To scale-up TB preventive therapy, we need to bundle tools & improve access
Approximately 1.7 billion individuals are estimated to be latently infected with Mycobacterium tuberculosis globally. While the majority will not progress to TB disease, we can and must prevent TB disease in those who are newly infected and those at high risk of progression.
Thankfully, there are now shorter treatments that are highly effective, and we now have good, consolidated guidelines from WHO. In parallel, high-burden countries are starting to acknowledge the need to test and treat TB infection in high-risk populations (e.g. people living with HIV, child contacts).
The global TB community has ambitious targets for preventive therapy. The first-ever UN General Assembly high-level meeting on TB on 26 September 2018 endorsed an ambitious and powerful political declaration which commits to offering preventive therapy to at least 30 million people, including 4 million children under 5 years of age, 20 million other household contacts of people affected by TB, and 6 million people living with HIV, receive preventive treatment by 2022."
Challenges
Before we can expect high-burden countries to treat 30 million people for TB infection, we need to not only enhance funding for national programs to take on LTBI treatment, but also solve a basic problem: our LTBI toolbox is currently broken. The Table below is my take on the challenges that countries face when it comes to tools that are essential for diagnosing and treating TB infection.
| Tool | Challenge | |
| Tuberculin | -PPD (purified protein derivative) shortages are reported in many countries, including US and many European countries -Staten Serum Institut, Denmark, a major PPD manufacturer sold their manufacturing unit to a Malaysian owned company in 2017 after several years of supply delays -Private companies (e.g. Span Diagnostics in India) make PPD of unknown quality and some data suggest suboptimal accuracy -India used to manufacture PPD in a public sector company, but stopped production circa 2004, resulting in the world's highest TB burden country not having access to quality-assured PPD |
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| Newer PPDs | -C-Tb (SSI, Denmark), an improved, more specific RD-1 antigen-based skin test has been validated in trials, but there is no commercial availability; product is yet to be endorsed by WHO -Diaskintest by Generium, a company in Russia, is commercially available, but there is little data in English literature, and the product is yet to be endorsed by WHO |
|
| IGRAs | -While interferon-gamma release assays (IGRAs) like QFT (Qiagen) and T-SPOT.TB (Oxford Immunotec) are included in WHO guidelines & WHO Essential Diagnostics List, these assays are expensive in LMICs. Further, these assays require laboratory capacity to perform ELISA and ELISPOT. Quality assurance is critical to address reproduciblity issues identified even in high-income countries. -In countries like India, Korea and China, there are locally made IGRAs (e.g. TB Platinum) of unknown or dubious quality; these assays are also being abused for active TB diagnosis |
|
| Chest x-rays & CAD | -Chest x-rays are recommended for ruling out active TB disease, before preventive therapy is initiated. But x-ray hardware, especially digital systems, cost tens of thousands of dollars. In many LMICs, x-rays are mainly available at hospitals and referral centers. -Even if hardware is available, scarcity of radiologists poses problems for reading of x-rays. Recently, computer-aided detection (CAD) software have been come available [e.g. CAD4TB by Delft & qXR by Qure.ai] and growing evidence show their value. But evidence gaps must be plugged and CAD data need to be reviewed and endorsed for clinical use by WHO. |
|
| Rifapentine | -The 3HP (Isoniazid and Rifapentine, once weekly for 3 months) regimen is endorsed by many guidelines, but rifapentine (Sanofi) is registered in only a small number of countries (e.g. Taiwan, Hong Kong, Philippines, Thailand, Indonesia, USA). -Concerns have also been raised about pricing of rifapentine, although the situation today is better than it was in the past |
With the challenges outlined above, we need to ask whether it is realistic or reasonable to expect LMICs to scale-up preventive therapy in the near future. While the WHO guidelines do not consider TST, IGRAs or CXR to be a mandatory requirement for preventive therapy in high-burden countries, these tools are routinely used in high-income countries. Their use is backed by evidence that preventive therapy is most effective when it is targeted at those with evidence of infection, and CXR is the current best tool for ruling out active TB.
Potential Solutions
One potential solution is to convene all LTBI product manufacturers (i.e. PPD, IGRA, x-ray hardware & software, and rifapentine manufacturers) to understand their constraints, and help them understand the growing interest in preventive therapy, updated guidelines, global targets, and the likely market in high-burden settings. These manufacturers also need to understand that several tools are necessary for a good preventive therapy program, and it is in their interest to collaborate.
The next step would be negotiate a 'bundled price' for LTBI. An LTBI bundle of tools, with special pricing for high-burden countries (along the lines of high-burden country (HBDC) pricing for Xpert MTB/RIF) might be exceedingly attractive for high-burden countries, as well as donors (e.g. Global Fund, Unitaid, USAID). Further, we must explore the option of making this bundle available via the Global Drug Facility, which is a leading supplier of TB tests and drugs.
To my knowledge, nobody in the TB field has convened all x-ray hardware makers (e.g. GE, Siemens, Delft, Philips, Fuji) to explore the possibility of a HBDC pricing for national TB programs, with the option of a CAD software bundled in. A similar strategy must be considered for manufacturers of quality-assured IGRAs.
An additional intervention could be the support companies that are struggling with production and regulatory issues. For example, can the SSI PPD or Tubersol be licensed to an Indian or Chinese generic manufacturer for increasing production and supply? Can global health agencies (e.g. WHO country offices) work with countries to speed up regulatory approval of rifapentine?
I welcome feedback on this post. There may be barriers and solutions that I have missed. At the very least, I hope it will spark a debate and encourage agencies such as WHO, Stop TB Partnership, USAID, Global Fund, Unitaid, FIND and TB Alliance to convene a meeting around this idea of an LTBI bundle of tools. Without such a market intervention, I worry about the ability of high burden countries to reach the ambitious targets we have set for scale-up of preventive therapy.
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Dear Dr.Pai,
I read your article with great interest.
I really like your idea of convening all x-ray hardware makers to get a discount pricing for NTP in high TB burden countries. However, if I may add, this agenda, making x-ray accessible to high burden countries, should be raised to the overall UHC agenda beyond TB field. X-ray is a multi disease a platform, than can be used for TB, other lung infectious diseases as well as for NCDs such as lung cancer. We are all aware that chest x-ray is one of the essential health services in high income countries. It's unfortunate that the recently published WHO list of essential diagnostics did not include diagnostic imaging withing the scope. Chest x-ray is often considered a barrier in resource limited settings and people try to think about strategies without using it. I believe it's time to seriously think about how to break that barrier instead of getting away from it and taking a detour.
Fully agree with you! X-rays should be an essential test in all health systems and is truly multi-disease. Also agree that it should be on the WHO Essential Dx list. WHO has begun the EDL with "in-vitro diagnostics" but definitely need to go beyond that to include imaging technologies.