all scientific research available. Additionally, other relevant scientific findings may have been reported since completion of this review. Please contact: htamalaysia@moh.gov.my, if you would like further information. Health Technology Assessment Section (MaHTAS), Medical Development Division Ministry of Health Malaysia Level 4, Block E1, Precinct 1 Government Office Complex 62590, Putrajaya. Tel: Fax: Available at the following website: ii

3 Prepared by: Syful Azlie Md Fuzi Senior Assistant Director Health Technology Assessment Section (MaHTAS) Ministry of Health Malaysia Reviewed by: Dr. Izzuna Mudla Mohamed Ghazali Public Health Physician Senior Principal Assistant Director Health Technology Assessment Section (MaHTAS) Ministry of Health Malaysia Datin Dr. Rugayah Bakri Public Health Physician Deputy Director Health Technology Assessment Section (MaHTAS) Ministry of Health Malaysia DISCLOSURE The author of this report has no competing interest in this subject and the preparation of this report is totally funded by the Ministry of Health, Malaysia iii

4 EXECUTIVE SUMMARY Introduction The diagnosis of latent tuberculosis infection (LTBI) is often challenged by the lack of a gold standard diagnostic test and the absence of clinical symptoms. Until recently, tuberculin skin test (TST) was the only diagnostic test available and has been widely used for diagnosis of both LTBI and active TB. However, certain limitations are associated with the use of TST. In the presence of chronic immunosuppression including autoimmune diseases, the test results may be falsely negative. In patients vaccinated against TB with Bacillus Calmette-Gue rin (BCG) and subclinical infection with non-tuberculosis mycobacteria (NTM), the skin test may lead to false positive results. To overcome the drawbacks of TST, new in vitro assays based on interferon-γ (IFN-γ) release in response to specific M. tuberculosis antigens encoded in Region of Difference-1 (RD-1) have been developed. Two IFN-γ release assays (IGRAs) are currently available: the T- SPOT.TB (Oxford Immunotec, Abingdon, UK), which is based on the enzymelinked immunospot (ELISpot) assay; and the two versions of the whole bloodbased QuantiFERON -TB (QFT) (the QFT Gold [QFT-G] and QFT Gold In-Tube [QFT-GIT] tests (Cellestis, Carnegie, Australia), which use enzyme-linked immunosorbent assay (ELISA) to detect IFN-γ in the culture supernatant. These new assay employ certain antigens like the ESAT-6 and CEP-10 (for T-SPOT.TB and QFT-G), as well as TB7.7 (only for QFT-GIT) to stimulate the production of IFN-γ from the T-cell lymphocytes. These antigens are theoretically more specific as they do not cross-react with the BCG and most NTM. This technology review was conducted following a request from Disease Control Division, Ministry of Health (MOH) Malaysia who received a proposal from a company to promote the usage of the whole blood-based test QuantiFERON -TB Gold in MOH facilities. Objective/aim The objective of this technology review was to review evidence on the efficacy, safety and cost-effectiveness of QuantiFERON -TB Gold as diagnostic tools for detection of patient with LTBI and active TB. Results and conclusions There was fair to good level of retrievable evidence to suggest that the whole blood-based QuantiFERON -TB (QFT) may be effective as diagnostic tools for detection of patient with LTBI and active TB. Despite the limitations, findings in general revealed that QFT appeared to have numerous advantages over TST such as higher specificity, PPV and NPV in adult population in low TB prevalence countries, better relationship with M. tuberculosis exposure, and lower crossreaction rates with BCG vaccination and NTM. By using a lower cut-off value for QFT, the assay sensitivity was improved with no decrease in specificity. Malaysian Ministry of Health Clinical Practice Guidelines on Management of iv

5 Tuberculosis (3 rd Edition) 2012 suggested that the situations where IGRAs may be used are as the following: i. As an alternative to TST for Patients who are not expected to/could not come back for a reading of skin induration after hours Patients who had recent BCG vaccination or past NTM infection ii. Where a 2-step test is considered (TST followed by IGRA) Close-contacts whose TST is in the range of 5-9 mm Patients who are offered LTBI treatment but are not convinced that they have LTBI Individuals who require annual screening of LTBI (such as health care providers working in high risk areas) There was no retrievable evidence related to adverse event of this assays. The only direct adverse effects on patient health from collecting the specimen for testing were those associated with venipuncture, namely a slight risk of bleeding, haematoma, and infection. Pain and redness at the site of injection were reported and some people became dizzy and/or faint when blood is drawn. QuantiFERON -TB Gold on the other hand is CE marked and approved by the US FDA as an in vitro diagnostic aid for detection of M. tuberculosis infection. The US FDA approval notes that QFT-G is intended for use in conjunction with risk assessment, radiography and other medical and diagnostic evaluations. There was also evidence to suggest that QFT-alone was likely to be more costly but more effective than TST in Japan and United States. Analyzing costeffectiveness is more complex because the results vary with many factors including the population being tested. Overall, due to its higher specificity and lower cross-reaction rates with BCG vaccination and NTM, whole blood-based QuantiFERON -TB (QFT) can be used as an alternative to TST for detection of patient with LTBI. Methods Literatures were searched through electronic databases specifically PubMed, Medline, Cochrane, Ovid, Horizon scanning databases, other websites; US FDA, MHRA and from non scientific database - Google search engine. In addition, a cross-referencing of the articles retrieved was also carried out according to the topic. Relevant articles were critically appraised and evidence graded using US/Canadian Preventive Services Task Force. v

6 QUANTIFERON -TB GOLD 1.0 INTRODUCTION Tuberculosis, MTB, or TB (short for tubercle bacillus) is an infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. It typically affects the lungs (pulmonary TB) but can affect other sites as well (extrapulmonary TB). The disease is spread in the air when people who are sick with pulmonary TB (PTB) expel bacteria, for example by coughing. Patients who have been infected but do not show any clinical manifestation of disease activity is said to have latent TB infection (LTBI). In general, a relatively small proportion of people infected with M. tuberculosis will develop TB disease. Studies have shown that the lifetime risk of developing TB reactivation among those with LTBI is about 5 to 10%. This reactivation tends to occur within the first two years after exposure. However, the risk is much higher in immunocompromised individuals. Tuberculosis is also more common among men than women, and affects mostly adults in the economically productive age groups. 1, 2 According to the World Health Organization (WHO), there were an estimated 8.7 million incident cases of TB in 2011 (13% co-infected with HIV). There were also 1.4 million deaths from TB (990,000 deaths among HIV-negative individuals and 430,000 among people who were HIVpositive). These deaths included 0.5 million among women, making TB one of the top killers of women worldwide. 1 In Malaysia, the incidence was 81.4 per 100,000 populations in year The number of new TB cases in the country increased from 15,000 in 2005 to 19,251 in While PTB was the commonest form of TB in Malaysia, extrapulmonary TB (EPTB) still posed a threat. 2 The diagnosis of LTBI is often challenged by the lack of a gold standard diagnostic test and the absence of clinical symptoms. Until recently, tuberculin skin test (TST) was the only diagnostic test available and has been widely used for diagnosis of both LTBI and active TB. However, certain limitations are associated with the use of TST. In the presence of chronic immunosuppression including autoimmune diseases, the test results may be falsely negative. In patients vaccinated against TB with Bacillus Calmette-Gue rin (BCG) and subclinical infection with nontuberculosis mycobacteria (NTM), the skin test may lead to false positive results. 2 To overcome the drawbacks of TST, new in vitro assays based on interferon-γ (IFN-γ) release in response to specific M. tuberculosis antigens encoded in Region of Difference-1 (RD-1) have been developed. Two IFN-γ release assays (IGRAs) are currently available: the T-SPOT.TB 1

7 (Oxford Immunotec, Abingdon, UK), which is based on the enzyme-linked immunospot (ELISpot) assay; and the two versions of the whole bloodbased QuantiFERON -TB (QFT) (the QFT Gold [QFT-G] and QFT Gold In-Tube [QFT-GIT] tests (Cellestis, Carnegie, Australia), which use enzyme-linked immunosorbent assay (ELISA) to detect IFN-γ in the culture supernatant. These new assay employ certain antigens like the ESAT-6 and CEP-10 (for T-SPOT.TB and QFT-G), as well as TB7.7 (only for QFT-GIT) to stimulate the production of IFN-γ from the T-cell lymphocytes. These antigens are theoretically more specific as they do 2, 3, 4 not cross-react with the BCG and most NTM. This technology review was conducted following a request from Disease Control Division, Ministry of Health (MOH) Malaysia who received a proposal from company to promote the usage of the whole blood-based test QuantiFERON -TB Gold in MOH facilities. Figure 1: Tuberculin Skin Test (TST) or Mantoux Figure 2: QuantiFERON -TB Gold 2.0 OBJECTIVE/AIM The objective of this technology review was to review evidence on the efficacy, safety and cost-effectiveness of QuantiFERON -TB Gold as diagnostic tools for detection of patient with LTBI and active TB. 2

8 3.0 TECHNICAL FEATURES The QuantiFERON -TB (QFT) (the QFT Gold [QFT-G] and QFT Gold In- Tube [QFT-GIT] is a whole blood interferon-γ ELISA test measuring responses to specific TB complex antigens (ESAT-6, CFP-10, and TB7.7). This test is performed in two stages: the first stage involved incubation of whole blood with antigens, and the second stage involve measurement of IFN-γ production in harvested plasma by ELISA. A 3 ml peripheral blood sample was obtained by venipuncture from each subject and the test was carried out and interpreted as per the manufacturer s protocol. Briefly, the blood sample after evenly mixing was aliquoted into each of the three QFT blood collection tubes, which include a nil tube (negative control), TB antigen tube (containing M. tuberculosis antigens ESAT-6, CFP-10, and TB7.7) and a mitogen tube (positive control). The contents of the tubes were thoroughly mixed with blood by shaking them for 5-10 seconds and immediately transferred to a 37±1 C incubator and kept for 16 to 24 hours. Plasma was then separated by high speed centrifugation and collected into plasma storage containers, labelled and sealed to prevent spills and evaporation at -80 C prior to ELISA. 5 Figure 3: QFT procedure Collect 1 ml of blood into Nil, Antigen, and Mitogen tubes Shake tubes 10 times at room temperature. Tubes can either be incubated then transported to lab or sent directly to lab for incubation Centrifuge tubes to separate plasma. Complete the ELISA and obtain absorbance values Calculate results using QFT software 3

9 In the second stage, the amount of IFN-γ (IU/mL) release was measured by ELISA using the reagents included in the test kit following the exact manufacturer s protocols. QuantiFERON -TB Gold IT Analysis Software, as available from the manufacturer, was used to analyze raw data and calculate results. The software performs a quality control assessment of the assay, generates a standard curve and provides a test result for each subject. The results was considered positive when the difference between the TB antigen tube value and the nil tube value was 0.35 international unit/ml or greater (IFN-γ 0.35 IU/mL) and the difference had to be 25% of the nil tube value to be valid. The mitogen stimulated plasma sample served as a positive control for each individual tested. A low response to mitogen (< 0.5 IU/mL) indicated an indeterminate result when a blood sample also has a negative response to the TB antigens. 5 Figure 4: Interpretation of results Figure 5: Interpretation flow diagram 4

10 4.0 METHODS 4.1. Searching Electronic databases searched through the Ovid interface: MEDLINE(R) In-Process and Other Non-Indexed Citations and Ovid MEDLINE (R) 1946 to present EBM Reviews Cochrane Central Registered of Controlled Trials May 2013 EBM Reviews Database of Abstracts of Review of Effects 2 nd Quarter 2013 EBM Reviews Cochrane Database of Systematic Reviews 2005 to May 2013 EBM Reviews Health Technology Assessment 2 nd Quarter 2013 EBM Reviews - NHS Economic Evaluation Database 2 nd Quarter 2013 Other databases: PubMed Horizon Scanning database (National Horizon Scanning Centre, Australia and New Zealand Horizon Scanning Network, National Horizon Scanning Birmingham) Other websites: US FDA, INAHTA, MHRA General databases such as Google and Yahoo were used to search for additional web-based materials and information. Additional articles retrieved from reviewing the bibliographies of retrieved articles or contacting the authors. The search was limited to articles on human. There was no language limitation in the search. Appendix 1 showed the detailed search strategies. The last search was conducted on 19 th Jun Selection A reviewer screened the titles and abstracts against the inclusion and exclusion criteria and then evaluated the selected full-text articles for final article selection. The inclusion and exclusion criteria were: Inclusion criteria Population Interventions Comparators Outcomes Study design Type of publication Latent tuberculosis infection (LTBI) and TB disease Interferon-gamma release assay (IGRA), QuantiFERON- TB Gold (QFT-G), QuantiFERON-TB Gold in Tube (QFT- GIT) Tuberculin Skin Test (TST) or Mantoux Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), detection rate, mortality rate, quality of life, QALY, cost-effectiveness Systematic reviews (SRs), randomised control trials (RCTs), cross-sectional, cohort, case control, case series English, full text articles 5

11 Exclusion criteria Study design Type of publication Case report, survey, anecdotal, animal studies Non-English Relevant articles were critically appraised using Critical Appraisal Skills Programme (CASP) checklist and evidence graded according to the US/Canadian Preventive Services Task Force (See Appendix 2). Data were extracted from included studies using a pre-designed data extraction form (evidence table as shown in Appendix 6) and presented in tabulated format with narrative summaries. No meta-analysis was conducted for this review. 5.0 RESULTS AND DISCUSSION The search strategies yielded an article from United State Food & Drug Administration (US FDA) on the use of whole blood-based test QuantiFERON -TB Gold as an in vitro diagnostic aid for detection of M. tuberculosis. There were nine retrievable articles related to the efficacy of this product whereas none on the safety or adverse event. There were also three economic evaluation articles related to the use of this assays. Articles consists one systematic review with meta-analysis; the rest were cross-sectional diagnostic accuracy studies. 5.1 Efficacy Diel R et al. (2011) conducted a systematic review and meta-analysis to compare the accuracy of QFT-GIT and T-SPOT.TB assays with TST for the diagnosis of LTBI in adult population in low TB prevalence countries. The Medline, Embase and Cochrane databases were explored for relevant articles. A total of 432 citations were identified, of which 60 articles were eligible for final inclusion for one or more of the following topics: specificity, NPV in patients with active TB, NPV and PPV for progression, and association of IGRAs and TST with M. tuberculosis exposure and BCG vaccination. The study indicated that specificity of the IGRAs ranged from 98.0% (95% CI: %) for the T-SPOT.TB to 100.0% (95% CI: %) for the QFT-GIT, for which specificity estimates were available in all four studies of 99.4% (95% CI: %). These results suggest that the IGRAs are more certain to correctly identify individuals not infected with M. tuberculosis as compared to the TST. However, the estimates have to be interpreted with caution due to the low number of included studies. The NPV in patients with active TB ranged between 74.4% and 100.0%, with a pooled value of 94.0% (95% CI: %) for the T-SPOT.TB and 88.0% (95% CI: %) for the QFT-GIT. This would suggest that IGRAs, especially the T- SPOT.TB, are effective at ruling out M. tuberculosis infection. On the other hand, high NPVs for progression were found for both the QFT-GIT and the T-SPOT.TB (pooled NPV of 97.8% and 99.8% respectively). This 6

12 indicates that an individual tested negative will most likely not develop TB in the future. The QFT-GIT and T-SPOT.TB both showed a similar PPV for progression, with a slightly wider range in values as compared to the TST ( % for QFT-GIT; % for T-SPOT.TB, and % for TST), suggesting that the IGRAs have a higher predictive value for progression to active disease as compared with the TST. In multivariate analysis, the odd ratios for TST positivity following BCG vaccination varied between 3 to 25, whereas IGRA results remained uninfluenced and IGRA positivity was clearly associated with exposure to contagious TB cases. 6 level I Onur H et al. (2012) investigated the concordance between QFT-GIT and TST in 97 children aged three months to 14 years, admitted to paediatric outpatient clinics with and without tuberculosis infection. Demographic features, TST results, history of exposure to active TB, chest x-ray findings, clinical history, and presence of BCG vaccination scar were recorded. Patients were categorized into four main groups namely, active TB (n=30), LTBI (n=15), non TB (n=27), and healthy children (n=25). Statistical Software Program (Utah, USA) was used for statistical analysis. Because there was no gold standard for diagnosis of LTBI, concordance between TST and QFT-GIT was assessed by using proportion agreement and kappa coefficients. Chi-square and Fisher s exact tests were used for categorical variables. The study showed that in all cases and groups, presence of BCG vaccination scar influenced neither TST nor QFT-GIT results (p>0.05). The QFT-GIT results were not affected by TST induration diameters; rate of QFT-GIT positivity was significantly higher in patients with an induration diameter of mm and 15 mm compared to other diameters. In active TB group, QFT-GIT results were positive in all patients with positive TST results. In LTBI group, TST positivity was not associated with QFT-GIT positivity (p>0.05). In non-tb group, there was no significant association between TST positivity and QFT-GIT positivity (p>0.05). When all cases were considered there was a statistically significant agreement between QFT-GIT and TST results (κ=0.486; p<0.01). In patients 5 years of age, there was a significant association between TST positivity and QFT-GIT positivity (p<0.01); positive TST result rates were significantly higher in patients with positive QFT-GIT results. The authors concluded that IGRAs may have numerous advantages over TST such as higher specificity, better association with M. tuberculosis exposure, and lower cross-reaction rates with BCG vaccination and NTM. Tests based on measurement of released IFN-γ may reduce false-positive results and prevent unnecessary treatment with 7 level III isonicotinyl hydrazide (INH) and its adverse effects. Casas S et al. (2011) assessed the performance of QFT-GIT and TST in 214 patients with immune-mediated inflammatory diseases (IMID) before anti tumour necrosis factor-α (TNF-α) therapy, and compared the results 7

13 with those from the healthy population (n=100). Univariate and multivariate logistic regression analyses were performed to determine the association of TST and QFT-GIT positive results with different factors. Agreement between tests was calculated using Cohen κ coefficient. The study demonstrated that TST was positive in 52/214 (24.3%) patients with IMID and in 23/100 (23.0%) controls (p=0.80), and QFT-GIT was positive in 45/214 (21.0%) of the IMID group and 16/100 (16.0%) of the control group (p=0.29). Of 163 patients receiving immunosuppressive treatment, 34 (20.9%) had a positive TST result, compared with 18 out of 51 (35.3%) without treatment (p=0.04); and 31 (19.0%) had a positive QFT-GIT result, compared with 14 (27.5%) without treatment (p=0.20). Sixty-four IMID patients had a positive result with one or both tests. Thirty-two (50%) were positive with both tests, 19 (29.7%) were positive with TST and 13 (20.3%) were positive with QFT-GIT (agreement 50%; 95% CI, ). Therefore, using positivity of either test as a criterion, 13 of 32 patients (40.6%) diagnosed with LTBI would have been missed with TST alone, and 19 (59.4%) with QFT-GIT alone. Based on the results, they suggested that QFT-GIT may be useful for diagnosing TB infection in IMID patients considered for anti-tnf-α therapy. However, given the poor agreement between TST and QFT-GIT, a strategy based on a simultaneous TST and QFT-GIT would maximize diagnostic sensitivity for the detection of LTBI. 8 level III Caglayan V et al. (2011) conducted a study to compare the TST with QFT- GIT for the detection of LTBI in 78 healthcare workers (HCWs). Mean age of the study population was ± 8.57 years. Participants with active TB, immunodeficiency or malnutrition were not included. The numbers of previous BCG vaccinations were also recorded. All volunteers had a new postero-anterior chest x-ray. The TST was administered by the Mantoux method with indurations 15 mm in BCG vaccinated, and 10 mm in unvaccinated HCWs were considered positive. From the study, there was a statistically significant relation between the number of BCG scars and the diameter of TST (p<0.01). The QFT-GIT results according to previous BCG vaccinations did not significantly differ (p>0.05). There was a statistically significant relation between TST diameter and QFT-GIT result (p<0.01). Concordance between test results from the TST and QFT-GIT assay was assessed using κ coefficient (κ: 0.346) and there was a poor concordance between two tests. The QFT-GIT has a sensitivity of 56.14% (both TST and QFT-GIT are positive), specificity of 90.48% (both TST and QFT-GIT are negative); PPV of 94.12% and NPV of 43.18% and accuracy is 65.38%. The authors concluded that TST is affected by previous BCG vaccinations while QFT-GIT is not. They suggested that QFT-GIT test can be used as an alternative to TST for the detection of LTBI in populations 9 level III with routine BCG vaccination programme. 8

14 Lighter-Fisher J and Surette AM (2012) evaluated an IGRA (QFT-GIT) in diagnosing LTBI in pregnant adolescents and women. A total of 280 females were enrolled into the study including 140 pregnant and 140 nonpregnant. Each patient was assessed for M. tuberculosis risk factors, had a TST placed, and an IGRA performed. The concordance between the TST and the IGRA was calculated and the results analyzed according to the likelihood of exposure to M. tuberculosis. Mean mitogen IFN-γ levels were used across groups to compare reliability between trimesters and assay performance in pregnant compared with non-pregnant females of childbearing age. The study revealed that among the 140 pregnant patients included in the analysis, nine (6.4%) had indeterminate IFN-γ release assay results. Among the 131 valid IFN- γ release assay results, 103 (79%) pregnant women and adolescents were TST-negative and 28 (21%) were TST-positive. Among the patients who had negative TST results, 100 (97%) of them also had a negative IGRA. All TST and IGRApositive patients had chest roentgenograms performed, none of which had findings of active TB. The IGRA was highly specific and its positivity was associated with a greater likelihood of exposure to M. tuberculosis. The overall agreement between TST and IGRA results were 88% for all pregnant patients, corresponding to a κ of (CI: ). There was no significant difference (p=0.126) between IFN-γ levels detected in each trimester of pregnancy. There was also no statistical difference (p=0.482) in the mitogen control in the non-pregnant and pregnant group. They concluded that the IGRA performed equally well in each trimester of 10 level III pregnancy with comparable results to non-pregnant females. There was limited data regarding the performance of an IGRA in sarcoidosis, particularly in a setting of high population prevalence of LTBI. Herein, Gupta D et al. (2011) studied the performance of IGRA in the diagnostic work up of 38 patients with sarcoidosis (22 men, 16 women; mean age 42.5 years), 30 patients of TB (18 pulmonary, 12 extrapulmonary) and 30 healthy controls. All patients and controls (except two patients with TB) were BCG vaccinated. They underwent TST using 0.1 ml (1 tuberculin unit) of purified protein derivative RT23, and IGRA using QFT-GIT in blood. For TST an induration 10 mm was taken as positive and QFT-GIT was performed and interpreted as per the manufacturer s instructions. The study indicated that TST was positive in 12 (40.0%) healthy controls, four (10.5%) sarcoidosis and 23 (76.7%) in TB patients. The QFT-GIT was positive in 15 (50.0%) healthy controls, 13 (34.2%) sarcoidosis and 18 (60.0%) patients with TB. Patients with sarcoidosis were more likely to have a negative TST compared to controls (89.5% vs. 60.0%, p=0.004) or TB (89.5% vs. 23.3%, p<0.001). However, QFT-GIT positivity was not significantly different in sarcoidosis compared to controls (34.2% vs. 50.0%, p=0.19), but was higher in TB compared to sarcoidosis (60% vs. 34.2%, p=0.03). The authors concluded that there was acquired tuberculin anergy in patients of sarcoidosis; however results 9

15 of QFT-GIT are not similarly affected. The QFT-GIT continues to remain positive in many patients with sarcoidosis and thus may be more accurate to detect LTBI in these patients. Also, in high TB prevalence countries, a negative TST helps in differentiating sarcoidosis from tuberculosis, whereas a positive QFT-GIT should not be a deterrent for diagnosing 11 level III sarcoidosis. Chung JH et al. (2011) evaluated the usefulness of the QFT-GIT and compared this assay with the TST for diagnosing tuberculosis pleural effusion (TPE) in South Korea, where tuberculosis is endemic and BCG vaccination is mandatory. The data of 97 patients were analyzed in this study. The TST was performed after the QFT-GIT, because the QFT-GIT results are influenced by the TST. A positive TST results was defined as an induration with a transverse diameter 10 mm. The results showed that 54 patients had confirmed TPE, and 43 were classified as non-tpe. Confirmed TPE was defined as positive M. tuberculosis culture (sputum, pleural fluid, or tissue) and/or histology keeping with TB (caseous necrosis or AFB with or without granuloma formation) and a clinic-radiologic picture consistent with TPE, including a clinical response to anti-tb treatment. All patients were HIV negative. Nine (9.3%) of the 97 patients had an indeterminate QFT-GIT test result. Excluding the indeterminate results, the QFT-GIT yielded a diagnostic sensitivity of 76.9% (95% CI: %), which was significantly higher (p=0.003) than the sensitivity of the TST (72.5%; 95% CI: %). The specificity was 61.1% (95% CI: ) for QFT-IT and 71.7% (95% CI: ) for TST. Among 90 subjects tested with the combination of both methods, 33 (36.7%) were negative and 6 (6.7%) were indeterminate. Excluding the indeterminate results, the sensitivity of the QFT-GIT plus TST was 83.7% (95% CI: %) with a specificity of 45.7% (95% CI: %). Based on the results, they concluded that QFT-GIT test may be more useful than the TST for diagnosing TPE in HIV-seronegative individuals. The combination of the TST and QFT-GIT test showed higher sensitivity (83.7%), suggesting that the two tests in combination may be useful in diagnosing TPE as a supplement marker along with existing diagnostic tools. However, their role was limited by poor specificity in clinical setting 12 level III because of the high prevalence of LTBI. Recently, Yilmaz N et al. (2012) compared QFT-G with TST for the detection of LTBI among patients with systemic lupus erythematosus (SLE). Seventy-eight patients with SLE who fulfilled the 1982 revised criteria of American College of Rheumatology and 49 healthy controls (HCs) were enrolled to the study. The median age was 38 (13 67) years in SLE patients and 31 (18 54) years in HC. Seventy-six SLE patients (97.4%) had been BCG vaccinated. All patients and controls were interviewed for a history of TB then BCG vaccinations were recorded and chest x-rays were examined for a sign of TB infection. The QFT-G and 10

16 TST were performed on both patients and controls. The QFT-G results were recorded as positive, negative or indeterminate. A positive TST for SLE was defined as > 5 mm. The concordance between TST and QFT-G was evaluated using agreement and the kappa analysis. The tests results were evaluated by using Cohen s kappa (k), with k value > 0.75 representing good agreement, fair to good agreement and < 0.40 poor agreement. The study revealed that in SLE patients, QFT-G was positive in 19 (24.3%), indeterminate in two (2.6%) and negative in 57 (73.1%) patients. The percentage of positive QFT-G results was 14/49 (28.5%) in the HC group. There was no difference between SLE patients and HCs for QFT-G positivity (p>0.05). The TST was performed on 76 of 78 SLE patients and 50% of them had a positive result when 5 mm induration was chosen as a cut-off value. However, when the TST cut-off value readjusted to 10 mm, the positivity decreased to 30.2%. The mean TST measurement was higher in QFT-G positive patients (13.4 ± 8.8 mm) than the QFT-G negative patients (4 ± 5.3 mm) (p<0.001). The agreement between QFT-G and TST was observed to be 49/76 (64.4%) (k=0.33). As can be expected, there were fewer positive QFT-G test results than positive TST results (24.3% vs. 50.0%; p<0.001). While 22 (28.9%) patients were TST (+) / QFT-G (-), there were only three (3.9%) patients with a TST (-) / QFT-G (+) result. When 10 mm diameter indurations was chosen as the TST cut-off value, an increased agreement was observed between the two tests to 58/76 (76.3%) with a k value of There was a significant difference in TST results between the patients who were treated with or without immunosuppressive agents (p<0.05). However, no difference was observed in the QFT-G result between the groups. The authors concluded that in a TB-endemic and BCG vaccinated population, the QFT-G seemed to be a more accurate test for the detection of LTBI in SLE patients. Although 5 mm is usually accepted to be the standard cutoff for TST in immunocompromised patients such as SLE, the level of agreement between QFT-G and TST was better with a 10 mm cut-off. 13 level III Soysal A et al. (2008) investigated the diagnostic accuracy of two commercial IGRA (QFT-G and T-SPOT.TB) and TST with different cut-off values for the diagnosis of M. tuberculosis. Study population included 100 patients with untreated culture-confirmed cavitary pulmonary TB and 47 healthy subjects. For the analysis of the sensitivity and specificity of the TST induration, two additional universal cut-off points were used to define a positive TST: > 5 mm and > 15 mm. The optimal cut-off level in the QFT- G assay was recalculated from receiver operator characteristic (ROC) analysis using data from 100 active TB patients and 47 low-risk subjects. Sensitivities and specificities of the QFT-G assay by using different cut-off values of IFN-γ above 0.30, 0.25, 0.20, 0.15 and 0.10 IU/ml. For the T- SPOT.TB assay, the diagnostic criteria were determined as the spot count of stimulated sample wells, irrespective of the spot count of the negative 11

17 control wells. By using cut-off values of 7, 5 and 3 spots in the stimulated sample wells, the sensitivity and specificity of the T-SPOT.TB assay were recalculated. The study demonstrated that among the 100 culture-confirmed cases, the TST induration (mean ± standard deviation [SD]) was 11.5 ± 6.9 mm. Among the three different cut-off values of TST for the determination of M. tuberculosis infection, an induration of > 5 mm had the highest sensitivity (81%), while an induration of > 15 mm had the highest specificity (60%). The sensitivities of the assays were TST 70%, QFT-G 78% and T-SPOT.TB 83.5%, while their specificities were TST 35%, QFT-G 89.4% and T-SPOT.TB 84.8%. Both QFT-G and T-SPOT.TB were significantly more specific than TST (both p<0.001), but were similar to each other (p=0.5). With respect to a cut-off of > 5 mm TST induration, the sensitivity of both T-SPOT.TB and QFT-G were found to be similar to that of TST (p=0.72 and p=0.71, respectively). However, if the > 15 mm cut-off was used, both T-SPOT.TB and QFT-G were found to be more sensitive than TST (both p<0.0001). Receiver operating characteristic analysis revealed that a cut-off value of IU/mL for QFT-G maximises specificity without significant loss of test sensitivity. Using lower cut-off values for T-SPOT.TB and TST, however, also increased the sensitivity of the assay but resulted in a significant decrease in specificity. They concluded that T-SPOT.TB and QFT-G have similar specificities and sensitivities for active TB. The determination of new cut-off values for both T-SPOT.TB and QFT-G may improve the assays sensitivity, especially in intermediate and high endemic populations. By using a lower cut-off value for QFT-G, the assay sensitivity was improved with no decrease in specificity. For T-SPOT.TB, however, lower cut-off spot counts did not 14 level III improve assay sensitivity. 5.2 Safety The QuantiFERON -TB Gold is CE marked and approved by the US FDA as an in vitro diagnostic aid for detection of M. tuberculosis infection. The US FDA approval notes that QFT-G is intended for use in conjunction with risk assessment, radiography and other medical and diagnostic evaluations. An erroneous result can lead to an adverse effect for the tested patient. A false-negative result could lead to an individual developing active TB disease, adversely affecting their health, and possibly facilitating the spread of M. tuberculosis to other individuals in the community. A false-positive response could lead to an individual being administered unnecessary prophylaxis for tuberculosis infection. Finding indicated that there were no retrievable articles related to adverse event of this assays. The only direct adverse effects on patient health from collecting the specimen for testing are those associated with venipuncture, namely a slight risk of bleeding, haematoma, and infection. Pain and redness at the site of injection were reported and some people became dizzy and/or faint when blood is drawn

18 5.3. Cost-effectiveness Kowada A et al. (2008) constructed a Markov Model to evaluate economic factors related to tuberculosis contact screening to identify the most costeffective approach for the screening of the Japanese population. Three contact screening strategies were QFT-alone, TST followed by QFT (TST/QFT), and TST-alone. The target population is a hypothetical cohort of 1,000 immunocompetent 20-year-old individuals who have had contact with sputum-smear-positive pulmonary tuberculosis patients. The main outcome measure was quality-adjusted life-years (QALYs) gained during a lifetime. All costs were adjusted to 2007 Japanese Yen using the medical care component of the Consumer Price Index and were then converted to US dollars using the OECD Purchasing Power Parity rate of 2006 (124.0 yen/dollar). Analysis was conducted from a societal perspective over the lifetime of a contact. All costs and clinical benefits were discounted at a fixed annual rate of 3%. They found that in the base case analysis, the QFT-alone strategy was the least expensive (USD$471.54) and the most effective ( QALYs), compared to the TST/QFT strategy (USD$500.55; QALYs) and TST-alone strategy (USD$573.98; QALYs). The incremental cost-effectiveness ratio (ICER) of the QFT-alone strategy was a cost saving of USD$24,175/QALY gained compared with the TST/QFT strategy. The authors concluded that the QFT-alone strategy is the most cost-effective for tuberculosis contact screening in Japan. 16 A Markov state-transition decision analytic model using the societal perspective and lifetime horizon was constructed by de Perio M et al. (2009). They compared costs and QALYs associated with the three screening strategies (QFT-G, QFT-GIT, and TST) for hypothetical 35-year old HCWs with or without prior BCG vaccination. Direct costs, costs of missed work time, and probabilities were based on data from the IGRA manufacturer, from the Veterans Health Administration (VHA) records, and from the published literature. Effectiveness was measured in QALYs and the incremental costs per QALYs gained for the three strategies were calculated. Future costs and QALYs were discounted at 3% per year. The base case results showed that both IGRAs were effective and less costly than the TST, whether or not the HCW had been vaccinated with BCG previously. For non-bcg-vaccinated HCWs, the ICER of the QFT-G compared with the QFT-GIT was USD$14,092/QALY. For BCGvaccinated HCWs, the ICER of the QFT-G compared with the QFT-GIT was USD$103,047/QALY. Based on the analysis, they concluded that QFT-G and QFT-GIT were clinically and economically worthwhile alternatives to the TST in testing HCWs for LTBI, as both IGRA strategies are more effective and less costly than the TST strategy. Hence, IGRA tests should be considered for screening non-bcg-vaccinated and BCGvaccinated new HCWs for LTBI

19 Table 1: Cost-effectiveness of three strategies for school-based tuberculosis screening More recently, Kowada A et al. (2012) assessed the cost-effectiveness of school-based TB screening using QFT-GIT versus the TST and chest x- ray examination (CXR). A Markov models of first-year high-school and university students, using a societal perspective, and followed-up until the age of 80 years was developed. Immunocompetent 16- and 19-year-old individuals were chosen as a hypothetical cohort of students with a lifetime horizon. The main outcome measure of effectiveness was QALYs gained. All costs and clinical benefits were discounted at a fixed annual rate of 3%. The incremental cost-effectiveness of each screening arm was applied and compared with those of the other screening arms. The range of cost-effectiveness was explored, using one-way and two-way sensitivity analyses, comparing all strategies simultaneously to determine which strategy yielded the greatest benefits. They also conducted probabilistic sensitivity analysis with Monte Carlo simulation, using the costeffectiveness acceptability curve. They found that in the base-case analysis of 16-year-old high-school students and 19-year-old university students, the QFT-GIT strategy yielded the greatest benefits at the lowest cost [in year 2009 values] (16-year-olds: USD$627.89, QALYs; 19-year-olds: USD$646.04, QALYs), compared with the TST strategy (16-year-olds: USD$943.50, QALYs; 19-year-olds: USD$998.62, QALYs) and the CXR strategy (16-year-olds: USD$7,286.24, QALYs; 19-year-olds: USD$7,305.19, QALYs) (see Table 1). On one-way sensitivity analysis, the BCG vaccination rate was not sensitive to the TST strategy. On probabilistic sensitivity analysis, the QFT-GIT strategy was the most cost effective, with a willingness-to-pay level of USD$50,000/QALY gained. Based on the analysis, the authors concluded that the QFT-GIT strategy provided the greatest benefits at the lowest cost for school-based TB screening. There appears to be little role for TST or CXR in screening of school populations. Current practices using either TST or CXR screening should be reconsidered on the basis of cost-effectiveness

20 The cost of the QuantiFERON -TB Gold is likely to be USD$30 to $60. For most TB control programs, QFT-G can yield dramatic cost savings in terms of medical staff time by elimination of a second patient visit for test interpretation, and the elimination of common false-positive results, the latter involving both unnecessary follow-up testing and treatment for LTBI. This test can eliminate the need for the repeat testing that is required when TST is used for screening HCWs and may lower the administrative cost of maintaining testing compliance in health care facilities, which may offset the slightly higher reagent cost compared to the TST Limitation Our review has several limitations. The selection of the studies and appraisal was done by one reviewer. Although there was no restriction in language during the search, only English full text articles were included in the report. Numerous reports and a number of studies have examined the performance of IGRAs, largely in comparison with TST. Studies have encompassed many populations including children, persons with HIV, pregnant and non-pregnant adolescent females and women, patients of sarcoidosis, patients with IMID, TPE, SLE, contacts of patients with TB, and HCWs. However, research in this area has been subject to at least two important methodological limitations. First, there is no gold standard for diagnosing LTBI. Sensitivity has usually been measured using persons with TB disease, and specificity has been measured using persons with no identifiable TB risk factors as surrogate standards. Second, studies of certain populations (children, sarcoidosis, HCWs, TPE, and SLE,) have been confined to relatively small sample sizes with inadequate statistical power. 6.0 CONCLUSION There was fair to good level of retrievable evidence to suggest that the whole blood-based QuantiFERON -TB (QFT) may be effective as diagnostic tools for detection of patient with LTBI and active TB. Despite the limitations, findings in general revealed that QFT appeared to have numerous advantages over TST such as higher specificity, PPV and NPV in adult population in low TB prevalence countries, better relationship with M. tuberculosis exposure, and lower cross-reaction rates with BCG vaccination and NTM. By using a lower cut-off value for QFT, the assay sensitivity was improved with no decrease in specificity. Malaysian Ministry of Health Clinical Practice Guidelines on Management of Tuberculosis (3 rd Edition) 2012 suggested that the situations where IGRAs may be used are as the following: 15

21 i. As an alternative to TST for Patients who are not expected to/could not come back for a reading of skin induration after hours Patients who had recent BCG vaccination or past NTM infection ii. Where a 2-step test is considered (TST followed by IGRA) Close-contacts whose TST is in the range of 5-9 mm Patients who are offered LTBI treatment but are not convinced that they have LTBI Individuals who require annual screening of LTBI (such as health care providers working in high risk areas) There was no retrievable evidence related to adverse event of this assays. The only direct adverse effects on patient health from collecting the specimen for testing were those associated with venipuncture, namely a slight risk of bleeding, haematoma, and infection. Pain and redness at the site of injection were reported and some people became dizzy and/or faint when blood is drawn. QuantiFERON -TB Gold on the other hand is CE marked and approved by the US FDA as an in vitro diagnostic aid for detection of M. tuberculosis infection. The US FDA approval notes that QFT-G is intended for use in conjunction with risk assessment, radiography and other medical and diagnostic evaluations. There was also evidence to suggest that QFT-alone was likely to be more costly but more effective than TST in Japan and United States. Analyzing costeffectiveness is more complex because the results vary with many factors including the population being tested. Overall, due to its higher specificity and lower cross-reaction rates with BCG vaccination and NTM, whole blood-based QuantiFERON -TB (QFT) can be used as an alternative to TST for detection of patient with LTBI. 16

22 7.0 REFERENCES 1. World Health Organization. Global Tuberculosis Report Available at Accessed on 25 th July Ministry of Health Malaysia. Clinical Practice Guidelines. Management of Tuberculosis (3 rd Edition) MOH/P/PAK/258.12(GU) 3. Lalvani A, Millington KA. Screening for tuberculosis infection prior to initiation of anti-tnf therapy. Autoimmun. 2008; 8: Menzies D, Pai M, and Comstock G. Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med. 2007; 146: QuantiFERON -TB Gold. Package insert for in vitro diagnostic use. Cellestis. United Kingdom. 6. Diel R, Goletti D, Ferrara G et al. Interferon-γ release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis. Eur Respir J. 2011; 37: Onur H, Hatipoglu S, Arica V et al. Comparison of quantiferon test with tuberculin skin test for the detection of tuberculosis infection in children. Inflammation. 2012; 35(4): Casas S, Andreu A, Juanola X et al. Diagnosis of tuberculosis infection by tuberculin skin test and a whole-blood interferon-γ release assay in patients considered for anti tumor necrosis factor-α therapy. Diagnostic Microbiology and Infectious Disease. 2011; 71: Caglayan V, Oznur AK, Dabak G et al. Comparison of tuberculin skin testing and QuantiFERON-TB Gold-In Tube test in health care workers. Tüberküloz ve Toraks Dergisi 2011; 59(1): Lighter-Fisher J and Surette AM. Performance of an interferon-gamma release assay to diagnose latent tuberculosis infection during pregnancy. Obstetrics & Gynecology. 2012; 119(6): Gupta D, Kumar S, Aggarwal A.N. et al. Interferon gamma release assay (QuantiFERON-TB Gold in Tube) in patients of Sarcoidosis from a population with high prevalence of tuberculosis infection. Sarcoidosis Vasc Diffuse Lung. 2011; 28: Chung JH, Han CH, Kim CJ et al. Clinical utility of QuantiFERON-TB GOLD In-Tube and tuberculin skin test in patients with tuberculous pleural effusions. Diagnostic Microbiology and Infectious Disease. 2011; 71: Yilmaz N, Aydin S, Inanc N et al. Comparison of QuantiFERON-TB Gold test and tuberculin skin test for the identification of latent Mycobacterium tuberculosis infection in lupus patients. Lupus. 2012; 21: Soysal A, Torun T, Efe S et al. Evaluation of cut-off values of interferongamma-based assays in the diagnosis of M. tuberculosis infection. Int J Tuberc Lung Dis. 2008; 12(1):

23 15. U.S. Food and Drug Administration 510(k) Premarket Notification Database. QuantiFERON -TB Gold. Available at Accessed on 25 th July Kowada A, Takahashi O, Shimbo T et al. Cost effectiveness of interferon-γ release assay for tuberculosis contact screening in Japan. Mol Diag Ther 2008; 12(4): de Perio M, Tsevat J, Roselle G et al. Cost-effectiveness of interferon gamma release assays vs. tuberculin skin tests in health care workers. Arch Intern Med. 2009; 169(2): Kowada A. Cost effectiveness of interferon-gamma release assay for school-based tuberculosis screening. Mol Diag Ther 2012; 16(3): Frieden T. QuantiFERON -TB Gold Fact Sheet. New York City Department of Health and Mental Hygiene. 18

24 8.0 APPENDIX 8.1 Appendix 1: LITERATURE SEARCH STRATEGY Ovid MEDLINE In-Process & Other Non-indexed Citations and Ovid MEDLINE 1948 to present 1. Tuberculosis/ 2. Tuberculo$.tw. 3. Latent Tuberculosis/ 4. (Latent adj1 tuberculosis infection$).tw. 5. (Latent adj1 tuberculo$).tw or 2 or 3 or 4 or 5 7. Interferon-gamma/ 8. (Interferon adj1 immune).tw. 9. (Interferon adj1 gamma).tw. 10. (Interferon adj1 type ii).tw. 11. Interferon-gamma Release Tests/ 12. (Interferon adj2 gamma release assay).tw. 13. (Interferon adj2 gamma release test).tw or 8 or 9 or 10 or 11 or 12 or Tuberculin Test/ 16. (Tuberculin adj1 test$).tw or and 14 and Limit 18 to (English language and humans and yr="2000 -Current") 20. Limit 19 to "diagnosis (best balance of sensitivity and specificity)" OTHER DATABASES EBM Reviews Cochrane Central Registered of Controlled Trials EBM Reviews Database of Abstracts of Review of Effects EBM Reviews Cochrane database of systematic reviews EBM Reviews Health Technology Assessment NHS economic evaluation database PubMed INAHTA US FDA Same MeSH, keywords, limits used as per MEDLINE search Same MeSH, keywords, limits used as per MEDLINE search 19