Towards ending tuberculosis: what gets measured gets done


A breakthrough in testing technology

When the emergence and spread of HIV brought TB roaring back, the tools for coping with the surge in cases were antiquated. Sputum microscopy, quick and cheap but tedious and prone to human error, had been the principal diagnostic test for more than a century. Growing the bacterium in culture was the highly accurate diagnostic “gold standard” but could take up to two months to get results. Drugs for treating drug-susceptible TB dated back to the 1950s and 1970s, with nothing new since. Needless to say, no ready-made diagnostic tools were on hand to manage the formidable new challenges of MDR-TB and XDR-TB.

TB patient taking medication
At the hospital for TB patients
WHO

In 2009, case-finding and testing were still missing nearly 40% of suspected TB cases. The prevalence of MDR-TB had increased to an estimated half a million cases, of whom fewer than 7% were diagnosed and, of those diagnosed, only one in five received treatment. Nearly two million people were still dying of TB each year, mainly from drug-susceptible forms of the disease that could have been easily and cheaply cured.

In the autumn of 2010, a breakthrough looked eminent. The Foundation for Innovative New Diagnostics, or FIND, in partnership with the Cepheid corporation and the University of Medicine and Dentistry of New Jersey, had developed a new molecular platform for the diagnosis of TB using the Xpert MTB-RIF machine, or Xpert. Many – though not all – hailed the new technology as having the potential to revolutionize TB testing.

With its compact and sleek table-top design that looked like an espresso machine, the Xpert machine had much to offer. Fully automated, it was easy to use and posed no biosafety hazards for staff. Large-scale testing and demonstration projects in India and South Africa showed high sensitivity and specificity in the detection of both drug-susceptible TB and MDR-TB. As a major advantage, the test produced results in less than two hours instead of weeks or months. That speed greatly increased the prospects of successful case management: patients waiting for test results could be immediately started on the right treatment.

However, as sceptical critics noted, operation of the machine required a steady and reliable supply of electricity. The machine needed yearly maintenance and calibration and performed best under controlled conditions of temperature and humidity – luxuries in most facilities providing care in high-burden countries. Moreover, with all its advantages, Xpert came on the market at a prohibitively steep price. The initial market price of different testing machines ranged from $17 000 to $62 000. The cost of the disposable test cartridges, with their short shelf lives and huge demands for storage space and waste disposal, ranged from $17 to $120 – equivalent to the entire annual per capita health expenditure in most high-burden countries.

In September 2010, FIND submitted its dossier of trial results to WHO for evaluation. In December 2010, WHO formally endorsed the use of the new molecular assay. WHO recommended Xpert as the first-choice test for presumptive TB in people living with HIV or suffering from severe disease, and in individuals with presumptive MDR-TB. That endorsement by WHO was the seal of approval needed to change the situation dramatically. What followed demonstrated the power of WHO to get multiple partners working in concert to take an innovation forward in a massive, structured, phase-wise campaign, precisely targeted at hot spots in greatest need and gathering further evidence along the way.

"Through the concerted and determined efforts of multiple partners, high-burden countries were indeed being equipped with a revolutionary new tool for detecting difficult forms of TB."

Dr Chan, WHO Director-General

FIND leveraged its investment by directly negotiating price reductions with the manufacturer; reduced prices were offered to nearly 150 purchasers in low- and middle-income countries. The US government, UNITAID, and the Bill and Melinda Gates Foundation provided upfront payment of $11 million to the manufacturer to reduce unit prices further. The price of cartridges dropped from $17 to under $10.

In 2013, UNITAID and WHO started the largest rollout of Xpert ever, with UNITAID investing nearly $26 million to purchase more than 220 Xpert machines and 1.4 million cartridges for 21 countries in Africa, Eastern Europe, and Asia. Through the concerted and determined efforts of multiple partners, high-burden countries were indeed being equipped with a revolutionary new tool for detecting difficult forms of TB .

Other new diagnostic options were also gaining recognition. As part of its programme for the testing of new technologies, WHO evaluated molecular line probe assays for the rapid screening of patients at risk of MDR-TB and issued policy recommendations on their use. WHO also evaluated the use of loop-mediated isothermal amplification (TB-LAMP), a manual assay that required less than one hour to perform and could be read with the naked eye under ultraviolet light. Nonetheless, the ideal of an inexpensive point-of-care diagnostic test that matched the simplicity and accuracy of HIV antibody tests and required no electricity remained elusive.