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Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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3

Detection

The first session of the second part of the workshop centered on the state of tuberculosis (TB) detection worldwide and advances that are currently underway to improve case finding, diagnostics, and case notification. The session began with progress updates on efforts to build a TB-free world by Jennifer Adams, acting assistant administrator, Bureau for Global Health at the U.S. Agency for International Development (USAID); Eric Goosby, professor of medicine at University of California, San Francisco, director of the Center for Global Health Delivery, Diplomacy and Economics at the Institute for Global Health Sciences, and United Nations (UN) Special Envoy on Tuberculosis; and Matteo Zignol, head of the Prevention, Care, and Innovation Unit of the Global TB Programme at the World Health Organization (WHO).

Matthew McMahon, director of the Small Business Education and Entrepreneurial Development Office at the National Institutes of Health, then discussed efforts to rapidly accelerate the development of diagnostics technology for COVID-19 and highlighted lessons learned that could potentially be applied to TB diagnostics. Next was a panel discussion on diagnostic advances that featured four panelists. Morten Ruhwald, head of tuberculosis at the Foundation for Innovative New Diagnostics, discussed point-of-care molecular platforms for diagnosis of TB and other infectious respiratory diseases. Zvi Marom, chief executive officer and founder at BATM Advanced Communications, described his organization’s innovative approach to tackling TB amid the COVID-19 pandemic by focusing on substantially reducing the cost of diagnostic testing and to initiate TB treatment rapidly after an accurate diagnosis. Luan Vo, chief executive officer at Friends for Interna-

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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tional Tuberculosis Relief, presented on the implementation of ultraportable X-ray technology and the use of AI for X-ray interpretation for TB detection in Vietnam. Kaiser Shen, senior TB diagnostic technical advisor at USAID’s Sustaining Technical and Analytic Resources project, shared insights from his work at USAID on point-of-care (POC) TB diagnostics, TB diagnostic networks, and implementation challenges.

The session then shifted focus to highlight efforts to improve adherence, infection control capacities, and cost-effectiveness. Amir Khan, executive director at Interactive Research and Development (IRD), discussed the comprehensive approach to COVID-19 and TB testing implemented in Pakistan by adapting IRD’s model of integrated community response to TB control. Bruce Thomas, founder and managing director of the Arcady Group, described how digital adherence technologies (DATs) can facilitate differentiated and virtual care for persons affected by TB. Monique Mansoura, executive director for Global Health and Biotechnology at the MITRE Corporation, explored innovative strategies to synergize investments in health care systems with a focus on whether cancer and TB care can protect against pandemics. Edward Nardell, professor of medicine at Harvard Medical School and the Harvard T.H. Chan School of Public Health and physician at Brigham and Women’s Hospital, outlined environmental transmission control lessons that can be gleaned from efforts to control TB over many decades and efforts to control COVID-19 since 2020. Gavin Churchyard, founder and chief executive officer of the Aurum Institute, discussed gaps and opportunities in the management of latent TB infection and barriers to the implementation of tuberculosis preventive therapy (TPT). The session was moderated by Lucica Ditiu, executive director of the Stop TB Partnership.

USAID’S COMMITMENT TO ADDRESSING TUBERCULOSIS WORLDWIDE

Presented by Jennifer Adams, United States Agency for International Development

Adams described how USAID has made a long-standing commitment to work with partners in addressing TB worldwide by reaching every person with TB, curing people in need of treatment, preventing new infections, and stopping the progression of TB from infection to active disease. Strong gains have been made over the past two decades. Between 2000 and 2019, more than 60 million lives were saved globally, TB incidence decreased by 29 percent, TB mortality decreased by 47 percent, and TB case notifications increased by 126 percent, Adams noted. USAID has contributed a focus on research and clinical trials to this effort, including the introduction and scal-

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×

ing up of new drugs and shorter treatment regimens and the development of stronger diagnostic tools and networks. In 2018, TB garnered renewed energy and attention with the UN High-Level Meeting on Ending TB, which set ambitious targets and generated increases in domestic resources and political commitments.

The COVID-19 pandemic has had devastating effects on the global TB response—in addition to other public health issues—and continues to dim the prospects of meeting the ambitious UN targets, said Adams. The social, economic, and biomedical consequences of the pandemic have created a perfect storm for TB and other public health issues. She noted that the COVID-19 pandemic has been particularly devastating for the poorest and most vulnerable populations in low- and middle-income countries (LMICs). These populations are more likely to suffer from other health problems, including malnutrition, and they often live in overcrowded spaces that increase their risk of contracting COVID-19 and TB. Adams recounted the waves of COVID-19 she witnessed while serving as the USAID mission director in Mozambique, the first of which caused all clinics to close, thereby interrupting access to TB care and other health services. Reports from Mozambique’s national TB program indicated that the number of people diagnosed with TB dropped by almost half during the pandemic. Simultaneously, TB personnel and services were repurposed and deployed in the response to COVID-19. Their experience in case detection, contact tracing, and airborne infection control were essential for the new and unprecedented pandemic, said Adams. She remarked that the focus should now be on ending the long-term negative effects that COVID-19 is having on other health needs, particularly on TB and in countries with very high TB burdens. This involves renewing commitments, reinvesting in infrastructure to meet unmet needs, and contributing to a consensus on how to best prepare for future pandemics. Much of what is being discussed in terms of pandemic preparedness and response directly aligns with TB interventions.

The COVID-19 pandemic has led to alarming drops in the number of people tested and treated for TB, Adams remarked. USAID focuses on TB programming in 23 countries, and reports indicate that 1 million fewer people had access to TB diagnosis and treatment in 2020 as compared to 2019, representing over a 20 percent decline. Partnerships between national TB programs and the Global Fund to Fight AIDS, Tuberculosis and Malaria are needed to mitigate this decline, and USAID has developed a 9-month recovery effort in seven countries with high TB burdens that have been most affected by pandemic-related service disruptions. These recovery activities focus on increasing access to services—including simultaneous testing for TB and COVID-19—with the aim of strengthening diagnostic networks, launching awareness campaigns, conducting community-based case finding, and expanding the use and availability of adherence tools. Adams noted that new

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×

tools and technologies, some of which were rapidly developed and adopted to support services during the COVID-19 pandemic, will be critical in helping countries to recover and restore public health efforts. Examples of innovation supported within USAID include computerized pillboxes, screening and tracking mobile applications, and video adherence monitoring technology.

The scale-up of all-oral treatment regimens has been critical in continuing multidrug-resistant (MDR) TB treatment for patients throughout the restrictions and lockdowns brought on by the pandemic, Adams remarked. Combinations of new regimes and technologies should continue beyond the COVID-19 pandemic, and USAID is focusing on mitigating the long-term consequences of COVID-19 on TB with interventions that are most effective. Adams noted that the use of TB systems and staff to combat COVID-19 reflects the value of TB investments. The investments made thus far by USAID and others have effectively built systems within communities that include primary and even tertiary care to cure people and save lives. Addressing TB in current times will require increased investment and political commitment, as well as innovation, adaptation, and aggressive action toward global targets to end TB.

BUILDING A TUBERCULOSIS-FREE WORLD: PROGRESS UPDATE

Presented by Eric Goosby, University of California, San Francisco

Goosby provided a progress update on efforts to build a TB-free world. He remarked that despite being preventable and curable, TB remains the largest infectious disease killer worldwide, while the burden of MDR TB continues to spread. Although effective diagnostics and therapeutics are available, their implementation has been hampered by the lack of sustained political commitment. TB control programs need to continuously outpace the transmission of mycobacteria through the population, yet governmental support of such efforts has been inconsistent over time. Further complicating the situation, the COVID-19 pandemic has displaced TB response efforts that will need to be reestablished and repositioned, he added.

Recent Milestones in Tuberculosis Control Advocacy

Before stepping down from the office of UN Secretary-General, Ban Ki-moon called for action to reinvigorate a global response to end the TB epidemic. Critical groundwork for addressing endemic diseases has been laid by efforts focused on human immunodeficiency virus (HIV), including the President’s Emergency Plan for AIDS Relief and the partnerships created between ministries of health in many countries with overlapping high burdens of HIV and TB. These collaborations gave reason to hope for rapid

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×

dialogue to facilitate a strengthened TB response and a more orchestrated universal health coverage agenda. Goosby described a coordinated effort between the Stop TB Partnership, the Global Fund, and the HIV community in lobbying for a high-level meeting on TB that served as an opportunity to identify priority-strengthening targets and encourage country-specific implementation efforts. Leading up to the meeting, working groups highlighted the need for legislative engagement in prioritizing TB when responding to ministry of health budgetary requests, said Goosby. Therefore, legislative leaders were targeted for education, and many of these leaders expressed surprise at the level of TB burden in their countries. Representatives from the Global TB Caucus attended G20 meetings to raise TB awareness for leaders from high-TB-burden countries. Stop TB focused advocacy efforts in Nigeria, India, and other countries to engage leaders in programming offered by their organization. Within that cohort of leaders, Stop TB worked to identify, create, and strengthen leadership to advocate for the prioritization and funding of TB response efforts among legislators.

Investment Priorities for Tuberculosis Control

In 2019, the Lancet Commission on Tuberculosis established five priority investment areas for addressing TB (Reid et al., 2019) (see Box 3-1), which recognized the importance of accounting for each country’s met and unmet needs when developing implementation strategies for effective TB diagnostic and treatment efforts (Reid and Yamey, 2019). However, collaborative attempts to converge efforts by the UN, WHO, and the Stop TB Partnership have not yet gained traction, he remarked. Although conversations are taking place, they have yet to translate into budgetary expansion and programmatic implementation decisions that expand TB capability worldwide. Goosby added that G20 countries can take a leadership role and emphasize the need for G7 countries to continue to expand their participation and financial support.

To create an enabling environment and hold countries accountable for making progress to end TB—the fifth priority of the Lancet Commission—Goosby suggested (1) recognizing the powerful role to be played by TB survivors and advocates; (2) committing to address drivers of TB including HIV, undernutrition, and pollution; and (3) advancing the universal health coverage agenda, given the foundation it provides for the prevention and treatment of all health conditions. Certain diseases such as HIV and TB have received unique funding, but expansion of the entire health care delivery platform to the population would strengthen efforts focused on specific diseases, Goosby stated. Ministers of health can be their countries’ strongest advocates for budgetary prioritization, but effective advocacy requires analyzing and understanding the situation and translating it into a narrative that attracts funding.

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×

COVID-19 Pandemic: Consequences and Opportunities for Tuberculosis

In the United States, the COVID-19 pandemic has displaced the national focus from diseases such as HIV and TB, noted Goosby. Many of the experts in the HIV and TB communities have the skill sets needed to identify, understand, and contain a new virus moving into a population. As a result, the United States and many European countries drew talent and human resources from the TB/HIV arena, and built upon those existing systems of care, to mount their responses to the COVID-19 pandemic. Moreover, the pandemic accelerated progress through the stages of identification, diagnostic capability, discerning high-risk groups, and prioritizing high-risk groups for diagnosis, treatment, and eventually, vaccination.

Although the International Health Regulations (IHR) of 2005 established a consensus about the need to strengthen outbreak surveillance capacities, this has not yet been achieved—which is particularly striking in countries where a pandemic threat is more likely to emerge. Goosby suggested that the United States should exercise leadership in G7 discussions to bring the issue of surveillance to G20 and establish the expectation that an IHR surveillance system will be built, monitored, and maintained. He proposed that countries that cannot afford to build surveillance systems should be accommodated by having a system built for them, but they should assume and maintain the responsibility for implementing the system. Additionally, each country’s system should be connected to the ministry of health, which should preserve the information system and use it to detect COVID-19 and other diseases. Goosby warned against creating parallel systems of surveillance, which has happened in the past with HIV.

Goosby added that the Biden administration has discussed strategies to increase pandemic preparedness by building upon established platforms, such as those for TB and HIV. These platforms would be strengthened

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×

and expanded to accommodate the demands from any new threat, such as COVID-19. Strengthening the capability for global response would also facilitate the identification and mitigation of inequities in capacities and distribution of resources. Questions persist as to where that capability will reside and which entities will be responsible for different components, he added, noting that dialogue around national security versus global health programming remains in equilibrium.

Discussion

Referencing a divide between the national security and global health communities, Mansoura asked how these communities can be brought together in recognizing the security elements and economic effects of TB. Goosby replied that the cultures within the national security and global health communities are quite different and are unfamiliar with one another. The national security community is viewed as being aligned with a military agenda that defines a threat as the topography of the area where it originated. The medical community tends to be uncomfortable with that perspective, and therein lies a tension, he remarked. Global health concerns can be overlaid on requests for resources for a governmental security expansion—requests that are unlikely to be denied—because global health issues can be justifiably aligned with funding that is motivated by security concerns, said Goosby. This process can be conducted in collaboration with, rather than controlled by, policy makers at the National Security Council.

Goosby voiced his confidence that this process will eventually take place, while acknowledging delays caused by disagreement around who should control the process and by a lack of sustained focus on the issue. He contended that rather than taking a solo approach to funding or implementing efforts, U.S. leadership can back a position that pivots global support into activities that expand capacity within each country. Such a path can incorporate needs related to the COVID-19 pandemic to create a sustainable system of agreements and synergies to address future pandemic threats. Goosby noted that the United States has the gravitas to convene discussions in the G7 and G20 summits around creating such a system. The current moment presents an opportunity to invigorate global health leadership. Rather than position itself as “the elephant in the room,” the United States can bring a herd of elephants into the room, said Goosby.

Marcos Espinal, director of the Department of Communicable Diseases and Environmental Determinants of Health at the Pan American Health Organization, said that the United States, the G7 countries, and WHO are positioned to lead the development of a pandemic preparedness platform, and this will be the focus of a special session of the World Health Assembly in November 2021. In 2015, WHO initiated emergency response reforms

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×

following the Ebola epidemic the year prior, including the creation of the WHO Health Emergencies Programme. However, a lack of connectivity between various platforms has emerged during the COVID-19 pandemic, said Espinal. The United States has an opportunity to use well-developed platforms—such as those for TB and HIV—for expansion into pandemic preparedness. He noted that the COVID-19 pandemic has created massive disruptions for TB and HIV programs and the administration of TB, diphtheria-tetanus-pertussis, and polio vaccines in Latin America and the Caribbean. Thus, major gains in the international community are currently threatened by the current pandemic, and preparedness is needed before the next pandemic.

Goosby stated that the United States has an opportunity to lead the pandemic preparedness effort in a respectful way that enhances the global perspective of U.S. leadership. Such an approach would avoid creating “islands of excellence” that cause and perpetuate disparities between those that benefit from the bilateral infusion of resources for a single disease and those that do not. Instead, a continued resource commitment can be used to strengthen ministries of health and expand their platforms, because this is the most sustainable way to preserve services for the population, said Goosby. The fifth priority from the Lancet Commission on Tuberculosis is holding countries and stakeholders accountable for making progress toward ending TB (Reid et al., 2019). When nations implement programs in other countries, this fragments responsibility and dilutes the ability to sustain and increase the effect of investments. Instead, systems and services that clearly designate the countries in which they are implemented as responsible for maintenance and continued performance should be created, Goosby remarked. The demands of the COVID-19 pandemic present an opportunity to reevaluate the global health development portfolio and expand platforms implemented in partnership with leaders responsible for the target population. This approach incorporates an understanding of accountability that has been missing, Goosby stated. He added that the United States could adopt this approach to create sustainable programs instead of solutions that last for 3 to 5 years and then disappear.

Eltony Mugomeri, lecturer at Africa University (AU) and project manager of a TB partnership program with AU and Zimbabwe’s Ministry of Health, remarked that countries with a high burden of TB need to strengthen information systems and diagnostic technologies—such as mobile X-ray machines and video conferencing equipment—while building capacity within a short time frame. He asked how affected countries can establish synergies to address these challenges. Goosby replied that the strongest approach is in-country civil society partners collaborating with the ministry of health to approach funders together. The current allocation of investments within the

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×

health care delivery system can be examined for repositioning opportunities. As new resources come in—for example, pandemic support—decision makers can examine their potential best uses in alignment with other needs within the same community. Additionally, a limited role for public–private partnerships should be circumscribed, suggested Goosby. Although public–private partnerships should not displace or dilute lines of responsibility, the private sector contains resources and expertise in procurement distribution systems, budget management, and human resource (HR) management that can benefit ministries of health. Shared HR positions, sites, and referral mechanisms can be formally defined to avoid duplicating systems of care that cross over from public to private, said Goosby.

REALITIES OF MULTIDRUG-RESISTANT TUBERCULOSIS

Presented by Matteo Zignol, World Health Organization

Zignol focused on the global burden and trends in MDR TB, the associated challenges that it poses to TB control, and progress in the treatment of MDR TB.

Burden and Trends in Multidrug-Resistant Tuberculosis

Zignol opened by presenting data about the global burden of TB and its epidemiological trends drawn from WHO’s 2020 Global Tuberculosis Report (WHO, 2020). In 2019, one-quarter of the world’s population was infected with TB and an estimated 10 million people developed TB disease. About 815,000 of those 10 million individuals had HIV-associated TB and 465,000 had MDR TB or rifampicin-resistant (RR) TB. The same year, roughly 1.4 million people died of TB—including deaths attributed to HIV/TB—and 208,000 died of HIV-associated TB, while 182,000 people died of MDR/RR TB. The majority of individuals with MDR/RR TB are located in a small number of countries with emerging economies, including India, China, Russia, South Africa, Indonesia, and the Philippines. While TB is a disease of the poor, the majority of the TB burden, particularly for MDR/RR TB, is located in growing economies.

The discussion of drug-resistant (DR) TB is typically framed in terms of resistance to rifampicin, which is one of the most powerful first-line TB drugs. However, Zignol noted that the total global burden of DR TB—which also includes isoniazid-resistant/rifampicin-susceptible TB—far exceeds that of RR TB alone (WHO, 2020). The combined burden of isoniazid resistance or rifampicin resistance amounts to about 1.5 million persons with TB that is resistant to the two most powerful first-line drugs every year.

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×

Trends in Levels of Tuberculosis Drug Resistance

Despite the development of advanced surveillance systems, TB surveillance is not yet adequate, said Zignol. In particular, the availability of TB data is limited in countries with high burdens of RR TB and, as of 2019, some countries had no data on RR TB. Further, many of the countries with data on RR TB have collected data on new case rates only a few times in the past 25 years, making it difficult to establish trends. Fortunately, data on MDR TB trends are available from multiple high-burden countries, including Azerbaijan, Belarus, Kazakhstan, Kyrgyzstan, Myanmar, Peru, Moldova, Russia, Tajikistan, Thailand, Ukraine, and Vietnam. In many of these countries, rates of both TB and MDR TB are declining, with MDR TB declining at a slower rate than TB in some settings. In other countries, such as the Russian Federation, TB is declining while MDR TB is not.

Zignol discussed findings from a 2017 study that modeled projected trends in the proportions of MDR TB and extensively drug-resistant (XDR) TB in India, the Philippines, Russia, and South Africa (Sharma et al., 2017). The study predicted that the proportion of MDR TB and XDR TB will increase in the next 20 years, with the expected increase in proportions of MDR TB and XDR TB linked to the expected decline in overall TB incidence. The reduction of TB incidence may foster the accumulation of drug resistance and create more favorable conditions for the transmission of DR TB, he added. A 2021 study projected the effect of a post-exposure vaccine on RR TB in India, Russia, China, and Nigeria, finding that post-exposure vaccines could have a favorable effect on RR TB incidence rates (Fu et al., 2021). Zignol added that post-exposure vaccines may also favorably affect the transmission of DR TB.

Challenges for Tuberculosis Control

Zignol discussed specific challenges for TB control posed by the COVID-19 pandemic in terms of diagnosis, notifications, and mortality. The COVID-19 pandemic had a substantial effect on TB notification rates. Global TB notifications dropped from 6.3 million in 2019 to 4.9 million in 2020, 28 percent less than the expected notifications for 2020. In some countries, the shortfall from expected notifications in 2020 was as high as 40 percent (WHO, 2021b). The COVID-19 pandemic is also expected to influence TB mortality in a manner correlated with shortfalls in case detection, leading to an estimated excess TB mortality of approximately 500,000 deaths.

Furthermore, the COVID-19 pandemic has reduced TB diagnosis rates, largely because of the limited availability of molecular tests for detecting TB and DR TB, said Zignol. Of the 10 million new people with TB disease every year, only 7.1 million are notified and 5.9 million of those are pulmonary

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×

TB cases. Only 3.4 million of those receive a bacteriologically confirmed TB diagnosis, and only one out of five of those individuals are diagnosed with rapid tests, which are the most sensitive and specific available. Thus, only about 20 percent of people who develop TB disease each year actually receive the proper diagnosis, he said. However, RR TB testing coverage among bacteriologically confirmed TB cases is now increasing; nearly 60 percent of new cases and 80 percent of repeat cases received testing for rifampicin resistance in 2019. The testing coverage rate for fluoroquinolone resistance among RR TB cases was 71 percent in 2019. He added that the lack of a POC diagnostic test for TB is a pressing concern and low-hanging fruit for improving TB control. Such a test could be quickly developed and would substantially strengthen global TB control efforts.

Advances and Progress in Tuberculosis Treatment

Zignol highlighted recent advances and progress in TB treatment. More treatment regimens are available than ever before, with many new shorter regimens now available for both DS and DR TB. However, despite innovations in TB treatment, uptake of new regimens has been limited and the lengthy timeline involved in implementing new regimens has been challenging. Before implementing new regimens, some countries require locally generated evidence, which extends the implementation timeline. The registration of new drugs and supply chain issues also present regimen implementation challenges globally. Advances toward shorter regimens and countries’ increasing interest in TB research are potential opportunities to be leveraged in the TB therapeutic space, he noted. Prior to the COVID-19 pandemic, global progress was being made toward achieving the United Nations High-Level Meeting targets for TB treatment for 2018–2022 (see Figure 3-1) (WHO, 2020).

Overview of the Global Burden of Drug-Resistant Tuberculosis in 2021

Zignol summarized major issues related to the global burden of DR TB as the COVID-19 pandemic continued through 2021. The global status of TB control has worsened because of the COVID-19 pandemic, and it will continue to worsen as the pandemic continues. He emphasized that DR TB is a major global health threat, but limited data are available to develop accurate projections of global DR TB trends. While absolute numbers of TB cases are decreasing, the proportion of DR TB is increasing. Current TB and DR TB testing practices and technologies are not sufficient, underscoring the urgent need for a POC TB test. Advances in research and practice have brought about more treatment regimens than have ever been available before—with many regimens shorter than ever

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×
Image
FIGURE 3-1 Progress toward 2018–2022 global targets for the number of people treated for tuberculosis.
SOURCES: Zignol presentation, September 14, 2021; WHO, 2020.

before—yet new regimen uptake is slow in many countries, meaning that significant progress must be made quickly in order to reach the 2018–2022 global TB treatment targets.

Discussion

Noting that the uptake by countries of new WHO recommendations on TB control is often slow, Ditiu asked about the slow pace of diagnostic development and the slow uptake of treatment regimens. Zignol cited supply chain constraints as a barrier to uptake. Manufacturers are often uninterested in investing in TB control products, particularly products for interventions that will ultimately benefit a relatively small number of patients. Countries’ preference for locally generated evidence is another factor, noted Zignol. A country that wants to replicate a study that has been conducted elsewhere may delay the implementation of a new regimen by 5 years or more. International coordination and convincing leaders of the reliability of global evidence could help to shorten the implementation timeline. Involving stakeholders from various countries in the planning of initial research efforts could also help to streamline the implementation process.

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×

RAPID ACCELERATION OF DIAGNOSTICS TECHNOLOGY: COVID-19 PANDEMIC EXPERIENCE

Presented by Matthew McMahon, National Institutes of Health

McMahon discussed efforts to rapidly accelerate the development of diagnostic technology for COVID-19 and highlighted lessons learned that could potentially be applied to TB diagnostics. He explained that the Rapid Acceleration of Diagnostics Technology program (RADx) is a large collaborative initiative to speed innovation in developing, commercializing, and implementing innovative approaches and technologies for COVID-19 testing.1 RADx was established in 2020, when the U.S. National Institutes of Health (NIH) allocated an unprecedented $1.5 billion to expand and optimize the performance of COVID-19 testing technologies, $500 million of which was channeled to RADx via the National Institute of Biomedical Imaging and Bioengineering. RADx was built and layered upon the Point-of-Care Technologies Research Network (POCTRN)2 (see Box 3-2) with the aims of expanding the number of, type of, and access to COVID-19 testing technologies and optimizing performance by aligning those testing technologies with community needs. POCTRN, like other proof-of-concept centers funded by NIH, combines and coordinates expertise from basic science communities and commercial stakeholders. This kind of cross-sectoral collaborative approach is fundamental to delivering innovative diagnostic technology into the hands of users, said McMahon.

Rapid Acceleration of Diagnostics Technology Innovation Funnel

McMahon described how RADx’s technology innovation funnel process was designed to advance COVID-19 diagnostics. The innovation funnel process was intended to rapidly identify and evaluate narrowly targeted proposals by first filtering all applications through an initial viability evaluation to identify the most promising technologies. Next, during the deep-dive (or “Shark Tank”) phase, a panel of technical and business experts worked intensively with proposers for a week to more comprehensively evaluate their proposed plans and ideas. Based on the deep-dive exercises, the first-phase awardees were selected to receive the first tranche of funding to conduct tech-

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1 More information about RADx is available at https://www.nih.gov/research-training/medical-research-initiatives/radx (accessed October 20, 2021).

2 More information about the Point-of-Care Technologies Research Network is available at https://www.poctrn.org (accessed October 20, 2021).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×

nology validation, prototype development, and other initial work to prepare for the next phase of funding for manufacturing scale-up.

In the first two rounds of innovation funnels (2020–2021), RADx received more than 800 applications—mostly from small businesses, but also from academic groups, start-up companies, and mid- and large-sized businesses—and 35 projects received major funding from initial product development to manufacturing scale-up. These projects included a wide range of diagnostic innovations, including POC and home-use diagnostic products, laboratory diagnostic tools, and laboratory products. A primary aim of the project was to accelerate the validation of emerging technologies, including next-generation technologies such as CRISPR and nanoparticle applications, noted McMahon. RADx funded the development of the first commercially available home-use COVID-19 diagnostic test in the United States, developed by Ellume.3 This home-use diagnostic tool used nanotechnology, mak-

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3 More information about Ellume is available at https://www.ellumehealth.com (accessed October 21, 2021).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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ing its rapid advancement from technological validation to emergency use authorization and commercial availability especially noteworthy.

Impact Effect of Rapid Acceleration of Diagnostics Technology Projects

McMahon described the impact of RADx projects as of July 2021.4 Cumulatively, RADx projects brought 667 million COVID-19 tests to market between September 2020 and July 2021, creating a COVID-19 diagnostic capacity equivalent to approximately 5 million tests per day. RADx has helped to secure 28 emergency use authorizations, including three for home-use tests and the first emergency use authorization for an over-the-counter COVID-19 diagnostic product. Furthermore, RADx has secured $1.1 billion from special congressional authorizations and $1.3 billion in private capital to support more than 100 companies since its inception.

“Say Yes! COVID Test” Program

McMahon highlighted RADx’s collaboration with the U.S. Centers for Disease Control and Prevention and the “Say Yes! COVID Test” program. This collaboration was aimed at delivering COVID-19 tests to those in underserved communities and in areas with high levels of social vulnerability.5 As of September 2021, the program had delivered 2 million home-use tests in numerous U.S. cities. The program was designed to assess the efficacy and effectiveness of providing home-use tests 2–3 times per week. The program’s outcome measures included SARS-CoV-2 prevalence and incidence, percentage of test positivity by volume, community cell phone mobility, and wastewater surveillance. The program also provided participants with an optional digital assistant that provided reminders and instructions, offered test interpretation and guidance for positive test results, and reported results to state agencies in Michigan and Tennessee.

While the “Say Yes! COVID Test” program has been effective in delivering tests to individuals in need, various challenges have been encountered, said McMahon. For instance, it is difficult to ensure that individuals who receive tests actually use them, and it is even more difficult to ensure that they are used serially to maintain surveillance. Additionally, there were concerns that some individuals may discontinue adhering to public health or medical guidelines upon receiving a negative COVID-19 test result—mean-

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4 More information about the impact of RADx is available at https://www.nibib.nih.gov/covid-19/radx-tech-program/radx-tech-dashboard (accessed October 21, 2021).

5 More information about the “Say Yes! Covid Test” program is available at https://sayyescovidtest.org/ (accessed October 21, 2021), and https://www.healthaffairs.org/do/10.1377/forefront.20211025.437195 (accessed January 28, 2022).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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ing that persons who test negative may discontinue quarantine practices or fail to follow up with health care providers. Such challenges demonstrate that technological innovation alone is not sufficient to address complex disease control challenges; social science, behavioral economics, and other disciplines must be involved in public health interventions. McMahon cited COVID-19 vaccine hesitancy as a prime example. The rapid development and distribution of messenger RNA (mRNA) vaccines were not sufficient to ensure maximal uptake of vaccines among U.S. or world populations, as vaccine hesitancy has stymied progress in vaccination rates, even in settings with ample vaccine supply.

Leveraging the Digital Health Infrastructure

Strengthening and leveraging the digital health infrastructure can facilitate linkages between diagnostic innovations, health systems, and health surveillance, said McMahon. For instance, providing home-use COVID-19 tests to individuals is valuable for the recipient, but these products have far greater effect if test results are connected to health and surveillance systems. In addition to developing and testing reporting standards for certain COVID-19 home-use tests, there are ongoing efforts to use the digital health infrastructure by providing incentives for people to use the at-home tests and connecting test users with health care providers after testing is complete. Mobile phone applications can be used to (1) provide users with testing instructions, (2) interpret test strip results using machine learning, (3) conduct surveys to screen users for symptoms, and (4) connect users’ data to data hubs for use in reporting, collecting state and federal data, validating health passes, and contact tracing. Because many diagnostic tools can be linked to public health systems in valuable ways, the RADx deployment core assists every RADx project in optimizing its use of the digital health infrastructure.

Lessons for Tuberculosis Control

McMahon highlighted several factors that have contributed to the success of the program and could be applied to TB control efforts: (1) obtaining a large-scale dedicated financial commitment made funding immediately accessible; (2) building upon existing programmatic infrastructure allowed for the rapid launch of the program within mere days of receipt of funding; (3) fostering direct, focused interagency collaboration, particularly with Food and Drug Administration (FDA), Centers for Disease Control and Prevention, and other partners; and (4) focusing intently on commercial viability.

Interagency collaboration has been invaluable to the success of RADx, said McMahon. For instance, FDA collaboration was vital for rapidly advancing RADx technologies from development to emergency use authori-

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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zation and commercial rollout. Weekly meetings between stakeholders from RADx and FDA’s in vitro diagnostics team were held to provide FDA with early previews of forthcoming and often novel technologies being developed through the initiative. RADx stakeholders used these meetings to establish a detailed understanding of the dynamic regulatory landscape, to inform the design of validation studies to address FDA’s concerns, and to streamline the authorization process. The Biomedical Advanced Research and Development Authority (BARDA) and various Department of Defense programs provided funding and support for rapid manufacturing scale-up of newly developed diagnostic tools.

McMahon also emphasized the importance of RADx’s narrow focus on ensuring commercial viability and bringing diagnostic tools to market as fast as possible. In the early months of RADx, White House leadership and the Department of Health and Homeland Security demanded frequent progress updates with a specific focus on test production and distribution status. This pressure to deliver commercially viable products to market was challenging for RADx leadership; however, this top-down focus on commercially viable products was instrumental in bringing about ground-breaking technological innovations. During the early phases of RADx, expert stakeholders were conducting multiple efforts in parallel: rapidly validating technologies, developing benchtop assays into prototypes, navigating the regulatory landscape, and gathering knowledge of distribution and supply chain needs for forthcoming diagnostic products. Despite the successes of RADx, McMahon acknowledged that much work remains to be done to improve COVID-19 testing capacity in the United States.

Ongoing Challenges and the Future of RADx

McMahon discussed RADx’s ongoing challenges and potential future applications of the model. Maintaining and monitoring the COVID-19 reporting infrastructure has been a major challenge since the onset of the pandemic (Banco, 2021). Furthermore, it has been difficult for public health officials to detect and quickly react to hotspots. Insufficient screening and surveillance—particularly in high-risk settings such as schools and long-term care facilities—has compounded these challenges (Geske, 2021; Vigdor, 2021). It has also been challenging to deliver simple, fast, and affordable POC testing solutions to those most in need.

In the future, the RADx process and networks will be used to address diagnostic needs for other pathogens and promote disease control preparedness, said McMahon. RADx is focusing on four pillars going forward:

  1. Facilitating real-time data collection by modernizing and expanding digital health infrastructure and reporting systems to integrate
Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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    diagnostic results from laboratory tests, POC tests, and over-the-counter tests;

  1. Expanding access to better rapid tests by using the disruptive power of e-commerce and direct-to-consumer practices to distribute over-the-counter and POC diagnostic tools and report results;
  2. Developing multiplex POC and laboratory tests for differential diagnostics, such as a single multiplex test to detect SARS-CoV-2, influenza A/B, and respiratory syncytial virus;6 and
  3. Enabling fast, accurate, and cost-effective surveillance that includes genetic sequencing to track variances in diseases across populations (e.g., using new laboratory and POC diagnostics tools to collect genotyping and informatics data; wastewater surveillance).

Discussion

Gail Cassell, senior lecturer on global health and social medicine at Harvard Medical School, asked whether TB might be well suited for addition into a multiplex test or whether standalone tests would be preferable for detecting TB. McMahon replied that multiplex tests could be used to detect TB, but the current global focus on COVID-19 has limited the scope of funding for such projects—for instance, all RADx funding is part of a larger allocation that is narrowly focused on the COVID-19 response. However, RADx has prioritized the development of platforms and multiplex technologies to facilitate the adaptation of new COVID-19 diagnostic tools to other pathogens in the future. Given the urgency to develop new TB diagnostic tools, Cassell asked whether it would be more prudent to forge ahead with standalone TB diagnostic research or to try to integrate advances in TB diagnostics into efforts to develop a respiratory multiplex assay that might be supported through COVID-19 response funding. She emphasized the potential benefits of a respiratory multiplex assay that could detect TB, COVID-19, influenza, and perhaps community-acquired pneumonia infections. McMahon said that numerous organizations are funding multiplex testing research—including BARDA. The narrow focus of RADx helped to catalyze funding and attention, thus TB diagnostic research could benefit from similarly focused efforts, he suggested.

Mansoura asked about the sustainability of RADx’s efforts—given how quickly the capacity for COVID-19 testing has accelerated and expanded worldwide—and how to use those efforts most effectively to address more

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6 McMahon pointed out that including COVID-19 testing in multiplex tests would present regulatory challenges. This is because COVID-19 tests are being approved under emergency use authorization, while other tests would likely be subject to the standard regulatory environment.

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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persistent diagnostic demands. She also asked about the constraints posed by temporary single-disease funding (e.g., during the Middle East respiratory syndrome coronavirus [MERS-Cov] and Ebola virus disease outbreaks). McMahon responded that RADx tries to select platform technologies that have the potential to be applied to other infectious diseases in order to achieve long-term sustainability. Ideally, partnerships forged in response to the COVID-19 pandemic will be able to flex and pivot rapidly, perhaps with government assistance, to new and forthcoming challenges as they arise.

Vo noted that the availability of disease-specific funding can influence research agendas. For instance, Ceres Nanosciences was supported by RADx during the COVID-19 pandemic; prior to the pandemic, the company was developing technologies for TB control. He asked how the rapid incubation model employed by RADx can be applied in fields with less funding, such as TB. McMahon said that the RADx model has been thoroughly studied so that it can be applied to future research needs. Further, he speculated that it may be possible to secure funding to replicate a RADx-like project aimed at TB diagnostics.

ADVANCES IN TUBERCULOSIS DIAGNOSTICS

Point-of-Care Molecular Platform for Diagnosis of Tuberculosis and Other Infectious Respiratory Diseases

Presented by Morten Ruhwald, FIND

Ruhwald presented on POC molecular platforms for diagnosis of tuberculosis and other infectious respiratory diseases. He commended advances in research and innovation achieved during the COVID-19 pandemic, highlighting the flexibility demonstrated by regulatory, political, and manufacturing stakeholders and the advances in manufacturing occurring in LMICs. However, the growing install base and integrated COVID-19 response from clinics and laboratories has come at the expense of certain TB control efforts.7 Moving forward, he suggested focusing on building back and expanding TB control capacity by building upon advances brought forth by the COVID-19 response, such as the expansion of digital health infrastructures and innovations in self-sampling and home-use tests. For TB control efforts to adapt to the new disease control landscape, TB control programs will need to break out of their silos, he said. Moreover, manufacturers will need incentives to develop new TB diagnostic tools and platform technolo-

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7 The term “install base” refers to the number of units of a product that is in use. See https://www.credenceresearch.com/info/installed-base-scenario-medical-devices (accessed February 25, 2022).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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gies by pivoting the newly developed footprint for COVID-19 diagnostics to explore simultaneous or bidirectional testing. The complexity of sputum testing is a pressing challenge in TB diagnostics, he said. Efforts are underway to develop simpler tongue-swab or urine-based diagnostic technologies and to explore the use of face masks or other strategies for capturing aerosol samples for diagnostic testing. He added that from the developers’ perspective, it would be helpful to shorten the length of clinical trials and facilitate the assessment of multiple technologies in parallel. TB diagnostics and control still rely largely upon older tools and analog reporting technology. To advance TB diagnostics and control into the digital age, he suggested using advances in POC diagnostic tools and data-tracking dashboards that have emerged in response to the COVID-19 pandemic.

Innovations for Tackling Tuberculosis in the Time of COVID-19

Presented by Zvi Marom and Eran Zahavy, BATM

Marom and Zahavy discussed BATM Advanced Communications’ innovative approach to tackling TB amid the COVID-19 pandemic. Its approach is to focus on substantially reducing the cost of diagnostic testing and to initiate TB treatment rapidly after an accurate diagnosis, including the diagnosis of antibiotic resistance in the same test. It is currently developing a new test to detect MDR/XDR TB that uses a combinatoric algorithm scanning system,8 which can be used for population screening at very low cost. The system can be used to run diagnostic tests for multiple respiratory diseases simultaneously (e.g., TB, COVID-19, influenza, pneumonia) in a single plate, with test results directly reported to digitized patient medical records. Based on modeling simulations of TB testing in Uganda, this system could potentially process more than 4,000 samples per day, reducing reagent costs by a factor of between 8 and 10 and enabling rapid testing of an entire country’s population.

The next step in the development process is to replace classical polymerase chain reaction (PCR) diagnostics with isothermal technology, said Marom. The isothermal single test is a diagnostic platform for conducting rapid, easy-to-use, saliva-based, molecular diagnostic screening for various indications. This disruptive, modular, and scalable approach is implementable in settings without access to laboratory services; it yields results within minutes that are even more precise than highly reliable lateral flow tests. Isothermal testing has already been used for COVID-19 diagnosis and

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8 More information about BATM Advanced Communications’ molecular diagnostic test for TB is available at https://www.batm.com/rns-rnr/posts/2021/march/batm-develops-molecular-diagnostics-test-for-tuberculosis (accessed October 25, 2021).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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could be adapted for new indications and targets. For instance, isothermal tests for TB diagnostics could be scaled up for deployment within 18 months, he said.

Marom compared BATM Advanced Communications’ isothermal system, called rolling circle amplification (RCA), with PCR diagnostic methods. RCA is qualitative—but will soon be quantitative—and is at least as sensitive and specific as PCR, but provides results within 25 minutes. The diagnostic system, called NATlab, is a fully automated, sample-to-answer system that provides multiplexed analysis of individual samples against 100 or more targets. If adapted for TB diagnosis, this technology could use a single sputum sample to diagnose TB, detect specific mutations to identify antibiotic resistance, and optimize patient treatment. Additionally, NATlab diagnostic devices harness Internet connectivity and AI to predict disease trends using diagnostic data; for example, NATlab diagnostic tools were used to predict and map the movement of the COVID-19 pandemic. Moreover, this platform-based diagnostic technology can be used to diagnose many diseases, including sexually transmitted diseases, meningitis, and others.

Improving X-ray Accessibility

Presented by Luan Vo, Friends for International Tuberculosis Relief

Vo described the implementation of ultraportable X-ray technology and the use of AI for X-ray interpretation for TB detection in Vietnam. He described how prior to the COVID-19 pandemic, around 170,000 people in Vietnam became sick with TB each year, but only 104,505 cases were treated—leaving approximately 65,000 untreated cases—and there were 11,400 TB-related deaths (WHO, 2020). To reduce the gap of untreated cases, Vietnam has used active case-finding techniques such as contact investigating, mobile mass screening, door-to-door screening, and seeking out vulnerable populations.

Vo compared the current standard for mobile X-ray with the new ultraportable X-ray technology that Vietnam began using in 2021. Currently, the trucks used for mobile X-ray screening weigh in excess of 2,000 kg and face significant logistical barriers. For example, to reach island populations, these X-ray trucks must be transported on freight ships. In contrast, new battery-operated, hand-held ultraportable X-ray devices are about the size of a camera and weigh only 3.5 kg. The extreme portability of these devices makes it possible to bring X-ray screening directly to the doorsteps of those most in need.

Early findings from a study comparing the new ultraportable X-ray system with conventional X-ray devices suggest that ultraportable X-ray systems can extend safe and reliable access to high-quality X-ray diagnostic services

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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to vulnerable groups (Vo et al., 2021). Based on these promising findings, Vietnam has piloted the use of ultraportable X-ray devices for screening 800 people for TB in two sites: an island and a mountainous district with several villages that were home to ethnic minority populations. The devices performed as expected and detected many cases of TB, despite the pilot being conducted during the COVID-19 pandemic when health seeking was restricted. However, further process optimization will need to address current limitations of the devices. For instance, the battery life was suboptimal and could capture only 40 images per charge (which takes 4 hours); this could result in TB screening campaigns being reliant on grid-powered systems. The ultraportable X-ray devices could last for an entire day using large capacity backup batteries, but these required power switches as charging was not possible during operation, undermining both user experience and device portability. The screening campaign also faced connectivity challenges related to the wireless detector panels that connect to the X-ray device, with loss of Bluetooth connectivity frequently causing delays in image transfers to the interpretation station.

Vo and colleagues have also evaluated the use of multiple AI solutions to aid chest radiography interpretation during TB screening, finding that many AI solutions can detect TB with a high level of accuracy.9 Vo shared that AI interpretations were on par with—or superior to—X-ray interpretations by intermediate radiologists (with 5 years or more of relevant experience), although none of the solutions were better at detecting TB than expert radiologists (30 years or more of relevant experience). The implementation results further suggest that AI interpretation could be used to triage out approximately 30 percent of non-TB X-rays with limited losses in sensitivity, thus saving radiologists’ time by reducing the number of non-normal X-ray images they need to evaluate for potential TB cases. Although AI interpretation has the potential to decrease cost and increase operational effectiveness, the technology will need further calibration to address confounders that can undermine its accuracy, such as history of TB, age, and the radiography equipment used.

Implementation Challenges with New Tuberculosis Diagnostics

Presented by Kaiser Shen, United States Agency for International Development

Shen shared insights from his work at USAID on POC TB diagnostics, TB diagnostic networks, and implementation challenges. Although the pipeline for TB diagnostics is expanding, the forthcoming tools will not be suf-

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9 This study has been published since the time of the workshop; see Codlin et al., 2021.

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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ficient because they remain primarily sputum-based tests. He highlighted the need for investment in developing biomarker-based tests to detect individuals most at risk of developing TB. Diagnostic systems also rely upon support systems—such as specimen referral systems and diagnostic data connectivity—that are necessary to ensure the full expression of new diagnostic technologies. He predicted that as new technologies are developed, the countries that are most in need of new assays are likely to encounter challenges in absorbing and implementing these new technologies. TB diagnostics have traditionally been configured using a tiered system that focuses on top-down approaches, but the availability of POC TB diagnostic tools would transform this paradigm, said Shen. As older tools that were implemented within a top-down infrastructure are replaced by new technologies—as occurred with the rollout of GeneXpert—their accompanying infrastructures will need to be replaced as well.

Implementation challenges associated with TB diagnostics include difficulties with POC testing in remote and rural locations, where it is difficult to provide services and conduct equipment maintenance. Health care providers in remote or rural locations also face challenges related to unstable power supplies or lack of adequately trained staff. Improving visibility within networks is another challenge that will require large investment in collecting and reporting diagnostic data, particularly in settings with gaps between diagnosis and reporting. Moving forward, Shen suggested implementing new systems to improve data collection and reporting to drive uptake and sustainability. He also noted that some countries scaled up GeneXpert implementation too rapidly without using data to inform the placement of diagnostic equipment. As new technologies are developed and implemented, better understandings of existing data and data flow could help inform clinical, programmatic, and political decision making.

IMPROVING ADHERENCE, INFECTION CONTROL CAPACITIES, AND COST-EFFECTIVENESS

Integrated Community Response to the COVID-19 Pandemic in Karachi, Pakistan

Presented by Aamir Khan, IRD

Khan discussed the comprehensive approach to COVID-19 and TB testing implemented in Pakistan that adapted the Interactive Research and Development (IRD) model of integrated community response to TB control. When Pakistan’s first COVID-19 surge began in March 2020 in Karachi—a large city center with a population of 20 million—a mass TB screening campaign was put in place using mobile X-ray vans. COVID-19 screening was

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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integrated into the existing TB screening resources to aid in the pandemic response by offering combined TB and SARS-CoV-2 screening across the city. Individuals were offered PCR testing if they had symptoms or had been exposed to COVID-19. Between April and July 2020, more than 23,000 people in Karachi received combined screening, of whom 112 were diagnosed with TB and 6 were diagnosed with TB and COVID-19. Through various combinations of symptoms, exposure information, and X-ray screening, the efforts diagnosed 1,385 cases of COVID-19 via PCR testing.

Adapting the TB Screening System to Address COVID-19

The existing TB screening system was modified by adapting IRD’s TB control model to address the high burden of COVID-19 in Karachi more directly, said Khan. IRD used its existing network of high school girls (i.e., Kiran Sitaras) trained to support TB control by having them promote mask use and handwashing in neighborhoods, screen households for potential cases of COVID-19, and distribute information. IRD engaged 200 mental health counselors to provide psychosocial support—for example, providing food packages and cash to patients in isolation and families in quarantine. They enlisted 200 contact tracers to locate all index patients, conduct a risk-based classification of contacts of confirmed COVID-19 patients, and track home-based quarantine using a mobile app and patient database. IRD also offered interventions to reduce COVID-19 stigma.

Khan explained that IRD had already been working with private providers in Karachi because it is the first line of care for many people with TB symptoms. Once IRD began shifting efforts toward the COVID-19 response, it worked with more than 1,000 private practitioners by offering training and equipping them with needed protective equipment, pulse oximeters, oxygen cylinders, and diagnostic referral links. Neighborhood clinics were able to triage COVID-19 cases, offering screening for symptoms, pulse oximetry, oxygen therapy, and oral or intravenous steroids. IRD also supported the provision of free X-ray diagnostics and oxygen therapy, as well as facilitated two-way referral between emergency rooms and isolation facilities. PCR and antibody COVID-19 testing were provided for a fee in the private sector, with PCR testing offered for free at certain public and nonprofit laboratories. IRD also systematically collected COVID-19 screening and treatment data throughout the community response to COVID-19.

Provision of Oxygen Therapy, COVID-19 Screening, and Phone-Based Contact Tracing

Khan provided an overview of efforts to provide oxygen therapy, conduct COVID-19 screening, and use phone-based contact tracing for COVID--

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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19 patients in Karachi. He emphasized that when setting up a city’s capacity to provide oxygen therapy, relatively few additional resources are needed to ensure complete coverage throughout the entire city. With the appropriate motivation and forethought, IRD was able to create an oxygen supply network so that anyone in Karachi with difficulty breathing could access oxygen. Among those who received oxygen therapy between June 2020 and August 2021, 96 percent were sent home and tested for COVID-19 in the following days, averting unnecessary emergency room visits during the pandemic. Although the absolute effect of these oxygen therapy interventions was relatively small, they demonstrate the value of using existing TB infrastructure in responding to a pandemic, he added.

IRD’s general practitioner network was instrumental to COVID-19 screening efforts in Karachi, said Khan. More than 47,000 presumptive-positive COVID-19 patients were screened at clinics in Karachi between June 2020 and July 2021. However, owing to limited testing access and the high cost of PCR testing in the private sector, a large proportion of patients were never tested for COVID-19 despite being presumptive positive and symptomatic (82 percent) or presumptive positive with subsided symptoms (99 percent).

Phone-Based Contact Tracing Among Patients Who Tested Positive for COVID-19

IRD realigned its existing TB contact-tracing team and system to conduct COVID-19 contact tracing, identifying almost 23,000 index patients, of whom about 16,000 were contacted. More than 7,300 reported untested contacts. This contact-tracing effort was the only method by which data were collected regarding the outcomes for patients with positive PCR tests—1 percent of the index patients had died, and 55 percent had recovered. Between April 2020 and April 2021, 128 patients who had tested positive for COVID-19 died in Karachi. Most deaths among those with positive PCR tests occurred within the first 2 weeks after testing positive and most died in health facilities, but many died at home after testing positive for COVID-19. Khan surmised that these deaths probably would not have been reported if not for the contact-tracing efforts. This is another example of the value of an existing TB infrastructure for COVID-19 response, said Khan.

Lessons Learned from Adapting Integrated Community Response to COVID-19 in Karachi

Khan highlighted lessons learned from Karachi’s COVID-19 experience and IRD’s adaptation of existing TB systems to manage the pandemic surge. A COVID-19 surge can quickly overwhelm any active TB screening system.

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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In Karachi, for example, there were about 10-fold more COVID-19 patients than TB patients in the first X-ray screening campaign. Thus, mass antigen rapid diagnostic testing will be key for addressing COVID-19 surges in the future. Such testing is now being supported by existing TB partners, including FIND and Stop TB. Khan emphasized that previous investments in TB control have supported the COVID-19 pandemic response, as demonstrated by the preexistence of a functional TB screening system that enabled Karachi’s initial COVID-19 response. Moreover, Karachi’s initial pandemic response was bolstered by the existing TB contact-tracing systems, mental health support systems, private-sector provider networks, and data-collecting and -reporting systems.

Telehealth and Digital Adherence Technologies

Presented by Bruce Thomas, The Arcady Group

Thomas discussed how DATs can facilitate differentiated and virtual care for persons affected by TB. Despite the fact that TB is treatable and curable, too few patients successfully traverse the TB care cascade from infection to successful treatment. For instance, a study evaluating TB treatment cascades in India and South Africa found that the proportion of individuals who completed each step of the TB care cascade progressively declined (Subbaraman et al., 2016). From burden to testing, diagnosis, treatment initiation, treatment completion, notification, and treatment success/recurrence-free survival, individuals fell off the care cascade at each step. He noted that the care cascade outcomes are often worse for patients with MDR TB or TB with HIV.10

Effect of the COVID-19 Pandemic on Global Tuberculosis Control

Thomas described the extent to which the COVID-19 pandemic has worsened global TB control. Overall, approximately 1 million fewer persons affected by TB were tested and treated in 2020 than in 2019, representing an 18 percent decline (Global Fund, 2021). During that time, the number of persons on treatment for MDR TB and XDR TB declined by 19 percent and 37 percent, respectively. Among those with HIV and TB, the number of persons on both antiretroviral treatment and TB treatment declined by 16 percent. Despite these challenges, the pandemic has had some limited

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10 Thomas shared the statistics that in India, only 41 percent of MDR TB cases were diagnosed, with only 11 percent of those achieving recurrence-free survival, and in South Africa, 82 percent of patients with HIV and TB co-infection were diagnosed, and 52 percent of those achieved treatment success.

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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favorable effects on TB treatment and control. For example, the COVID-19 pandemic has accelerated the trend of giving TB patients custody of their own medications, and patients self-administering their TB medications has become far more common. TB programs have also increasingly taken advantage of digital tools—such as telehealth and digital adherence monitoring—to bring TB services to the people and communities in need. These trends are expected to outlast the COVID-19 pandemic and strengthen efforts to fight other diseases, he added. According to a letter from the executive director in the Global Fund’s Results Report 2021:

COVID-19 has catalyzed a multitude of innovations across all three diseases, such as multi-month dispensing of TB and HIV drugs; using digital tools to monitor TB treatment or enhance prevention interventions; and introducing patient-centered diagnostic approaches, such as co-testing for HIV, TB and COVID-19. Many of these innovations will outlast the crisis and strengthen our fight against HIV, TB, and malaria. (Global Fund, 2021)

Differentiated Care Through Integrated Digital Adherence Technologies

Thomas discussed the challenges in TB treatment adherence and the potential benefits of DATs, which have particular value in the context of the COVID-19 pandemic. Adherence is a multifactor behavioral issue that changes over time. Poor adherence in TB treatment can be attributed to various factors such as the prevalence of long and complicated treatment regimens, confusion about dosing, treatment side effects, and the use of a directly observed therapy–short course. The last factor is known to be stigmatizing, burdensome, and inconsistent with many patients’ lifestyles. Poor adherence is known to be associated with TB recurrence (Thomas et al., 2005), making adherence critical for success in TB treatment. Their 2005 study found a strong relationship between adherence and post-treatment TB recurrence; recurrence rates for very irregular adherence were found to be 25 percent (Thomas et al., 2005). A 2018 meta-analysis found that TB patients taking shortened regimens with less than 90 percent adherence had a 5.6 times increased risk of recurrence (Imperial et al., 2018).

Integrated DATs are being developed to support TB patients while capturing their dosage histories, said Thomas. These technologies have been designed to be affordable, scalable, TB-appropriate, and accessible to patients in high-TB-burden regions through the use of phones and other available technological platforms. Importantly, these technologies are integrated such that a single system can be used to assign DATs to any patient and allow providers to access and review compiled dosing histories. These technologies also offer patients and providers choices so they can select the tools that best fit patients’ lifestyles and treatment regimens.

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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Thomas presented several examples of integrated DATs. 99DOTS uses augmented packaging to reveal codes as a person takes their medications,11 and users report their dose adherences using a toll-free call or SMS. Video-observed therapy can also be used in lieu of directly observed therapies by allowing patients to share videos of themselves taking their medications, which can be reviewed by health care workers to understand their patients’ adherence. Various forms of “smart pillboxes” contain electronic components that remind patients to take their treatments and send signals reporting adherence when the box is opened. The Everwell Hub is an open-source digital platform that allows providers to register patients, allocate them to specific DATs, and review data such as historical adherence.

Thomas presented a model for using DATs to provide differentiated and virtual care (Subbaraman et al., 2018). Differentiated care refers to providing different intensities and types of care based on a patient’s level of medication adherence as measured by the DAT. In this model, DATs provide self-administering patients with reminders and dosing assistance. DATs can be used to electronically observe or verify daily dosing, to deliver detailed dosing histories to health systems, and to apply evidence-based escalation protocols. Dosing histories are used to continuously triage patients and identify nonadherent patients, who can be prioritized for engagement by providers to understand and assess reasons for poor adherence (e.g., experiencing side effects, needing refill, being asymptomatic). He also presented an example of a patient adherence timeline, which detailed a patient’s treatment adherence over time, including treatment registration, medication receipt, automated patient reminders and adherence, instances of patient non-adherence, health staff interventions, and overall adherence at the time of treatment completion.

The rationale for using a DAT-enabled differential care approach is strong, said Thomas. These approaches reduce the burden on patients and empower them to manage their treatments unless they have demonstrable adherence issues. These approaches are also transparent—giving patients and providers equal access to patients’ dosing history—and thus promote trust between patients and providers. They shift the perception of adherence measurement to be similar to other vital signs. Health systems gain behavioral insights into dosing histories to highlight unique patient-specific patterns of non-adherence. Additionally, these approaches enable and inform patient–provider discussions about adherence challenges and the specific steps patients can take to address those challenges. He added that DAT approaches are approved by WHO based on favorable results from a range of trials conducted in the United States, European Union, and high-burden regions. For

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11 More information about 99DOTS is available at 99dots.org (accessed November 3, 2021).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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instance, one study found that DATs significantly improved adherence among antiretroviral therapy patients in China (Sabin et al., 2010).

Thomas described progress in building a strong evidence base for DAT in clinical trials and implementing DAT in clinical practice between 2015 and 2020, prior to the COVID-19 pandemic, leading to WHO’s approval. The process began with a catalytic innovation phase to develop DAT tool kits, followed by a proof-of-concept phase with evaluations conducted in India and China. WHO then issued supportive guidance for DATs, and TB Resource Group for Advocacy and Community Health grants funded the implementation of 13 projects across 11 countries. During the subsequent transition to scale phase, funded by Unitaid, DATs were scaled up to more than 70,000 patients. In 2020, the Global Fund began providing multiyear support for DATs in approximately 13 countries, and continued phases of innovation since 2020 have been led by Global Health Labs and the Bill & Melinda Gates Medical Research Institute.

Effect of COVID-19 on Digital Adherence Technologies

Thomas highlighted lessons learned from the implementation of DATs and ways that the COVID-19 pandemic has improved the DAT landscape. DATs are relatively affordable, readily scalable, and generally well accepted by patients and providers. However, lack of health care provider contact can cause patients to disengage from DATs. To address this issue, DATs provide escalation-based task lists to providers to help facilitate essential patient engagement and follow-up. When implemented properly, patients see their DAT as a direct connection to their provider, which encourages them to use DAT tools to facilitate that connection—for example, to use e-prescribing and refills or to ask questions about facility operations, dosing, side effects, or direct benefit transfer.

The COVID-19 pandemic provided an opportunity for DAT tool kits to be used to provide more virtual and at-home care in areas with limited access to health care facilities. DAT tool kits were rapidly adapted to address arising needs and to support virtual care. While DAT tool kits originally focused exclusively on adherence monitoring, they now offer patient-facing applications that provide patients with access to a wealth of information about their treatments, adherence, and overall care. These applications help to facilitate real-time virtual engagement between patients and providers. For instance, the Everwell Hub Health companion application and India’s TB Aarogya Sathi application provide these features to patients around the world.

Thomas described advances in video observation technology, emphasizing that video observation can be useful for more than just dose monitoring. For instance, it can be used to facilitate asynchronous observation. Patients can use smartphones to record medication ingestion, and then

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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health care workers can asynchronously view and record their observations via encrypted video. In addition to functioning as a standalone adherence system, this technology can be used as part of an integrated DAT approach using a digital platform (e.g., Everwell Hub). Video observation technology can also be used in clinical trials and in clinical practice. In response to the COVID-19 pandemic, SureAdhere, a video observation technology platform, has added two-way secure messaging to its platform, and soon its platform will offer live teleconsultations via video web conferencing.

The COVID-19 pandemic has accelerated a shift toward at-home care for persons affected by TB, said Thomas. It has fostered an unprecedented willingness to consider approaches other than facility-based care and tools, with existing DATs being used to foster a new model of at-home care that (1) allows patients to self-administer drugs with remote monitoring, (2) provides patients with dosing support and other support, (3) facilitates dose-history-informed differentiated care, (4) integrates diagnostics to support a “test and treat” model, and (5) fosters patient–provider engagement as virtual care increases. He was optimistic that TB care would not revert to the pre-pandemic condition and that many persons affected by TB will not be restricted to facility-based care in the future.

Innovative Strategies to Synergize Investments in Health Care Systems

Presented by Monique K. Mansoura, MITRE

Mansoura explored innovative strategies to synergize investments in health care systems with a focus on whether cancer and TB care can protect against pandemics. “TB is a natural partner in our efforts to better prepare for and protect populations against pandemics, while we are also building critical infrastructure for cancer and TB,” she remarked. Various synergies at the molecular and health systems levels could be leveraged across TB, cancer, and pandemic events and allow for the whole health system to be improved, but such synergistic surpluses are not possible without deliberate action, meaningful measures, and checks to ensure accountability. Meaningful measures and accountabilities also help to build credibility with donors and investors, as well as incentivizing and rewarding innovations in flex competence, which Mansoura defined as the ability for a system’s components and resources to be deployed to various efforts depending on changing needs. Through sustained commitments from leadership, governments, and investors, these synergies can improve care and preparedness. Mansoura maintained that TB and cancer care are naturally aligned in the effort to build a stronger critical infrastructure to support pandemic preparedness.

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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Mansoura emphasized the importance of a systems approach to the provision of care. A systems approach recognizes the roles of facilities, staff and workforce, and the materials and equipment that are all necessary to provide comprehensive care. Such an approach is key for leveraging synergies and achieving benefits, cost-effectiveness, and building capacity. A primary challenge in global health security is persistence in building capacity and the maintenance of sustained commitments. Investments that are more broadly targeted—investments that target more than one disease—help to maintain such a sustained commitment, she added.

Matrix of Preparedness and Event Occurrence

To discuss challenges related to preparedness for potential pandemics and health attacks, Mansoura presented an outcomes matrix showing potential outcomes based on the combination of event occurrences and preparedness (see Figure 3-2). COVID-19 is an example of a “horrible scenario” wherein a pandemic has occurred while preparedness measures were in place, yet they were inadequate to prevent immense loss of life and livelihood—although the consequences of the pandemic would have undoubtedly been even worse if no preparedness measures were in place at all. Mansoura emphasized the tenuousness of the “second guessing” outcome, wherein investments are made in preparedness but no attacks or pandemics occur, so there is continual second guessing about why that money was spent. For instance, no coronavirus vaccine was developed after SARS outbreaks in the early 2000s, nor was a vaccine developed in response to the MERS outbreak

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FIGURE 3-2 Preparedness framework.
* U.S. government programs, such as BioShield, the Biomedical Advanced Research and Development Authority, and the Public Health Emergency Medical Countermeasures Enterprise were designed to prevent worst-case scenarios.
SOURCES: Mansoura presentation.
Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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in 2012. She suggested that this failure to follow up was caused by second guessing of the investment in preparedness during times in which no immediate threat was present. Second guessing about preparedness for events that have not occurred is a “persistent paralyzer,” said Mansoura. However, she continued, there is no reason to doubt that attacks and pandemics will occur in the future, so the “dream outcome” of no pandemics and a total lack of preparation should not be considered a realistic option. Synergistic investment in more persistent health spaces, such as TB and cancer, can help to address the barriers caused by second guessing. Moreover, the capacity developed through these investments can be leveraged in times of need to respond to attacks or pandemics, she added.

Current State of Global Cancer Care

Mansoura described the work of the International Cancer Expert Corps (ICEC) to transform global cancer care, reduce mortality, and improve the quality of life for people with cancer in LMICs and underserved regions worldwide through catalytic and disruptive innovation. Currently, underserved populations lack access to cancer care experts. Mansoura shared that while there is a surge of interest in the developed world to deliver high-quality cancer care, the current global health care environment encourages the depletion of talent (via brain drain) in LMICs. ICEC mentoring programs are designed to match experts with global needs through partnership programs and matched funding to support participants. ICEC helps to transform cancer care by partnering with local communities to build sustainable infrastructure and programs. Innovation in cancer care equipment is another pressing concern for ICEC. Radioactive cobalt-60 machines present environmental and security risks, and these devices lack the sophistication needed for modern radiotherapy. Additionally, there is no practical, accessible, and affordable technology available to meet global cancer care needs. ICEC is promoting innovation in equipment design by working to convene and engage stakeholders in the radiotherapy equipment design sector.

Achieving Health Systems with Flexible Competence

“Flexible competence” can be achieved by bridging the investment dichotomy between cancer and infectious diseases such as TB, suggested Mansoura. Overlaying the hotspots for infectious diseases and disease burdens for noncommunicable diseases reveals clear geographic alignment (Coleman et al., 2020). The control of both infectious diseases and noncommunicable diseases requires early detection and rapid response, and thus building capacity and capability in those areas will have multiple benefits. Convergent, adaptable medical care capacity building is a

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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cost-effective and necessary approach for improving care for both infectious and noncommunicable disease, as both disease types have similar etiology and systemic responses (e.g., infectious agents, immunology, and inflammation).

Mansoura and colleagues have developed a model for dual-capacity health systems with flex competence that improves outcomes and preparedness for infectious diseases, including pandemics and TB, and noncommunicable diseases such as cancer (Coleman et al., 2020). The model highlights the interrelationships between noncommunicable diseases and infectious diseases. For instance, some cancers are caused by infectious diseases, and cancer patients are often susceptible to infection. Both disease groups can benefit from rapid, population-level assessment, which is a foundational capacity both for pandemic response, and ongoing prevention and treatment. Both disease groups require similar health care capacity for physical examination, laboratory and molecular diagnostics, diagnostic imaging, treatment and recurrence prevention, and modulation to address immune response and inflammation. An integrated health care system could offer flex competence in areas applicable across infectious diseases, noncommunicable diseases, pandemics, and disasters:

  • Prevention of infectious diseases and immunization;
  • Population surveillance;
  • Prevention of noncommunicable diseases (e.g., screening, healthy lifestyle promotion, diet);
  • Diagnostic capacity;
  • Treatment, including palliative care; and
  • Patient surveillance.

Ideally, these components would be built into an integrated health care system with the capacity to flex to address a range of disease types—including TB, COVID-19, and cancer—to improve health outcomes and strengthen preparedness.

Mansoura explained that the concept of flex competence refers to a health care system’s adaptability to changing needs (Coleman et al., 2020). A high degree of flexibility and adaptability enables common health care capacities and resources to be continually evaluated and adapted based on need; leaders can then deputize these tested resources to where they are most needed. For instance, a health system may typically focus on noncommunicable diseases while maintaining baseline pandemic surveillance and infectious disease control efforts. However, in an early outbreak, that system might reduce noncommunicable disease capacity and shift its focus to pandemic surveillance and infectious disease control. On the other hand, a well-vaccinated community might focus more resources on noncommuni-

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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cable diseases while maintaining reduced pandemic surveillance and infectious disease efforts.

Measuring Flex Competence

Mansoura presented metrics that can be applied to measure the flexibility of each sector (Coleman et al., 2020). Capacity and capability can be measured in terms of expanding facilities for routine care, program development (e.g., prevention and treatment programs), staff expertise, global quality standards, and sustainable funding. Multilevel planning for rapid response can be evaluated in terms of the robustness of data systems, management structure and communication systems that support implementation and adaptation, and regional planning for rapid decision making. Specifically, Mansoura noted the importance for regional planning to adapt and change resource deployment, with triggers and systems in place to initiate access to global resources as needed. Health care system competence can be measured in terms of management and staff ability to rapidly change systems and focus, staff training and cross-training (e.g., interactive education programs), and ability to provide online access to educational resources for unanticipated or urgent needs. Finally, global resource access can be measured through assessments of readiness to meet standards, supply chain networks, access to expertise from high-income countries and staff mentorship, and standardized data reporting. Mansoura emphasized the need for readiness assessments to meet standards as a key for global flex competence.

In 2019, the Global Health Security Index was published, measuring the health preparedness of each country.12 However, the COVID-19 pandemic revealed that this index was not highly effective at predicting countries’ pandemic preparedness, and it remains unclear how this can best be measured (Crosby et al., 2020). Still, Mansoura reaffirmed that meaningful measures are required for effective investment.

Challenges and Ways Forward to Leverage Synergies and Build Flex Competence

In moving forward with efforts to leverage synergies and build flex competence, Mansoura highlighted the potential challenge of cultural rifts that can arise as the public health sector mobilizes to address pressing disease outbreaks that may have immense impact on public health, national security, and economic security (Bernard, 2013). She called for the health community

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12 More information about the 2019 Global Health Security Index is available at https://www.ghsindex.org (accessed November 7, 2021).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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to temper its strongly held convictions and to encourage defense and foreign affairs communities to embrace relevant health issues in the first tiers of policy and budget concerns. However, health professionals and health organizations often have little experience crafting messages and presenting issues in a manner that will sway the critical actors in foreign policy, intelligence, and defense sectors. Mansoura acknowledged that this cannot be blamed solely on public health actors, as the security sector is often unenthusiastic about efforts to prioritize pandemics or other public health issues as security issues. She also noted the importance of building trustful relationships for addressing health issues such as TB, cancer, and COVID-19. The potential consequences of mistrust have recently been demonstrated by the variance in vaccine distribution and vaccination during the COVID-19 pandemic (Cheney, 2021).

Promising findings demonstrate the potential synergistic effect of flex competence, said Mansoura. For example, 940,000 children in contact with TB patients received preventive therapy in 2020, representing a 13 percent increase over 2019 and suggesting that COVID-19 response efforts had a synergistic positive effect on child contact preventive therapy (Global Fund, 2021). Anticipating and preparing for public health crises is the cornerstone of recognizing and leveraging powerful synergies, she added. Resources that are redirected in a crisis response can create major deficits in other health care areas and damage existing structures of care; these consequences can be avoided by preparation and integration efforts across the infectious disease, noncommunicable disease, and preparedness communities.

Environmental Transmission Control Lessons from COVID-19 and Tuberculosis

Presented by Edward Nardell, Harvard Medical School and the T.H. Chan School of Public Health

Nardell described environmental transmission control lessons that can be gleaned from efforts to control TB over many decades and efforts to control COVID-19 since 2020. The COVID-19 pandemic response has benefited from lessons learned through TB control; now, there is ample opportunity to apply lessons from the COVID-19 pandemic to TB control.

Mechanisms of Transmission for Tuberculosis and COVID-19

Nardell compared the mechanisms of transmission that underpin the spread of TB and COVID-19. Although they have much in common, they also have differences that are relevant to determining the most effective means of transmission control. TB is predominantly spread indoors and almost exclu-

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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sively through airborne transmission and inhaled aerosols because Mycobacterium tuberculosis (MTB) must reach the alveolar macrophage to cause infection, which is only possible for particles 1–5 µm in size (Milton, 2020). Furthermore, MTB is environmentally adapted, making it stable in airways and capable of traversing ventilation systems. COVID-19 also spreads mostly indoors through inhaled aerosols. For both TB and COVID-19, large droplet spread and surface spread are relatively less important, and RNA found on surfaces and in air is not replication competent. However, unlike MTB, SARSCoV-2 has multiple mucosal targets in the eyes, nose, and airways—including angiotensin-converting enzyme receptors in the respiratory tract—making it possible for particles of various sizes (1 µm to greater than 100 µm) to cause infection. SARS-CoV-2 is also unlike MTB in that its envelope RNA viruses are fragile in the environment; no evidence of ventilation duct transmission of SARS-CoV-2 has yet been reported. The infectious dose of MTB can be as low as a single bacterium, while the infectious dose of SARS-CoV-2 is quite high (300–1,000 virus particles). MTB is chronically infectious and mostly spread by symptomatic individuals. In contrast, SARS-CoV-2 can spread asymptomatically for a short infectious period of roughly 48 hours, making it unusual among infectious diseases.

The outbreak of COVID-19 at the Skagit Valley Chorale rehearsal in March 2020 was instrumental in confirming that SARS-CoV-2 is primarily airborne, rather than spread through droplets, said Nardell (Miller et al., 2021).13 Nardell considered the difference in transmission that is most likely to occur through rebreathed air in an indoor room compared with transmission through the ventilation circuit in a building or other structure. Although a common COVID-19 control recommendation is to improve filters in ventilation systems, SARS-CoV-2 appears to be very delicate and generally incapable of traversing ventilation systems or remaining intact when diluted with air from other rooms. In contrast, Nardell stated, it has been established from a TB outbreak on a naval vessel that TB can readily spread through ventilation systems—if present—and from room to room. At the time of the workshop, COVID-19 is not known to travel through ventilation systems (i.e., infectious viral particles being taken into a ventilation system and then released in a different room to cause infection in the absence of person-to-person contact). Nardell contended that COVID-19 seems to be spread primarily through rebreathed air among persons in the same indoor room, with the implication that changing duct filters—a com-

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13 None of the participants who attended the 2.5-hour indoor choir rehearsal were symptomatic, yet 53 of the 61 attendees were later found to have COVID-19 and two attendees died. Strict social distancing and hand sanitization measures were in place, thus large droplet and surface spread are highly unlikely to account for the extent of transmission.

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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mon recommendation for environmental control of SARS-CoV-2—may not be helpful in reducing transmission.

Air Disinfection for Infectious Disease Control

COVID-19 has raised the profile of air disinfection in poorly ventilated buildings, said Nardell. Because COVID-19 is spread primarily through rebreathed air in indoor rooms, he suggested approaches to air disinfection for COVID-19 control be room-based. Options for room-based air disinfection include natural ventilation, mechanical ventilation, room air cleaners, upper-room germicidal ultraviolet (GUV) air disinfection, and newer technologies brought about by the COVID-19 pandemic.

Natural ventilation—which has been relied upon in TB control for many years—is capable of reducing transmission, but it is highly variable depending on building design and other conditions. Use of natural ventilation for air disinfection is also under threat from the effects of climate change. Mechanical ventilation can help to dilute air and reduce transmission of COVID-19, but this option is rarely available in countries with high TB burdens. Mechanical ventilation is also limited by air flow, thus not an ideal solution. Similarly, room air cleaners have been distributed as a tool for TB control in many countries, but not all models contribute significantly to overall air flow.14

Nardell described the benefits of using upper-room GUV for air disinfection. These devices are not limited by air flow; instead, they treat large volumes of air instantaneously, making them highly economical. GUV air disinfection is also safe for room occupants and effective against various infectious disease agents, including MTB, SARS-CoV-2, influenza viruses, and the measles virus. Upper-room GUV air disinfection is an old and affordable technology, but companies have not traditionally been motivated to develop this technology for TB control. However, the COVID-19 pandemic has spurred new developments in upper-room GUV air disinfection that will likely benefit TB control efforts, said Nardell. These advancements include lowered costs, more evidence of efficacy, and expanded support systems for GUV technology. The pandemic has also spurred advancements in ultraviolet technology, he added. New 222-nm “far-UV” devices can be used directly around room occupants without any concern for eye or skin irritation. Although far-UV devices are currently too expensive for widespread use, they will likely become more affordable over time. New ion generators are also being developed in response to the COVID-19 pandemic.

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14 Nardell noted that a key concern for measuring air flow is to measure the number of equivalent air changes contributed by a device. Thus, the effectiveness of any ventilation-based disease control is closely linked to the number of equivalent air changes that it provides.

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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Prevention of COVID-19 and Tuberculosis Transmission Using Upper-Room Germicidal Ultraviolet Systems

Nardell described how upper-room GUV disinfects large volumes of air at one time. In a room with 9-foot ceilings, UV-C radiation is projected throughout the airspace above 7 feet from the ground. This creates a zone of air disinfection in the unoccupied space 2 feet below the ceiling. As contaminated warm air rises, it naturally circulates cooler disinfected air back down into the occupied space. Low-velocity ceiling fans are added to these systems to ensure good air mixing. Unlike upper-room GUV, far UV can be used to disinfect the entire room rather than only unoccupied space.

Use of upper-room GUV has a long history in infectious disease control, said Nardell. A 1942 study demonstrated that upper-room GUV in school rooms effectively prevented the transmission of measles, the most infectious known respiratory pathogen (Wells et al., 1942). Given that measles is far more contagious than COVID-19, upper-room GUV could also stop the spread of COVID-19, which is highly UV-susceptible. Upper-room GUV has also been shown to be 80 percent effective against TB transmission, capable of adding the equivalent of 24 air changes per hour (Mphaphlele et al., 2015).

In addition to being effective in halting transmission, upper-room GUV is also cost-effective, added Nardell. One unpublished study used a renovated hospital room to introduce an aerosolized test organism and perform quantitative air sampling, finding that upper-room GUV was far less expensive per year per equivalent air changes per hour compared to mechanical ventilation or three different commercial air cleaners; in fact, upper-room GUV was more than 9 times more cost-effective than the other technologies (Nardell, 2021).

Effects of Climate Change on Airborne Disease Control

Nardell discussed the effects of climate change on airborne disease control. As temperatures have risen, the use of ductless air conditioning units has expanded. For instance, he found that ductless air conditioning sales in India rose dramatically between 2010 and 2015, and that trend appeared to continue between 2015 and 2021. Because windows are closed when air conditioners are in use and ductless air conditioning units do not use ventilation, ductless air conditioners create unventilated spaces. In addition to cooling spaces, it is also necessary to replace the ventilation lost to ductless air conditioners. This trend is directly linked to increased risk of airborne infection transmission: the risk of airborne infection doubles within 1 hour of closing the windows in a space cooled with ductless air conditioning (Nardell et al., 2020).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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Gaps and Opportunities in Management of Latent Tuberculosis Infection

Presented by Gavin Churchyard, the Aurum Institute

Churchyard discussed gaps and opportunities in the management of latent TB infection and barriers to the implementation of TPT. He also identified research gaps within the TB prevention cascade—specifically for people living with TB and HIV and for household contacts of people with TB—and highlighted prospects for future TB regimens. Although progress has been made toward achieving the UN High-Level Meeting targets for 2022 for scaling up the provision of TPT to people of all ages and people living with HIV, efforts to scale up TPT for household contacts have been insufficient to meet the 2022 goals. Notably, less than 1 percent of the targeted 20 million household contacts age 5 years or older have received TPT (WHO, 2020). Churchyard noted that a recent WHO meeting identified barriers to TPT implementation, research gaps along the cascade of prevention, and specific research gaps related to high-risk groups (Oxlade et al., 2021).

Research Priorities in the Implementation of Tuberculosis Preventive Treatment and the Prevention Cascade

At the health system level, barriers to TPT implementation include a lack of priority of TB control programs, limited access to diagnostics and drugs, inadequate financing, and lack of a patient-centered perspective (Oxlade et al., 2021). To overcome those barriers, research priorities include:

  • Collecting data to build a stronger public health case for the programmatic management of TPT;
  • Creating simplified diagnostic algorithms for TB disease and developing shorter treatment regimens;
  • Understanding financing gaps, modeling the cost-effectiveness of TPT, and modeling the effect of TPT on TB incidence and mortality; and
  • Better understanding the perspectives of patients and clients in diverse settings about the risks and benefits of TPT.

Research gaps also pervade the cascade of prevention, said Churchyard. He highlighted sets of research needs and priorities in the domains of (1) better identifying and connecting to populations at risk, (2) improving screening and testing for TB infection, (3) more accurately excluding active TB infection, and (4) improving the initiation and completion of TPT (see Box 3-3) (Oxlade et al., 2021).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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Research Progress and Priorities in Tuberculosis Preventive Treatment for High-Risk Groups

Churchyard highlighted research progress and priorities in the provision of TPT to high-risk groups, including people living with HIV, household contacts under 5 years old, household contacts age 5 years or older, and other people at risk.

WHO recommends a range of TPT regimens for people with HIV, including isoniazid and rifapentine for 3 months (3HP) and isoniazid and rifapentine for 1 month (1HP). The DOLPHIN trial showed that 3HP was well tolerated by and safe for people with HIV on antiretroviral therapy without dose adjustment of dolutegravir, and virologic suppression was maintained through the regimen (Dooley et al., 2020). The DOLPHIN TOO trial is amending the original protocol to describe the rate of decline of plasma HIV-1 viral load among antiretroviral naïve participants starting isoniazid preventive therapy or 3HP regimens with a dolutegravir antiretroviral regimen.15

TPT guidelines for children younger than 5 are complex, Churchyard explained. Regimens are determined by age, HIV status, and whether or not the antiretroviral therapy includes nevirapine or lopinavir/ritonavir. Consequently, these guidelines require three different child-friendly TPT regimens. The guidelines should be simplified such that all children and older contacts in each household can receive the same TPT regimen, he said. Tuberculosis Trials Consortium Study 35 is a dose-finding and safety study of providing 3HP to HIV-infected and HIV-uninfected children with latent TB infection.16 The study is testing a child-friendly, fixed-dose combination tablet of 3HP that dissolves in water to optimize doses for the youngest children. In 2022, the DOLPHIN KIDS study will assess the safety, tolerability, and pharmacokinetics of 3 months of 3HP among infants, children, and adolescents living with HIV and taking dolutegravir as an antiretroviral therapy.17

The Brief Rifapentine-Isoniazid Evaluation for TB Prevention (BRIEF TB) trial demonstrated the efficacy of an ultrashort course 1HP regimen of daily isoniazid and rifapentine in HIV-positive persons (Swindells et al., 2019).18 Compared to the 9-month isoniazid regimen, 1HP was noninferior in terms

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15 More information about the DOLPHIN TOO trial is available from https://clinicaltrials.gov/ct2/show/NCT03435146 (accessed January 3, 2022).

16 More information about Tuberculosis Trials Consortium Study 35 is available from https://clinicaltrials.gov/ct2/show/NCT03730181 (accessed December 15, 2021).

17 More information about the DOLPHIN KIDS study is available from https://clinicaltrials.gov/ct2/show/NCT05122767?term=dolphin+kids&draw=2&rank=1 (accessed January 3, 2022).

18 More information about Brief Rifapentine-Isoniazid Evaluation for TB Prevention (BRIEF TB) trial is available from https://clinicaltrials.gov/ct2/show/NCT01404312 (accessed December 15, 2021).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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of efficacy and superior in terms of safety, tolerability, and treatment completion. Currently, there is no evidence for use of this regimen in HIV-negative persons, children, or pregnant women, and dolutegravir doses may need to be adjusted for HIV-positive patients on antiretroviral therapy.19 The Impact4TB One-to-Three superiority trial will compare the use of the 1HP regimen to the 3HP regimen in adult and adolescent HIV-positive persons and household contacts in terms of treatment completion, treatment-limiting adverse events, safety, and cost-effectiveness. The study will begin in August 2022 across sites in South Africa, Indonesia, India, and Mozambique.

Churchyard added that more cost-effectiveness data are required to support the increased use of 1HP. The cost-effectiveness of 1HP is driven by 1HP completion rates and efficiency, the cost of rifapentine, and the prevalence of latent TB. The 1HP regimen would cost substantially more to achieve the outcomes currently achieved by 3HP regimens. However, a reduction in the price of rifapentine can significantly lower the regimen cost.

Pregnant women have a higher risk of TB, said Churchyard. Two clinical trials suggest an association between HIV-infected pregnant women receiving isoniazid preventive treatment and increased risk of adverse pregnancy outcomes. Evidence for the use of rifapentine-based TPT regimens among pregnant women is beginning to emerge. The IMPAACT 2001 study provided the first evidence that rifapentine was safe for HIV-infected and HIV-uninfected pregnant women and that the dose of rifapentine need not be adjusted. The WHIP3TB trial has collected data on pregnancy outcomes for pregnant HIV-positive women, which were reported in late 2021 (Chihota et al., 2021). In late 2022, the DOLPHIN MOMS study will evaluate the safety, tolerability, and pharmacokinetics of 1HP in comparison with 3HP initiated antepartum versus postpartum.

Churchyard also discussed the use of TPT for household contacts of TB patients by presenting results from the Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (PHOENIx MDR-TB) trial conducted in eight high-burden countries.20 The PHOENIx MDR-TB feasibility trial demonstrated that 77 percent of household contacts of MDR TB patients were in a high-risk group for developing TB (Gupta et al., 2020). Among household contacts that were not in a risk group at baseline, more than 20 percent tested positive for infection within 1 year, suggesting that the majority of household contacts of MDR TB patients are at risk of developing TB and would benefit from TPT.

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19 The A5372 trial will evaluate whether doses of dolutegravir need to be adjusted for patients taking this 1HP regimen.

20 More information about the Protecting Households on Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients trial is available from https://clinicaltrials.gov/ct2/show/NCT03568383 (accessed December 15, 2021).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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However, further research is needed to understand the advantages and disadvantages of testing for TB infection among household contacts. Furthermore, the feasibility trial demonstrated that children younger than 5 years and HIV-infected household contacts age 5 years and older had the greatest risk of developing TB. Research is also needed to understand the epidemiological effects of treating high-risk household contacts of various ages. It has been suggested that TPT has limited value in high-transmission countries because of the risk of reinfection in communities, Churchyard added. One modeling study conducted in 2014 found that while household contact tracing alone may not be sufficient to reduce TB incidence, the combination of TPT with household contact tracing may significantly increase reductions in TB incidence (Kasaie et al., 2014).

To address the gap in evidence from randomized trials on providing TPT for contacts exposed to MDR TB, three trials are underway: the Tuberculosis Child Multidrug-resistant Preventive Therapy trial (TB-CHAMP),21 the VQUIN MDR trial,22 and PHOENIx MDR-TB. TB-CHAMP is a cluster randomized, community-based superiority trial providing pediatric dispersible levofloxacin tablets daily for 6 months to children age 5 years or younger. The VQUIN MDR trial is evaluating a 6-month daily levofloxacin regimen in a cluster randomized, community-based superiority trial targeting tuberculin skin test (TST)–positive participants of all ages, including infants less than 6 months old. The PHOENIx MDR-TB trial is comparing 26-week daily regimens of isoniazid or delamanid, targeting children younger than 5, people who are HIV-positive, and people older than 5 who tested positive for TB through either the TST or interferon gamma release assay (IGRA).23 While awaiting results from these trials, WHO has conditionally recommended the use of a TPT regimen of 6 months daily levofloxacin with or without ethambutol or ethionamide (WHO, 2018).

Future Tuberculosis Preventive Treatment Regimens

Churchyard emphasized the importance of managing the global burden of TB infection to meet End TB targets. In addition to addressing research gaps described above, further research is needed to improve potency and further reduce the duration of treatment for TPT. Although TPT regimens have advanced in recent years, maximizing the benefits of TPT warrants fur-

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21 More information about TB-CHAMP is available from https://www.mrcctu.ucl.ac.uk/studies/all-studies/t/tb-champ (accessed December 15, 2021).

22 More information about the VQUIN MDR trial is available from https://www.woolcockvietnam.org/vquin (accessed December 15, 2021).

23 There are two tests that can be used to detect TB infection, the tuberculin skin test (or TB skin test, TST) and a blood test to measure release of interferon gamma (IGRA). See https://www.cdc.gov/tb/topic/testing/tbtesttypes.htm (accessed January 3, 2022).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
×

ther innovation, said Churchyard. To that end, additional ultra-short-course regimens are currently being evaluated. The 2R2 trial is comparing the use of higher doses of rifampicin for 2 months with the standard TPT rifampicin dose with the aim of determining whether doubling or tripling the standard dose is safe and effective. The Assessment of the Safety, Tolerability, and Effectiveness of Rifapentine Given Daily for Latent Tuberculosis Infection (ASTERoiD) study is assessing the safety, tolerability, and effectiveness of a 6-week daily rifapentine regimen with regimens between 12 and 16 weeks in length.24 It may be possible to reduce the duration of TPT for DS TB infections using 2-week regimens containing bedaquiline with rifapentine (Zhang et al., 2011). Furthermore, it may be possible to reduce the duration of TPT for MDR TB contacts to 1 month with bedaquiline alone or in combination with other drugs. Long-acting injectable TB drugs may also hold great promise for TPT in the future, Churchyard added.

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24 More information about the ASTERoiD study is available from https://clinicaltrials.gov/ct2/show/NCT03474029 (accessed December 15, 2021).

Suggested Citation:"3 Detection." National Academies of Sciences, Engineering, and Medicine. 2022. Innovations for Tackling Tuberculosis in the Time of COVID-19: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26530.
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Despite being preventable and curable since the middle of the twentieth century, tuberculosis (TB) has long persisted as the world's deadliest infectious disease, with the communities most devastated by TB among the poorest and most vulnerable in the world. Only about half of people with TB receive successful treatment each year. As the global threat of antimicrobial resistance continues to escalate, so do cases of drug-resistant TB, or TB that is resistant to various antibiotics that constitute standard treatment regimens.

In response, the National Academies of Sciences, Engineering, and Medicine's Forum on Microbial Threats held a two-part virtual workshop on July 22 and September 14-16, 2021 titled Innovations for Tackling Tuberculosis in the Time of COVID-19. The aims of the workshop were to evaluate the current status of TB elimination, assess the effects of the COVID-19 pandemic on the global fight against TB, and examine technical and strategic innovations that could be leveraged to meet the United Nations High-Level Meeting on Tuberculosis targets in 2022 and The World Health Organization's END TB Strategy targets by 2030. This publication summarizes the presentations and discussions of the workshop.

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