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Genexpert Test – TB diagnosis and resistance Testing

The Genexpert test is a molecular test for TB which diagnoses TB by detecting the presence of TB bacteria, as well as testing for resistance to the drug Rifampicin.

Some organisations have claimed that the Genexpert  test is going to revolutionize the diagnosis and care of people with TB.1“WHO endorses new rapid tuberculosis test”, WHO, Geneva, 8 December 2010 www.who.int/mediacentre/news/releases/2010/ So what are the advantages and disadvantages of the Genexpert, how is the Genexpert test used, and is it really going to result in the breakthroughs that are claimed?

Genexpert Test © GHE

Genexpert Test

How does the Genexpert test work?

The test is a molecular test which detects the DNA in TB bacteria. It uses a sputum sample and can give a result in less than 2 hours. it can also detect the genetic mutations associated with resistance to the drug Rifampicin.2“Two hour detection of MTB and resistance to rifampicin”, Cepheid International, 2011 www.cepheidinternational.com

Who developed the Genexpert test?

The Genexpert has been developed by the Foundation for Innovative New Diagnostics (FIND), who have partnered with the Cepheid corporation and the University of Medicine and Dentistry of New Jersey. Some of the funding for the development of the Genexpert  was provided by the NIH.3“Policy statement: Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system”, WHO, Geneva, 2011 www.who.int/tb/features_archive/xpert_rapid_tb_test/

When did the Genexpert test first become available?

The Genexpert system was launched in 2004, and the development of the Genexpert  test, based on the Genexpert platform, was completed in 2008.4“New laboratory diagnostic tools for tuberculosis control”, WHO, Geneva, 2008 www.who.int/tdr/publications 5“Policy statement: Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system”, WHO, Geneva, 2011 www.who.int/tb/features_archive/xpert_rapid_tb_test/

The first clinical validation studies were carried out in 2009.6Helb, D “Rapid Detection of Mycobacterium tuberculosis and Rifampin Resistance by Use of On-Demand, Near-Patient Technology”, Journal of Clinical Microbiology, January 2010 229 jcm.asm.org/content/48/1/229.full A large scale demonstration project was then carried out in a number of different countries including South Africa and India to assess the implementation of the Genexpert.7Boehme, C “Rapid molecular detection of tuberculosis and rifampin resistance”, The New England Journal of Medicine, 2010 Sep 1005-15 www.nejm.org/doi/full/

Data from these studies were then submitted to the World Health Organisation (WHO) for evaluation in September 2010. In December 2010 WHO endorsed the Genexpert  technology and released a recommendation and guidance for countries to incorporate the new test into their programs.

Alternatives to GeneXpert

When the WHO endorsed Genexpert it was expected that many similar tests would follow shortly afterwards. Seven years later progress has been slow, with a number of tests having been dropped. Of the alternative tests Molbio’s TrueNat is the furthest along, with a large mulitcentre evaluation underway supported by the Indian Council of Medical Research. Review for approval is expected in late 2017. This test is a near Point of Care test, and it can be used in complementary circumstances where Genexpert cannot be used. There is more about Truenat.8Lessem, E, “The Tuberculosis Diagnostics Pipeline”, Treatment Action Group. 2017, www.treatmentactiongroup.org/pipeline-report/

What is the cost of the Genexpert TB test?

FIND originally negotiated discounts for the Genexpert test in 120 high burden and in all low and middle income countries and the initial cost was approximately US$17 per cartridge.

In June 2012 the organisation UNITAID approved funding of $30 million with the aim of scaling up access to the Genexpert test. It was hoped that the roll out of the test would bring the price down from US$17 to US$10. However the roll out proceeded slower than expected and it is believed that many customers delayed ordering as they expected the price to be reduced following the UNITAID announcement.

GeneXpert 4 module machine © GHE

GeneXpert 4 module machine

It was subsequently announced in August 2012 that Cepheid had entered into an agreement with the Bill and Melinda Gates Foundation, PEPFAR, and USAID to further bring down the cost of the test. It was agreed that the test would immediately be available for US$9.98 with the difference between this and the earlier US$16.86 being paid by the collaborators with an initial US$3.5 million being provided by the Bill and Melinda Gates Foundation.9“Cepheid’s MTB/RIF Test Price Falls – Analyst Blog”, //community.nasdaq.com/News/2012-08/cepheids-mtbrif-test-price-falls-analyst-blog The concessionary cost is however only available for the public sector and for NGOs. This causes problems for countries such as India, where initial diagnosis often takes place in the private sector.

In addition to the cost of each test there is the cost of the Genexpert device. The device comes in different sizes providing for a different number of samples to be tested simultaneously. The commonly used GX4 which has 4 modules, has a cost of approximately US$17,000. There are in addition costs for delivery and installation, and there is an annual servicing cost.10Abdurrahman, S “The hidden costs of installing xpert machines in a tuberculosis high-burden country: experiences from Nigeria”, Pan Afr Med J,  2014 www.ncbi.nlm.nih.gov/pmc/articles/

The use of the Genexpert test

WHO recommended that the test should be used as the initial diagnosis test in individuals suspected of having MDR TB, or HIV associated TB. They also suggested that it could be used as a follow on test to microscopy in settings where MDR TB and/or HIV is of lesser concern, especially in smear negative specimens, because of the lack of accuracy of smear microscopy. They did however say that they recognised the major resource implications of using it in this second way.11“Roadmap for rolling out Xpert MTB/RIF for rapid diagnosis of TB and MDR TB”, WHO, Geneva, 8 December 2010 www.who.int/tb/laboratory/roadmap_xpert_mtb-rif.pdf

WHO did also emphasize that the test does not eliminate the need for conventional microscopy culture and drug sensitivity testing, as these are still required to monitor treatment progress and to detect other types of drug resistance. The Genexpert MTB/RIF cannot be used for treatment monitoring, as it detects both live and dead bacteria.

Further guidance was subsequently provided by WHO on the rapid implementation of the new test.12“Xpert MTB/RIF – rapid TB test – WHO publishes policy and guidance for implementers”, WHO, Geneva, May 2011 www.who.int/tb/features_archive/ 13“Rapid implementation of the Xpert MTB/RIF diagnostic test. Technical and operational ‘How-to’. Practical considerations, WHO, Geneva, May 2011 apps.who.int/iris/bitstream/10665/44593/1/9789241501569_eng.pdf

Advantages and disadvantages of the test

WHO have been particularly keen on the use of the test and in 2010 said that:

“This new test represents a major milestone for global TB diagnosis and care. It also represents new hope for the millions of people who are at the highest risk of TB and drug resistant disease.”

Dr Mario Ravihlione, Director of WHO Stop TB Department14“WHO endorses new rapid tuberculosis test”, WHO, Geneva, 8 December 2010 www.who.int/mediacentre/news/releases/2010/

The test does however have disadvantages as well as advantages.

Disadvantages

The disadvantages include:

  • The shelf life of the cartridges is only 18 months;
  • A very stable electricity supply is required;
  • The instrument needs to be recalibrated annually;
  • The cost of the test;
  • The temperature ceiling is critical.15Trebucq, A “Xpert MTB/RIF for national tuberculosis programmes in low income countries: when, where and how?”, Int J Tuberc Lung Dis, October 2011 1567-1571 www.ncbi.nlm.nih.gov/pubmed/22005110

Advantages

The main advantages of the test are, for diagnosis, reliability when compared to sputum microscopy and the speed of getting the result when compared with the culture test. For diagnosis of TB, although sputum microscopy is both quick and cheap, it is often unreliable. It is particularly unreliable when people are HIV positive. Although culture gives a definitive diagnosis, to get the result usually takes weeks rather than the hours of the Genexpert test.

The main advantage in respect of identifying rifampicin resistance, is again the matter of speed. Normally to get any drug resistance result takes weeks rather than hours.

Review articles

A considerable number of articles have been written reviewing the use of the Genexpert test, and the WHO maintains a list of some of the major articles.16“Published evidence and commentary on the Xpert MTB/RIF assay”, WHO, 5 April 2013 www.stoptb.org/wg/gli/assets/documents/map/XpertPublications.pdf

Generally the views given are extremely variable, with some people considering that the test is extremely useful, as well as cost effective, and should be used in as many places as possible as soon as possible. Other people consider that it is not really suitable and practical at the present time for major use in low and middle income countries.17Trebucq, A “Xpert MTB/RIF for national tuberculosis programmes in low income countries: when, where and how?”, Int J Tuberc Lung Dis, October 2011 1567-1571 www.ncbi.nlm.nih.gov/pubmed/22005110 18Singh, J “The ethics of national tuberculosis programmes in low income countries not rolling out Xpert MTB/RIF”, Int J Tuberc Lung Dis, October 2011 1563 www.ncbi.nlm.nih.gov/pubmed/22118160 19Evans, C “GeneXpert – A game changer for tuberculosis control?”, PLoS Med, July 2011 www.plosmedicine.org/article/

In October 2013 a multi centre trial comparing the use of the Genexpert  to microscopy, concluded that using the Genexpert meant that more patients had a same day diagnosis and same day treatment initiation, but the benefits did not translate into lower TB morbidity.20Theron, G “Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial”, The Lancet 28 October 2013 www.thelancet.com

“Earlier diagnosis by the Genexpert test did not reduce overall severity of TB related illness.”

Study leader, Keertan Dheda, University of Cape Town21“Sputum test may not hold key to TB eradication, study says”, Medical Express 27 October 2013 www.medicalxpress.com

The global roll-out of the Genexpert

The global rollout of the test was initially slower than organisations such as WHO and FIND would probably have wished. By the end of 2011 a total of 460 Genexpert machines (comprising 2,401 modules) and 591,450 Genexpert  test cartridges had been bought for 47 countries, using the special pricing arrangements arranged by FIND with Cepheid.

Over half of the Genexpert  cartridges (330,540 cartridges) had been bought for use in South Africa. Other countries who had bought cartridges were Pakistan (21,440), Kenya (20,140), the Philippines (17,440) and Swaziland (16,600).22“Update on Xpert MTB/RIF roll out Xpert MTB/RIF February 2012”, WHO, February 2012 www.stoptb.org/wg/gli/xpert.asp There is more about TB in South Africa.

By the end of September 2012 a total of 898 Genexpert machines (comprising 4,660 modules) and 1,482,550 cartridges had been purchased in 73 of the 145 countries eligible for concessional pricing. There was an increase in the purchase of cartridges in the third quarter of 2012, which it is likely was associated with the drop in cartridge price around that time.23“Update on Xpert MTB/RIF roll out Xpert MTB/RIF December 2012”, WHO, December 2012 www.stoptb.org/wg/gli/xpert.asp

 

Procurement of Xpert MTB/RIF modules and cartridges under concessionary pricing by quarter in 2010 - 2015 (Cepheid data)

Procurement of Xpert MTB/RIF modules and cartridges under concessionary pricing by quarter in 2010 – 2015 (Cepheid data)

The UNITAID TBXpert Project

In September 2013 UNITAID and WHO started the largest rollout of GeneXpert with UNITAID investing US$25.9 million to purchase over 220 GeneXpert machines and 1.4 million test cartridges for 21 countries in Africa, Eastern Europe and Asia.24“Largest ever roll-out of GeneXpert rapid TB test machines September 2013”, UNITAID, September 2013 www.unitaid.eu/en/resources/press-centre/releases/ However, it is still a challenge as the machines need a continuous power supply and air conditioning is also needed where there are high temperatures.25“Largest ever push to diagnose tuberculosis within two hours”, Citizen News Service, September 14 2013 www.tbonline.info/posts/2013/9/20/largest-ever-push-diagnose-tuberculosis-within-two/

By 2014 the use of the GeneXpert had expanded significantly. In total 4.8 million cartridges were bought in 2014 by 116 low and middle income countries at concessional prices. By 2015 69% of the countries recommended using Genexpert as the initial diagnostic test for people at risk of developing drug-resistant TB and 60% recommended it as the initial diagnostic test for people living with HIV. Between 2011 and 2016 more than 16 million tests had been carried out in 122 countries.26“Development, roll-out and impact of Xpert MTB/RIF for tuberculosis: what lessons have we learnt and how can we do better?”, European Respiratory Journal 2016 48: 516-525 erj.ersjournals.com/content/48/2/516

The use of the GeneXpert test in India

The GeneXpert test first started to be used to test for TB in India when it was used in reference laboratories as part of a demonstration project. Subsequently a two year project is taking place to evaluate the use of the test at 18 sites across India.27Sayyed-Pathan, N  “2 hour test pilot to start at Dharavi”, DNA, Mar 23 2012 www.dnaindia.com/mumbai/ In March 2012 it was announced which hospitals were going to benefit by being the first sites where the GeneXpert will be installed.28Isalkar, U “Two govt hospitals to get device that detects drug-resistant TB in 2 hours”, The Times of India, Mar 23 2012 articles.timesofindia.indiatimes.com/

It has been said that it might not be as effective in India as elsewhere as the heat and humidity could affect the equipment. The result could be that:

“The technique cannot be used for routine testing. We have pilot projects at 18 sites going on to test its feasibility in the Indian situation where the climate and temperature conditions are different from the western countries. … Solid culture/sputum testing remains the golden standard for Indian conditions.”

Ashok Kumar, Deputy Director General, Central TB control Division, Ministry of Health and Family Welfare29“90-minute TB test not a game changer for India”, Indo Asian News Service, 29 August 2011 news.bioscholar.com/2011/08/

The Xpert MTB/RIF Omni

The Xpert MTB/RIF Omni

New developments Ultra & Omni

In 2017 the Xpert Ultra assay was launched. It was found to be non-inferior to the standard Xpert MTB assay for the diagnosis of TB and the detection of rifampicin resistance and it can be used as an alternative to the latter in all settings. Cepheid plans to gradually phase out and replace the current Xpert MTB assay with the Ultra assay.30“WHO meeting report of a technical expert consultation: Non-inferiority analysis of Xpert MTB/RIF Ultra compared to Xpert MTB/RIF”,  Geneva, World Health Organisation; 2017, www.who.int/tb/areas-of-work/laboratory/

A new device called the GeneXpert Omni is currently under development. It is intended for point of care testing for TB and rifampicin resistance, using the same cartridges as those used in the current Genexpert machine. It is expected that it will be smaller, lighter and less expensive than the current Genexpert. It will also come with a built-in 4 hour battery.

You can read more about TB tests by looking at

TB tests
Truenat
Drug susceptibility testing.

References

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1. “WHO endorses new rapid tuberculosis test”, WHO, Geneva, 8 December 2010 www.who.int/mediacentre/news/releases/2010/
2. “Two hour detection of MTB and resistance to rifampicin”, Cepheid International, 2011 www.cepheidinternational.com
3. “Policy statement: Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system”, WHO, Geneva, 2011 www.who.int/tb/features_archive/xpert_rapid_tb_test/
4. “New laboratory diagnostic tools for tuberculosis control”, WHO, Geneva, 2008 www.who.int/tdr/publications
5. “Policy statement: Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system”, WHO, Geneva, 2011 www.who.int/tb/features_archive/xpert_rapid_tb_test/
6. Helb, D “Rapid Detection of Mycobacterium tuberculosis and Rifampin Resistance by Use of On-Demand, Near-Patient Technology”, Journal of Clinical Microbiology, January 2010 229 jcm.asm.org/content/48/1/229.full
7. Boehme, C “Rapid molecular detection of tuberculosis and rifampin resistance”, The New England Journal of Medicine, 2010 Sep 1005-15 www.nejm.org/doi/full/
8. Lessem, E, “The Tuberculosis Diagnostics Pipeline”, Treatment Action Group. 2017, www.treatmentactiongroup.org/pipeline-report/
9. “Cepheid’s MTB/RIF Test Price Falls – Analyst Blog”, //community.nasdaq.com/News/2012-08/cepheids-mtbrif-test-price-falls-analyst-blog
10. Abdurrahman, S “The hidden costs of installing xpert machines in a tuberculosis high-burden country: experiences from Nigeria”, Pan Afr Med J,  2014 www.ncbi.nlm.nih.gov/pmc/articles/
11. “Roadmap for rolling out Xpert MTB/RIF for rapid diagnosis of TB and MDR TB”, WHO, Geneva, 8 December 2010 www.who.int/tb/laboratory/roadmap_xpert_mtb-rif.pdf
12. “Xpert MTB/RIF – rapid TB test – WHO publishes policy and guidance for implementers”, WHO, Geneva, May 2011 www.who.int/tb/features_archive/
13. “Rapid implementation of the Xpert MTB/RIF diagnostic test. Technical and operational ‘How-to’. Practical considerations, WHO, Geneva, May 2011 apps.who.int/iris/bitstream/10665/44593/1/9789241501569_eng.pdf
14. “WHO endorses new rapid tuberculosis test”, WHO, Geneva, 8 December 2010 www.who.int/mediacentre/news/releases/2010/
15. Trebucq, A “Xpert MTB/RIF for national tuberculosis programmes in low income countries: when, where and how?”, Int J Tuberc Lung Dis, October 2011 1567-1571 www.ncbi.nlm.nih.gov/pubmed/22005110
16. “Published evidence and commentary on the Xpert MTB/RIF assay”, WHO, 5 April 2013 www.stoptb.org/wg/gli/assets/documents/map/XpertPublications.pdf
17. Trebucq, A “Xpert MTB/RIF for national tuberculosis programmes in low income countries: when, where and how?”, Int J Tuberc Lung Dis, October 2011 1567-1571 www.ncbi.nlm.nih.gov/pubmed/22005110
18. Singh, J “The ethics of national tuberculosis programmes in low income countries not rolling out Xpert MTB/RIF”, Int J Tuberc Lung Dis, October 2011 1563 www.ncbi.nlm.nih.gov/pubmed/22118160
19. Evans, C “GeneXpert – A game changer for tuberculosis control?”, PLoS Med, July 2011 www.plosmedicine.org/article/
20. Theron, G “Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial”, The Lancet 28 October 2013 www.thelancet.com
21. “Sputum test may not hold key to TB eradication, study says”, Medical Express 27 October 2013 www.medicalxpress.com
22. “Update on Xpert MTB/RIF roll out Xpert MTB/RIF February 2012”, WHO, February 2012 www.stoptb.org/wg/gli/xpert.asp
23. “Update on Xpert MTB/RIF roll out Xpert MTB/RIF December 2012”, WHO, December 2012 www.stoptb.org/wg/gli/xpert.asp
24. “Largest ever roll-out of GeneXpert rapid TB test machines September 2013”, UNITAID, September 2013 www.unitaid.eu/en/resources/press-centre/releases/
25. “Largest ever push to diagnose tuberculosis within two hours”, Citizen News Service, September 14 2013 www.tbonline.info/posts/2013/9/20/largest-ever-push-diagnose-tuberculosis-within-two/
26. “Development, roll-out and impact of Xpert MTB/RIF for tuberculosis: what lessons have we learnt and how can we do better?”, European Respiratory Journal 2016 48: 516-525 erj.ersjournals.com/content/48/2/516
27. Sayyed-Pathan, N  “2 hour test pilot to start at Dharavi”, DNA, Mar 23 2012 www.dnaindia.com/mumbai/
28. Isalkar, U “Two govt hospitals to get device that detects drug-resistant TB in 2 hours”, The Times of India, Mar 23 2012 articles.timesofindia.indiatimes.com/
29. “90-minute TB test not a game changer for India”, Indo Asian News Service, 29 August 2011 news.bioscholar.com/2011/08/
30. “WHO meeting report of a technical expert consultation: Non-inferiority analysis of Xpert MTB/RIF Ultra compared to Xpert MTB/RIF”,  Geneva, World Health Organisation; 2017, www.who.int/tb/areas-of-work/laboratory/