NIHR Signal Rapid tests for diagnosing drug resistant tuberculosis are accurate and may be cost effective

Published on 9 November 2015

This NIHR funded systematic review and economic evaluation found that three rapid tests for diagnosing drug resistant tuberculosis were highly accurate and likely to be cost effective in the UK. These tests produce results within one day of obtaining a sample. This is a significant reduction compared with the standard tests which can take about six weeks or even longer to grow the bacteria. Adding rapid testing to current diagnostic pathways could speed up access to the best treatment and shorten the time people without the disease are kept in isolation as a precaution. This could save money, reduce the spread to others, and lower the overall public health risk of tuberculosis.

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Why was this study needed?

A 2014 Public Health England report showed that tuberculosis (TB) rates in the UK continue to be among the highest of West European countries. There were 7,892 cases of TB recorded in the UK in 2013, around 12 per 100,000 people. TB that does not respond to two of the standard treatments, called multidrug resistant TB, is becoming more common in the UK. Between 2004 and 2011, the proportion of cases with multidrug resistant TB increased from 1.1% (49/4,504) to 1.6% (86/5,397 cases). Treating multidrug resistant TB can take up to two years and is less likely to be successful. The current diagnostic tests involve growing TB bacteria in the laboratory. This can take 42 days or more to give a result. Earlier diagnosis could accelerate people’s access to the most effective treatment and ensure people without TB are not kept in isolation unnecessarily.

The NIHR funded this systematic review and economic evaluation to see whether rapid tests to diagnose drug resistance were accurate, and to estimate the value of adding these tests to current diagnostic strategies.

What did this study do?

This systematic literature review used robust methodology to identify and assess the quality of 56 studies comparing the diagnostic accuracy of rapid TB tests with standard TB tests. All three commercially available rapid tests were included: INNO-LiPA, GeneXpert MTB/RIF and MBTDRplus. Studies looked at their accuracy for diagnosing TB resistant to two commonly used TB drugs: rifampicin and isoniazid. Where possible, the accuracy results from different studies were pooled using meta-analysis.

The economic evaluation considered 44 different treatment pathways for the different diagnostic strategies examined. These pathways determined which medical treatments and health services people with TB would receive. The cost and health impact of each pathway was estimated in terms of the number of years of good quality life that would be lost or gained as a result of TB and its treatment (quality-adjusted life-years, QALYs).

What did it find?

  • All three commercially available rapid tests showed a high level of accuracy (sensitivity between 94.6% and 96.8%) for correctly diagnosing TB resistant to the drug rifampicin. The rapid tests also correctly ruled out between 98.2% and 99.7% (the test specificity) of people who did not have rifampicin resistant TB.
  • One of the rapid tests (MTBDRplus) was tested for its accuracy for diagnosing TB resistant to the drug isoniazid. This test correctly identified 83.4% of cases of TB that were resistant to isoniazid, and correctly ruled out almost all cases (99.6%) that did not have isoniazid resistant TB.
  • If added to current diagnostic pathways all three rapid tests were predicted to improve the number of years spent in good health and were cost effective. The costs of testing and treatment were similar for both the rapid tests and standard tests.
  • The rapid tests were confirmed to be cost effective for the three ethnic groups that account for a large proportion of TB cases in the UK (Black African, South Asian and Eastern European). The major cost saving of the rapid tests comes from the reduced time spent in isolation until the diagnosis is confirmed.

What does current guidance say on this issue?

The 2011 NICE clinical guideline on tuberculosis recommends diagnosing active TB infection using chest X-rays in combination with collecting multiple sputum (phlegm) samples to identify TB bacteria under a microscope and grow the TB bacteria in the laboratory. Screening for latent TB (Mantoux testing) is recommended for people who may come into contact with people with active infection.

The 2011 NICE guideline recommends that a risk assessment for drug resistance should be made for each patient with TB. If the risk is significant, urgent molecular tests for rifampicin resistance should be performed on sputum material positive for TB or on positive cultures when they become available.

The 2012 NICE public health guideline on identifying and managing tuberculosis among hard-to-reach groups recommends screening high-risk groups such as people who are homeless, people with drug and or alcohol problems, prisoners, or immigrants from countries where TB is common. In 2012 pre-entry TB screening was introduced for migrants from high-risk countries.

In addition to these groups, the 2014 Public Health England guidance also recommends screening healthcare workers and other people in close contact with people with TB or suspected TB.

What are the implications?

Rapid tests for diagnosing TB that is resistant to standard drugs give results within one day of obtaining a sample. This is a significant reduction when compared with the current standard culture test which can take up to 42 days or even longer to grow the bacteria. All three rapid tests in this review had high accuracy for correctly identifying people with and without drug-resistant TB. They were also likely to be more cost-effective than the standard test.

Adding these rapid tests to the current TB diagnostic pathway could accelerate people’s access to the most appropriate TB treatment which would improve their outlook and reduce the spread of TB to others. This could help the NHS achieve its dual goals of reducing the number of TB cases and reducing the wider public health risk of TB.

Citation

Drobniewski F, Cooke M, Jordan J, et al. Systematic review, meta-analysis and economic modelling of molecular diagnostic tests for antibiotic resistance in tuberculosis. Health Technol Assess. 2015;19(34):1-188.

This project was funded by the National Institute for Health Research Health Technology Assessment programme. This study is registered as PROSPERO CRD42011001537.

Bibliography

NHS England. NHS England launches £11.5M strategy to wipe out tuberculosis in the UK. London: NHS England; 2015.

NICE. Tuberculosis: Clinical diagnosis and management of tuberculosis, and measures for its prevention and control. CG117. London: National Institute for Health and Care Excellence; 2011.

NICE. Identifying and managing tuberculosis among hard-to-reach groups. PH37. London: National Institute for Health and Care Excellence; 2012.

Public Health England. Tuberculosis screening. London: Public Health England; 2014.

Public Health England. Tuberculosis in the UK: 2014 report. London: Public Health England; 2014.

Why was this study needed?

A 2014 Public Health England report showed that tuberculosis (TB) rates in the UK continue to be among the highest of West European countries. There were 7,892 cases of TB recorded in the UK in 2013, around 12 per 100,000 people. TB that does not respond to two of the standard treatments, called multidrug resistant TB, is becoming more common in the UK. Between 2004 and 2011, the proportion of cases with multidrug resistant TB increased from 1.1% (49/4,504) to 1.6% (86/5,397 cases). Treating multidrug resistant TB can take up to two years and is less likely to be successful. The current diagnostic tests involve growing TB bacteria in the laboratory. This can take 42 days or more to give a result. Earlier diagnosis could accelerate people’s access to the most effective treatment and ensure people without TB are not kept in isolation unnecessarily.

The NIHR funded this systematic review and economic evaluation to see whether rapid tests to diagnose drug resistance were accurate, and to estimate the value of adding these tests to current diagnostic strategies.

What did this study do?

This systematic literature review used robust methodology to identify and assess the quality of 56 studies comparing the diagnostic accuracy of rapid TB tests with standard TB tests. All three commercially available rapid tests were included: INNO-LiPA, GeneXpert MTB/RIF and MBTDRplus. Studies looked at their accuracy for diagnosing TB resistant to two commonly used TB drugs: rifampicin and isoniazid. Where possible, the accuracy results from different studies were pooled using meta-analysis.

The economic evaluation considered 44 different treatment pathways for the different diagnostic strategies examined. These pathways determined which medical treatments and health services people with TB would receive. The cost and health impact of each pathway was estimated in terms of the number of years of good quality life that would be lost or gained as a result of TB and its treatment (quality-adjusted life-years, QALYs).

What did it find?

  • All three commercially available rapid tests showed a high level of accuracy (sensitivity between 94.6% and 96.8%) for correctly diagnosing TB resistant to the drug rifampicin. The rapid tests also correctly ruled out between 98.2% and 99.7% (the test specificity) of people who did not have rifampicin resistant TB.
  • One of the rapid tests (MTBDRplus) was tested for its accuracy for diagnosing TB resistant to the drug isoniazid. This test correctly identified 83.4% of cases of TB that were resistant to isoniazid, and correctly ruled out almost all cases (99.6%) that did not have isoniazid resistant TB.
  • If added to current diagnostic pathways all three rapid tests were predicted to improve the number of years spent in good health and were cost effective. The costs of testing and treatment were similar for both the rapid tests and standard tests.
  • The rapid tests were confirmed to be cost effective for the three ethnic groups that account for a large proportion of TB cases in the UK (Black African, South Asian and Eastern European). The major cost saving of the rapid tests comes from the reduced time spent in isolation until the diagnosis is confirmed.

What does current guidance say on this issue?

The 2011 NICE clinical guideline on tuberculosis recommends diagnosing active TB infection using chest X-rays in combination with collecting multiple sputum (phlegm) samples to identify TB bacteria under a microscope and grow the TB bacteria in the laboratory. Screening for latent TB (Mantoux testing) is recommended for people who may come into contact with people with active infection.

The 2011 NICE guideline recommends that a risk assessment for drug resistance should be made for each patient with TB. If the risk is significant, urgent molecular tests for rifampicin resistance should be performed on sputum material positive for TB or on positive cultures when they become available.

The 2012 NICE public health guideline on identifying and managing tuberculosis among hard-to-reach groups recommends screening high-risk groups such as people who are homeless, people with drug and or alcohol problems, prisoners, or immigrants from countries where TB is common. In 2012 pre-entry TB screening was introduced for migrants from high-risk countries.

In addition to these groups, the 2014 Public Health England guidance also recommends screening healthcare workers and other people in close contact with people with TB or suspected TB.

What are the implications?

Rapid tests for diagnosing TB that is resistant to standard drugs give results within one day of obtaining a sample. This is a significant reduction when compared with the current standard culture test which can take up to 42 days or even longer to grow the bacteria. All three rapid tests in this review had high accuracy for correctly identifying people with and without drug-resistant TB. They were also likely to be more cost-effective than the standard test.

Adding these rapid tests to the current TB diagnostic pathway could accelerate people’s access to the most appropriate TB treatment which would improve their outlook and reduce the spread of TB to others. This could help the NHS achieve its dual goals of reducing the number of TB cases and reducing the wider public health risk of TB.

Citation

Drobniewski F, Cooke M, Jordan J, et al. Systematic review, meta-analysis and economic modelling of molecular diagnostic tests for antibiotic resistance in tuberculosis. Health Technol Assess. 2015;19(34):1-188.

This project was funded by the National Institute for Health Research Health Technology Assessment programme. This study is registered as PROSPERO CRD42011001537.

Bibliography

NHS England. NHS England launches £11.5M strategy to wipe out tuberculosis in the UK. London: NHS England; 2015.

NICE. Tuberculosis: Clinical diagnosis and management of tuberculosis, and measures for its prevention and control. CG117. London: National Institute for Health and Care Excellence; 2011.

NICE. Identifying and managing tuberculosis among hard-to-reach groups. PH37. London: National Institute for Health and Care Excellence; 2012.

Public Health England. Tuberculosis screening. London: Public Health England; 2014.

Public Health England. Tuberculosis in the UK: 2014 report. London: Public Health England; 2014.

Systematic review, meta-analysis and economic modelling of molecular diagnostic tests for antibiotic resistance in tuberculosis

Published on 9 May 2015

Drobniewski, F.,Cooke, M.,Jordan, J.,Casali, N.,Mugwagwa, T.,Broda, A.,Townsend, C.,Sivaramakrishnan, A.,Green, N.,Jit, M.,Lipman, M.,Lord, J.,White, P. J.,Abubakar, I.

Health Technol Assess Volume 19 , 2015

BACKGROUND: Drug-resistant tuberculosis (TB), especially multidrug-resistant (MDR, resistance to rifampicin and isoniazid) disease, is associated with a worse patient outcome. Drug resistance diagnosed using microbiological culture takes days to weeks, as TB bacteria grow slowly. Rapid molecular tests for drug resistance detection (1 day) are commercially available and may promote faster initiation of appropriate treatment. OBJECTIVES: To (1) conduct a systematic review of evidence regarding diagnostic accuracy of molecular genetic tests for drug resistance, (2) conduct a health-economic evaluation of screening and diagnostic strategies, including comparison of alternative models of service provision and assessment of the value of targeting rapid testing at high-risk subgroups, and (3) construct a transmission-dynamic mathematical model that translates the estimates of diagnostic accuracy into estimates of clinical impact. REVIEW METHODS AND DATA SOURCES: A standardised search strategy identified relevant studies from EMBASE, PubMed, MEDLINE, Bioscience Information Service (BIOSIS), System for Information on Grey Literature in Europe Social Policy & Practice (SIGLE) and Web of Science, published between 1 January 2000 and 15 August 2013. Additional 'grey' sources were included. Quality was assessed using quality assessment of diagnostic accuracy studies version 2 (QUADAS-2). For each diagnostic strategy and population subgroup, a care pathway was constructed to specify which medical treatments and health services that individuals would receive from presentation to the point where they either did or did not complete TB treatment successfully. A total cost was estimated from a health service perspective for each care pathway, and the health impact was estimated in terms of the mean discounted quality-adjusted life-years (QALYs) lost as a result of disease and treatment. Costs and QALYs were both discounted at 3.5% per year. An integrated transmission-dynamic and economic model was used to evaluate the cost-effectiveness of introducing rapid molecular testing (in addition to culture and drug sensitivity testing). Probabilistic sensitivity analysis was performed to evaluate the impact on cost-effectiveness of diagnostic and treatment time delays, diagnosis and treatment costs, and associated QALYs. RESULTS: A total of 8922 titles and abstracts were identified, with 557 papers being potentially eligible. Of these, 56 studies contained sufficient test information for analysis. All three commercial tests performed well when detecting drug resistance in clinical samples, although with evidence of heterogeneity between studies. Pooled sensitivity for GenoType((R)) MTBDRplus (Hain Lifescience, Nehren, Germany) (isoniazid and rifampicin resistance), INNO-LiPA Rif.TB((R)) (Fujirebio Europe, Ghent, Belgium) (rifampicin resistance) and Xpert((R)) MTB/RIF (Cepheid Inc., Sunnyvale, CA, USA) (rifampicin resistance) was 83.4%, 94.6%, 95.4% and 96.8%, respectively; equivalent pooled specificity was 99.6%, 98.2%, 99.7% and 98.4%, respectively. Results of the transmission model suggest that all of the rapid assays considered here, if added to the current diagnostic pathway, would be cost-saving and achieve a reduction in expected QALY loss compared with current practice. GenoType MTBDRplus appeared to be the most cost-effective of the rapid tests in the South Asian population, although results were similar for GeneXpert. In all other scenarios GeneXpert appeared to be the most cost-effective strategy. CONCLUSIONS: Rapid molecular tests for rifampicin and isoniazid resistance were sensitive and specific. They may also be cost-effective when added to culture drug susceptibility testing in the UK. There is global interest in point-of-care testing and further work is needed to review the performance of emerging tests and the wider health-economic impact of decentralised testing in clinics and primary care, as well as non-health-care settings, such as shelters and prisons. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001537. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Tuberculosis (TB) is an airborne infectious disease caused by the bacterium Mycobacterium tuberculosis. In most healthy people the immune system can kill the bacteria. In others, the immune system can’t kill the bacteria but they don’t develop any symptoms. This is called latent TB. Latent TB can eventually progress to active TB in about 1 in 10 people. Active TB causes a persistent cough producing a sometimes bloody phlegm, high temperature, weight loss and lethargy.

Active TB infection can be cured with a six-month course of antibiotic drugs that usually includes rifampicin and isoniazid. To get appropriate treatment people need to be tested for drug-susceptibility.

Multidrug resistant TB is defined as resistance to, at least, rifampicin and isoniazid, the two most powerful first-line anti TB drugs. Multidrug resistant TB has worse outcomes than drug sensitive disease. Treating TB that is resistant to one or both these drugs also takes longer, is much more expensive and can require more toxic drugs.

Sensitivity is one of a set of measures used to show the accuracy of a diagnostic test. Sensitivity is the proportion of people with a disease who are correctly identified as having that disease by the diagnostic test. For example, if a test has a sensitivity of 90%, this means that it correctly identified 90% of the people with the disease, but missed 10% (these people were ‘false negatives’ on the test).

Specificity is another one of a set of measures used to assess the accuracy of a diagnostic test. Specificity is the proportion of people without a disease who are correctly identified as not having that disease by the diagnostic test. For example, if a test has a specificity of 95%, this means that it correctly identified 95% of the people who did not have the disease, but that 5% of people without the disease were incorrectly diagnosed as having the disease (these people were ‘false positives’ on the test).

Expert commentary

One of the main challenges faced in TB control in the UK is long diagnostic delay. Reducing this delay would ensure patients are diagnosed, isolated when necessary and start effective treatment, particularly for those with drug resistant TB. This would provide benefits both to the patient and reduce the risk of transmission within the community. This review and evaluation concluded that including a rapid molecular test in the TB diagnostic pathway would provide accurate results significantly faster while being cost-effective. The systematic roll out of rapid molecular tests throughout the NHS would contribute to reducing diagnostic delay of TB in the UK.

Dr Maeve Lalor, Principal Scientist, TB section, National Infection Service, Colindale, Public Health England