2

Current Tools and Challenges

Part 1 of the workshop series, which focused on current tools and challenges related to tackling tuberculosis during the COVID-19 pandemic, was moderated by Kenneth Castro, professor of global health, epidemiology, and infectious diseases at Emory University, and Gail Cassell, senior lecturer on global health and social medicine at Harvard Medical School. The workshop featured three opening addresses on the current status and urgency of ending TB around the world. Jim Yong Kim, vice president and partner at Global Infrastructure Partners, highlighted the critical role of leadership and the value of strong community-based public health systems. Salmaan Keshavjee, director of the Harvard Medical School Center for Global Health Delivery and chair of the Steering Committee of the Zero TB Initiative, discussed progress toward global TB elimination and presented a comprehensive epidemic control strategy with potential to bolster those efforts. Eric Rubin, editor-in-chief of the New England Journal of Medicine, focused on innovations and translatable lessons from the COVID-19 pandemic regarding diagnostics, therapeutics, and vaccines for TB.

The subsequent session explored challenges and innovations in efforts to eliminate TB. Soumya Swaminathan, chief scientist of the World Health Organization (WHO), described new technologies and remaining gaps in TB diagnostics. Emilio Emini, director of the human immunodeficiency virus (HIV) and TB program at the Bill and Melinda Gates Foundation (BMGF),¹

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¹ Since the time of the workshop in July 2021, Emini transitioned to a new role as the chief executive officer at the Bill & Melinda Gates Medical Research Institute.

explored challenges and opportunities in developing improved TB therapeutics and vaccines. Kevin Outterson, co-director of the Boston University Health Law Program and the founding executive director of the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X),² delved into the collective social value of infectious disease interventions.

LEADERSHIP FROM PUBLIC HEALTH WORKERS IN ENDING TUBERCULOSIS—PAST AND PRESENT

Presented by Jim Yong Kim, Global Infrastructure Partners

Kim opened by describing the value of strong community-based public health systems and the critical role of leadership in driving efforts to eliminate TB. To reflect on ways the approach to TB specifically—and to global health more broadly—have both changed and remained constant over the past 2 decades, he began by recounting his experience working in Peru with Partners In Health in the 1990s.³ His team identified 50 cases of multi-drug resistant (MDR) TB in a squatters’ settlement, and proposed to the country’s National TB Program that those people should be treated, both for the patients’ direct benefit and to halt future transmission to other members of the community. Kim’s team was surprised to encounter strong opposition from both the National TB Program leader and from WHO. At the time, Kim said, WHO was actively discouraging the treatment of MDR TB in developing countries owing to concerns that it would draw attention away from the standard, “directly observed treatment, short-course” (DOTS) program,⁴ which had been a transformative innovation in TB control (Partners In Health, 2006). Kim and his team eventually persuaded the National TB Program to explore the potential benefits of treating people with MDR TB, and WHO has since changed its policy. However, the team later faced similar resistance when advocating to the global health community for the treatment of HIV infections in some low- and middle-income countries (LMICs) in Africa, which was presumed to be infeasible to implement. That barrier was also surmounted, and today more than 20 million people are receiving HIV treatment in LMICs in Africa.

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² For more information on CARB-X, visit https://carb-x.org (accessed August 18 2021).

³ More information about Partners in Health is available at https://www.pih.org (accessed December 15, 2021).

⁴ Directly observed treatment, short-course (DOTS) is an approach to managing TB whereby patients consume their doses of antituberculosis drugs under the supervision of a health care worker to ensure that the patient receives the appropriate medication at the right doses and intervals (Otu, 2013). WHO began promoting the DOTS approach in 1993, after the declaration of TB as a global health emergency, and it has had broad uptake worldwide.

This pattern of resistance has continued to the present day, Kim noted. When COVID-19 began to spread in early 2020, he was told by leaders in the U.S. public health community that it was “too late or too complicated” to conduct widespread contact tracing and stop the spread in the United States; others recommended waiting for herd immunity to develop. Kim countered that view by highlighting the substantial pandemic-related economic loss due to COVID-19, estimated at $16 trillion by Cutler and Summers (2020), with $7.6 trillion in lost economic output. Cutler and Summers contended that those potential losses serve as reasonable justification for spending $100 billion per year to build U.S. public health system capacities, including testing and contact-tracing systems. Kim reaffirmed that mitigating MDR TB will require vaccines, therapeutics, and diagnostics. Further, he said that a solid public health foundation is a critical element of the task. Those in the TB community have a wealth of experience in building that ground game, Kim said, and he encouraged them to take central leadership roles in establishing public health systems that can stop TB, COVID-19, and other infectious disease threats yet to come. Kim posited that the COVID-19 pandemic will catalyze more funding support to counter a range of infectious diseases, but that “leaders in the community must put forth a brilliant, compelling, integrated vision of what these new public health systems will look like” in order to optimize these resources.

Cassell asked how development banks might help accomplish that goal. Kim replied that his former colleagues at the World Bank are eager to support countries that are seeking to develop public health systems that are fully equipped for a range of infectious and noninfectious health threats. Development banks are looking for models of more horizontal health systems—such as programs delivered by community health workers (CHWs)—that are broader in scope and could therefore have a higher return on investment than vertical programs (e.g., TB-only projects). He emphasized that the TB community is uniquely qualified to lead in these horizontal programs by drawing upon decades of experience in implementing components of DOTS that could be applied to other efforts: finding cases, investigating contacts, promoting treatment adherence, and implementing infection control and prevention measures. For example, Kim noted, Partners in Health developed a program in Massachusetts to highlight the host of benefits of CHW engagement that evolved from early contact-tracing efforts:

• Close proximity to and relationships with community members, which contributed to the success of various health care interventions (e.g., supporting patients in isolation, conducting vaccination outreach, delivering treatments);
• Increased ability to reach isolated communities;

• Horizontal integration of multiple disease programs to appeal to global funders; and
• Economic stimulus to enable individuals who might otherwise be unemployed during a disease outbreak to remain in the workforce, with their salaries returned to the local economy through spending.

Cassell relayed a question about the relationship between metrics to assess global health preparedness and the access and sustainability of financing for such efforts. Kim highlighted the fundamental role of leadership in ensuring the success of multilateral systems and noted that the bottleneck to be addressed is not a lack of money—as evidenced by the economic stimulus measures taken by the United States and other countries—but the lack of alignment and agreement across the leadership of the multilateral organizations. Discord among leaders or a change in leadership can render current systems—including metrics—and available funding both irrelevant and ineffectual. Thus, the challenge is to use the attention and new sources of capital associated with the COVID-19 pandemic to build better systems, including metrics, and establish strong baseline capacities that are resilient to changes in leadership.

PROGRESS TOWARD GLOBAL TUBERCULOSIS ELIMINATION GOALS AND OPPORTUNITIES FOR MOVING FORWARD

Presented by Salmaan Keshavjee, Harvard Medical School

Keshavjee discussed the status of efforts to eliminate TB in the time of COVID-19 and opportunities to move those efforts forward. According to WHO’s Global Tuberculosis Reports for 2019 and 2020, roughly 10 million people became ill and were diagnosed with TB each year, but there were an estimated additional 3 million undiagnosed or unreported TB cases. Although TB has been curable since the 1940s, only 56 percent of total TB treatments in 2019 and 2020 were successful, and an estimated 1.5 million people died from TB in each of those years—including more than 250,000 people living with HIV annually. Around the world, about 500,000 new people fell ill in 2019 and 2020 with drug-resistant (DR) TB, only one in three had access to treatment, and only one in five were cured (WHO, 2019, 2020).

Keshavjee provided an overview of progress toward global TB elimination targets set forth by WHO and the United Nations High-Level Meeting (UNHLM) on Tuberculosis (UN, 2018) to emphasize that the TB community fell dramatically short of reaching the End TB Strategy goals for 2015–2020 and that efforts were insufficient to meet the UNHLM goals for 2018–2020 (Box 2-1). This glacial pace of progress over the past decade extends across epidemiological trends for both drug-sensitive (or drug-susceptible, DS)

TB and DR TB, he noted. One of the goals set by the End TB Strategy is to achieve a 20 percent reduction in TB incidence between 2015 and 2020. Prior to the COVID-19 pandemic, only a 9 percent reduction in global TB incidence rate was reported. Between 2006 and 2016, the annualized incidence rate for DS TB and DR TB saw only small declines of 1.3 percent and 2.1 percent, respectively (Kyu et al., 2018). During the same period, the annualized incidence rate for extensively drug-resistant (XDR) TB increased by 7.9 percent. Moreover, 70 percent of the officers from Global Fund implementing countries reported a decrease in the number of TB patients receiving treatment during COVID-19, with 88 percent reporting a reduction of TB case notification (Stop TB Partnership, 2021). Even more worrisome, noted

Keshavjee, is that WHO has estimated that more people will develop the disease in 2021, creating the potential for 1.8 million deaths attributable to TB. Keshavjee emphasized that the current rate of treatment being delivered is low, particularly in high-burden countries.

Potential Pathway to the Elimination of Tuberculosis: Search-Treat-Prevent Strategy

Despite acknowledging these concerning trends and stagnated progress toward global TB control targets, Keshavjee was resolute in his belief that TB elimination is possible and can be achieved by implementing a comprehensive epidemic control strategy—“search-treat-prevent”—that has existed since the 1960s but has yet to be implemented on a global scale, particularly in high-burden LMICs. Beyond addressing the global burden of TB, the strategy could also serve as a platform for controlling other infectious disease threats such as COVID-19. Knowledge and practice of each component in the search-treat-prevent strategy date back to the beginning and middle of the twentieth century, said Keshavjee. He explained how each component of the three-pronged strategy can be applied to TB control.

The first prong is to search for people with TB infection and disease through active case finding around small numbers of cases or community screening in epidemic settings. It has been established since the early twentieth century that early case detection leads to lower mortality, even before TB treatments were available (Golub et al., 2005). Today, active case finding using a sensitive diagnostic remains a critical tool for finding active cases and stopping transmission of TB. Keshavjee noted that mobile X-ray has been the primary diagnostic modality since the last century. Today, a range of other diagnostic tools is available including artificial intelligence (AI)-supported X-ray screening, culture testing, and rapid molecular testing tools to confirm TB infection, disease, and drug susceptibility. However, these tools are not being deployed everywhere they could be, and they are often entirely unavailable in high-burden TB countries, thus contributing to the lack of progress in driving down TB rates worldwide, Keshavjee added.

The second prong is to treat TB disease by administering the correct medicines with the fewest side effects over the shortest possible treatment period. As the global TB statistics demonstrate, the TB control community has fallen significantly short of treating the numbers of TB patients needed to stop community transmission of the disease and avert death and suffering. However, one opportunity to address this treatment gap is the availability of new drug regimens that are less burdensome to patients—such as short-course DS TB regimens that reduce treatment time from 6 to 4 months and all-oral DR TB regimens. The provision of patient supports, such as food

and cash transfers and other economics-based behavior innovations, can also encourage treatment completion.

The third prong aims to prevent infections from turning into active disease as well as stop the transmission of TB infections. One preventive approach to infection and transmission control that has long been discussed for TB, but has recently risen to prominence during the COVID-19 pandemic, involves the use of respirators, ventilation, and upper-room ultraviolet germicidal lighting. However, these have been difficult to roll out in resource-limited settings because of a lack of focus on implementing engineering controls for preventing TB transmission in congregate settings.

It has been established since the 1950s that active case finding, treatment of all forms of TB disease, and treatment of TB infection using isoniazid prophylaxis could virtually eliminate household and community TB transmission (Kaplan et al., 1972). Between 5 and 10 percent of individuals infected will develop TB disease during their lifetime; of these, about 50 percent will develop TB within 2 years of infection (CDC, 2014). Thus, based on current TB incidence statistics, tens of million contacts should receive prophylactic treatment each year worldwide. He acknowledged that this number may seem daunting, but pointed out that it is logistically feasible to reach and treat the close contacts of patients who are already receiving treatment for active TB. He added that the conceptualization of latent versus clinically active TB is a false binary (Cadena et al., 2016); rather, there is a continuum between infection and disease. “Sometimes people that don’t really appear to have clinically active disease are actually shedding bugs,” he said. Keshavjee highlighted new tools and opportunities that have recently emerged or been expanded in the prevention domain, such as new short-course preventive treatment regimens for DS TB (e.g., 1 month of isoniazid or rifapentine, or 3 months of once weekly isoniazid and rifapentine) and new treatment regimens for MDR and XDR TB (e.g., bedaquiline, ongoing clinical trial using levofloxacin). Opportunities also exist to use existing treatment regimens to increase coverage of preventive therapy, he added.

The search-treat-prevent strategy has been effectively applied to accelerate TB elimination in settings around the world since the 1950s, notably in Alaska and New York City in the United States; Tomsk, the Russian Federation; and Karachi, Pakistan (Keshavjee et al., 2008). Keshavjee called for renewed commitment to build on those past success in designing and implementing TB elimination initiatives that are comprehensive, simultaneous, and based on efficacious tools and strategies as the standard of care for TB. Moreover, he suggested that donor countries insist that global development funders support programs that are comprehensive and designed to meet global TB elimination targets, rather than fund programs that do not perform to their optimal potential despite continued investment.

Building a Versatile Platform for Community-Based Care Delivery

Keshavjee explained how a community-based TB care delivery platform could evolve into a platform that supports the treatment and prevention of a wide range of diseases—including endemic infectious diseases, noncommunicable diseases (e.g., diabetes, heart disease, and mental illness), and emerging infectious diseases such as COVID-19—by extending the capabilities and deepening the reach of clinics into communities. He added that the present moment offers an opportunity to shift the global TB control paradigm in a way that will strengthen global biosecurity. Establishing comprehensive TB control systems is synergistic with efforts to bolster global biosecurity and pandemic preparedness because the capacities required for TB control are broadly applicable to many different biosecurity-related health care priorities. However, catalytic investment through global funding mechanisms and bilateral programs is needed to support communities and programs in implementing the comprehensive search-treat-prevent strategy worldwide.

Keshavjee laid out a research agenda to improve this strategy, including the development of faster point-of-care (POC) tests, more effective vaccines for different indications, and immunomodulators to complement the antibiotics arsenal. He entreated the TB community to build more than just a TB program and aim for a community-based platform for better overall health care delivery. Keshavjee ended by showing how being able to diagnose and treat diseases is not only good for TB and a number of other infectious and noninfectious diseases but is also an important frame for biosecurity, as we have seen recently with COVID-19.

CHALLENGES AND INNOVATIONS

Presented by Eric Rubin, New England Journal of Medicine

Innovations and Translatable Lessons for TB Control from the COVID-19 Pandemic

Rubin highlighted innovations and translatable lessons from the COVID-19 pandemic that are applicable to diagnostics, therapeutics, and vaccines for TB.

Diagnostics

A major advance in diagnostics has been the scale-up and widespread implementation of polymerase chain reaction (PCR)-based testing during the COVID-19 pandemic, which holds promise for the application of simi-

lar technologies to pulmonary TB and perhaps other TB syndromes. Other innovative new technologies have been developed, such as rapid, cheap, POC diagnostics (Joung et al., 2020). However, implementation rates have been low for new tools such as rapid antigen-based testing, for example, and a POC PCR test has yet to be developed.

Therapeutics

Rubin noted the relative lack of progress during the COVID-19 pandemic in the domain of therapeutics, which has been largely caused by the lengthy therapeutic development timeline and the small existing pipeline for coronaviruses. Although there has been some success in developing glucocorticoids and other anti-inflammatory agents—and some modestly effective antivirals—no truly new agents have been developed and there have been no dramatic successes. Of the more than 200 clinical trials listed for COVID-19 therapeutics at the time of the workshop, many of them had been withdrawn, had repetitive trial designs, or had small sample sizes unlikely to yield useful results. These issues underscore the importance of coordination and thoughtfulness in the clinical trials enterprise to avoid redundancy and improve efficiency, especially for expensive and lengthy trials conducted across multiple groups. In the context of TB therapeutics, Rubin highlighted the need to maintain the drug development pipeline—which is already more robust for TB than it is for coronaviruses—and to continue designing and conducting cost-efficient clinical trials in the face of limited funding.

Vaccines

Rubin commended the unprecedentedly swift advances in the vaccine domain seen during the COVID-19 pandemic, from the rapid development and deployment of vaccines to extensive real-world safety testing for vaccine delivery methods. These efforts were bolstered by large randomized controlled trials conducted quickly while maintaining high quality (Polack et al., 2020; Tait et al., 2019). He noted that the success and widespread use of new technologies, such as messenger RNA (mRNA) and adenovirus vector vaccines, have broadened opportunities to rapidly test new antigens with less dependence on expensive and scarce adjuvants. However, he noted that the global case incidence for TB tends to be lower than case incidence for COVID-19, as the latter is in the midst of global outbreak. This disparity in case numbers contributes to a smaller effect size and complicates the conduct of vaccine trials. Rubin added that the identification of biomarkers that correlate with protection remain a critical knowledge gap in both TB and COVID-19 research. Without biomarkers or new and persuasive models, there are few available tools to assist with accelerating progress for large phase 3 trials.

NEW TECHNOLOGIES AND REMAINING GAPS IN TUBERCULOSIS DIAGNOSTICS

Presented by Soumya Swaminathan, World Health Organization

Swaminathan presented on new technologies and remaining gaps in TB diagnostics. She predicted that one long-term effect of COVID-19 is a likely increase in unreported and untreated cases of TB and other diseases for years to come. Modeling estimates suggest that 1.4 million fewer people received TB care in 2020 compared to 2019, with a 21 percent relative shortfall in TB case notifications during that period—giving rise to the potential for 500,000 additional TB deaths as a result (WHO, 2021b). The effect on the pediatric TB population is likely to be even greater, given the challenges associated with TB diagnosis in children such as children’s difficulty producing sputum, their higher rates of extrapulmonary forms and disseminated forms of TB, and the lack of non–symptom-based sensitive and specific diagnostic tests. However, Swaminathan also noted that many countries have already begun to revitalize their TB programs, in some cases through conducting joint TB and COVID-19 response activities.

Innovations in Sample Types and Collection Methods

Swaminathan described a range of innovations in sample types and collection methods for POC or self-administered tests that have been developed for COVID-19 and could potentially be used for TB (Ruhwald et al., 2021). These include improvements in polyester swabs and new sampling protocols that use mouthwashes, oral swabs, or absorbent strips in facemasks. The use of easy-to-obtain samples, such as saliva, could transform TB and COVID-19 diagnosis by improving access to decentralized testing with drive-through facilities, mobile testing sites, community health workers, pharmacies, schools, and workplaces. Pharmacy-available, single-use self-testing kits also hold promise as rapid diagnostic tools, she added.

Innovations in Point-of-Care and Molecular Diagnostics

In the realm of POC diagnostics, Swaminathan highlighted several biomarker-based tests that use emerging technologies and that are currently under clinical evaluation and review, including the second-generation lateral flow lipoarabinomannan assay using urine samples. These tests have performed promisingly for people living with HIV/AIDS and may have potential to be expanded as a POC test for all forms of pulmonary TB. WHO plans to convene a Guideline Development Group in 2022 to review the clinical evidence for these tests (WHO, 2020). Swaminathan added

that many countries have now scaled up their capacities to run molecular tests by using the foundations of existing TB and HIV programs, which had already centralized multidisease molecular platforms (e.g., HIV viral load assays) and could be further expanded to meet greater demand (Venkatesan, 2020). Several countries have used automated, cartridge-based molecular technologies, such as GeneXpert and TrueNAT, for both TB and COVID-19. However, such multidisease diagnostic platforms could be more robust, used more broadly in family health centers, and expanded in multiplex capabilities in order to achieve better cost and efficiency, said Swaminathan. She also noted that the broader use of molecular technologies and bidirectional testing would benefit TB diagnosis and reduce the reliance on suboptimal tools, such as smear microscopy (MacLean et al., 2020). It will not be possible to achieve TB elimination goals without more robust diagnostic tests, she warned.

Innovation in Digital Tools and Artificial Intelligence

Swaminathan remarked that the development of digital tools and AI have also accelerated during the COVID-19 pandemic (Budd et al., 2020). For example, digital solutions deployed for the mass dissemination of COVID-19 information such as smartphone apps and chat bots for education, risk communication, referrals, and contact tracing could be repurposed for TB to promote patient-centered care. Innovations in the application of AI to COVID-19 diagnostics, such as cough analyzers, digital stethoscopes, and automated X-ray interpretation—which had already been used for TB but saw expanded use during the pandemic—could be used for high-throughput screening and integrated testing for both TB and COVID-19, particularly if combined with portable X-ray units.

Innovations in Genomic Sequencing and Data Sharing

The capacity to rapidly collect and analyze large volumes of genomic sequencing data that was expanded and used during the COVID-19 pandemic could augment efforts to combat TB, noted Swaminathan. She remarked that the COVID-19 pandemic occurred during the digital era with the availability of real-time data sharing, large platforms, and user AI application analysis that enable rapid updates of data visualizations to inform public communications and direct the public health response. However, “TB still remains an analog disease, unfortunately, relying on paper-based systems and annual summary reporting. We really have to move away from that paradigm,” she urged.

The knowledge gap around the genetic sequence-based detection of drug resistance to antibiotics (other than rifampicin) is widening, cautioned

Swaminathan. To address this gap, WHO has an ongoing effort to collaborate with global partners and countries worldwide to maintain a catalog of more than 17,000 mutations coming from a database with 38,000 isolates, with data on both whole genome sequencing and phenotypic drug susceptibility testing for 13 anti-TB drugs from 40 countries (WHO, 2021a). WHO is also planning to convene a Guideline Development Group for next-generation sequencing for TB in 2022 (WHO, 2020). The advances in genetic sequencing seen during the COVID-19 pandemic could be a major boon to TB diagnostics, she added. For instance, coupling data from next-generation sequencing to drug resistance would allow for the most relevant mutations for each drug to be identified and for future molecular tests to provide updated susceptibility information at the time of diagnosis.

In comparison, researchers have amassed nearly 2.5 million whole genome sequences for SARS-CoV-2 in the 2 years since the onset of the COVID-19 pandemic. COVID-19 variants have engendered renewed interest and investment in enhancing sequencing capacities in many countries. Such investments in robust data systems and data integration will benefit control efforts for TB as well as many other diseases, she added. Swaminathan suggested that WHO should take a central role in convening stakeholders to design data-sharing platforms for TB and other diseases that are similar to the database for COVID-19, which currently contains data from more than 350,000 individual patients from more than 60 countries. However, the dynamic and collaborative nature of this multilateral data platform will need to be balanced by safeguarding the confidence and interests of researchers from the Global South, she said.

Summary of Innovations

Swaminathan categorized emerging innovations from the COVID-19 pandemic into three major new domains: POC biomarkers in rapid diagnostic tests, multidisease platforms, and next-generation whole genome sequencing. She framed these efforts as being part of pandemic planning, preparedness, and coverage, thus warranting a focus on developing multidisease, multiplatform technologies and databases with crosscutting coverage across diseases. She pointed to the Access to COVID-19 Tools Accelerator (ACT-A) as an example of the progress that can be accomplished when multilateral stakeholders come together with a singular focus on addressing a disease.⁵ Swaminathan concluded by reiterating key challenges and opportunities in advancing TB diagnostics (see Box 2-2).

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⁵ To learn more about the ACT-A, visit https://www.who.int/initiatives/act-accelerator (accessed August 18, 2021).

IMPROVING TREATMENT REGIMENS AND VACCINE DEVELOPMENT

Presented by Emilio Emini, Bill & Melinda Gates Foundation

Emini explored challenges and opportunities related to developing and improving TB therapeutics and vaccines. He cautioned that TB would return to being the largest cause of infectious disease mortality worldwide after the COVID-19 pandemic is brought under control. The response to COVID-19 has illustrated the value of political commitment, global coordination, and robust funding in addressing infectious disease challenges. Although TB is difficult to address in many respects, Emini noted that the technical and scientific infrastructure for improved and effective versions of TB therapies and vaccines already exist. However, they must continue into the later phases of development, which will require—at minimum—the same level of global engagement and funding that supported the COVID-19 response.

Therapeutic Regimens

Emini explained that the rationale for developing new therapeutic regimens is to help reduce two gaps in the TB care cascade: the gap between

diagnosis and treatment initiation, and the gap between treatment regimen completion and nonrelapsing cure. The current standard of care for TB treatment is too lengthy (i.e., 6 months, which contributes to loss to followup) and too toxic (associated with hepatitis, neuropathy, eye toxicity, skin reaction, and joint pain). It also has too many drug interactions, chief among them being with hormonal contraceptives and antiretroviral agents used to treat people living with HIV, who are particularly at risk of developing and dying from active TB. Consequently, the number of cured cases of DS TB has remained relatively stagnant over the past 5 years (WHO, 2020). During the same period, greater progress has been achieved in treating DR TB and MDR TB; this is attributable to rapid developments in the treatment for MDR TB, but these drug regimens are still too long and too toxic, he added.

Optimal Target Regimen Profile

Emini presented the optimal target regimen profile developed by BMGF to guide the development of new therapeutic regimens for TB. The criteria include:

1. Project to Accelerate New Treatments for Tuberculosis (Pan-TB): no requirement for drug sensitivity testing, ideally fewer patients lost to follow-up after diagnosis
2. Short: 3 months or less to achieve nonrelapsing cure, allowing for improved adherence, improved outcomes, and reduced transmission
3. Safe: minimal side effects to eliminate the need for baseline or ongoing safety monitoring and improve adherence
4. Simple: fully oral instead of injectable regimens, daily administration without drug–drug interactions to manage
5. Efficacy: noninferior to standard of care, minimizing gap between efficacy and effectiveness
6. Affordable: reducing financial barriers to uptake

Emini acknowledged that although this optimal target regimen profile is aspirational, some notable strides have been made toward achieving it. Several studies have already investigated whether various novel combinations of existing TB drugs could be noninferior to the current standard 6-month regimen in terms of treatment success over a shorter duration of time. Notably, the Tuberculosis Trials Consortium Study 31/AIDS Clinical Trials Group A5349⁶ (TBTC Study 31/A5349) recently demonstrated noninferiority in

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⁶ For more information on Tuberculosis Trials Consortium Study 31/AIDS Clinical Trials Group A5349, see https://clinicaltrials.gov/ct2/show/NCT02410772 (accessed December 15, 2021).

treating DS TB using combinations of isoniazid, rifapentine, moxifloxacin, and pyrazinamide over a 4-month course.⁷ This study demonstrates that shorter treatment regimens are achievable with the appropriate selection of drugs. However, Emini noted that the challenge going forward is determining which novel drugs or combination of drugs under development will fulfill other criteria of the optimal target regimen profile—particularly tolerability and ease of use—without requiring continuous clinical and drug monitoring.

Global Pipeline for New Tuberculosis Drugs

Emini noted that the Stop TB Partnership’s Working Group on New TB Drugs has been tracking the global pipeline for new tuberculosis drugs,⁸ which is extensive as of 2021, even without including the large number of drugs in the discovery phase. Many of these new drugs have emerged from large research collaborations between academic institutions and biopharmaceutical companies, such as the TB Drug Accelerator, the European Regimen Accelerator for Tuberculosis (ERA4TB) collaborative from the Innovative Medicines Initiative, and the recently established Project to Accelerate New Treatments for TB (PAN-TB) collaboration.^9,10 For example, the PAN-TB collaboration is bringing novel and potentially promising combinations of TB drugs into phase 2b clinical studies to assess and prioritize these candidates based on the optimal target regimen profile. However, a challenge on the horizon for these efforts will be garnering funding for the exponentially higher cost of large, extensive phase 3 trials needed to yield meaningful and actionable outcomes, he noted.

Vaccines

New vaccines are required to accelerate progress toward eliminating TB, said Emini. He noted that WHO’s long-standing priority targets for TB vaccines include (1) preventing TB disease or infection in children and adults through vaccines that protect from TB by preventing infection or development of active disease, (2) preventing disease in neonates and infants through vaccines with a safety and efficacy profile comparable with Bacillus Calmette-Guérin (BCG) that protect against all forms of TB, and (3) protec-

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⁷ This is a recently completed clinical trial led by the Tuberculosis Trials Consortium at the U.S. CDC, with collaboration from the AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases. See CDC, 2020, and https://clinicaltrials.gov/ct2/show/NCT02410772 (accessed August 18, 2021).

⁸ See https://www.newtbdrugs.org/pipeline/clinical (accessed August 18, 2021).

⁹ For the TB Drug Accelerator Program from Global Health Progress, see https://globalhealthprogress.org/collaboration/tb-drug-accelerator-program (accessed August 18, 2021).

¹⁰ For the IMI European Regimen Accelerator for Tuberculosis, see https://www.imi.europa.eu/projects-results/project-factsheets/era4tb (accessed August 18, 2021).

tion against TB recurrence following initial cure through therapeutic use of vaccines. Emini noted the particular lack of progress toward the second priority—developing a safe and efficacious vaccine for neonates and infants—and remarked that after a century of work in this area, BCG remains the only approved TB vaccine. There are currently a number of candidate TB vaccines in the global clinical pipeline, including some using an mRNA platform, that are in preclinical development and at various stages of clinical trials. Like the development of new treatment regimens, however, TB vaccine development also requires significant sources of funding for large and expensive phase 3 trials. Emini emphasized the significant funding challenges associated with advancing any vaccine candidate into a 20,000-participant phase 3 study: the chemistry, manufacturing, and control process development for the vaccine; epidemiology and capacity studies to identify critical trial sites with a high incidence of TB; and capacity building to support the study.

Emini highlighted two promising vaccine study candidates: BCG revaccination and the M72/AS01_E vaccine. The potential efficacy of BCG revaccination was discovered unexpectedly when a statistically significant 50 percent decline in a signal for TB infection was observed in a control group that had essentially received a BCG revaccination during an unrelated study in 2018.¹¹ A second, larger study was initiated to determine if these results could be replicated,¹² which could lead to a major policy change for BCG use, he noted. M72/AS01_E is a subunit vaccine that consists of M72—a fusion protein of two potential immunological targets from the pathogen—and the proprietary adjuvant AS01_E.¹³ He noted that phase 2 trial results demonstrated an efficacy of only about 50 percent, but that level of efficacy could still have a substantial effect on TB epidemiology, particularly in high-burden settings.¹⁴

COLLECTIVE SOCIAL VALUE OF INFECTIOUS DISEASE INTERVENTIONS

Presented by Kevin Outterson, Boston University School of Law and CARB-X

Outterson explored the collective social value of infectious disease interventions. He discussed policy and economic considerations for building new

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¹¹ For more information on the BCG revaccination study, see https://clinicaltrials.gov/ct2/show/NCT04152161 (accessed August 18, 2021).

¹² This study was still in progress at the time of the workshop.

¹³ AS01_E is approved for use as part of the Shingrix vaccine. For more information on the M72 vaccine trial, see Tait et al., 2019.

¹⁴ There are conflicting views associated with revaccination. For additional perspectives, see Ahmed et al., 2021.

antibiotic development business models and identified potential translatable lessons for ongoing TB efforts.

Many organizations, funding streams, government agencies, and scientific communities associated with infectious diseases are separated by strong disciplinary boundaries drawn around diseases of focus. As a consequence, the disparate funding streams for efforts around antimicrobial resistance, TB, HIV, and other areas “becomes something of a zero-sum game in which we compete,” he said. However, these groups could derive mutual benefit by learning from and sharing common experiences among each other, he added.

Broadening the Definition of Value for the Cooperative Production of Public Goods

It can be challenging for models for the cooperative production of public goods—such as treatments and interventions for infectious disease outbreak preparedness and response—to adopt a strategic perspective, noted Outterson. To address this issue, he suggested an alternative approach of adopting a broader view in defining the value of these antimicrobial interventions. For example, CARB-X encourages the framing of antibiotics as a “safety net” that enables modern medicine and creates a favorable risk–benefit calculus for common medical procedures such as cesarean sections and knee replacements, and cancer treatments. As with anti-TB interventions, it is difficult to quantify the value of effective antibiotics in an individual patient even though, as reported in a forthcoming study, infection is the second leading cause of death for people with cancer.

To elucidate the challenge of funding antimicrobial interventions, Outterson outlined five benefits gleaned from the health economics literature about the population-level benefits of effective antimicrobial therapy:

1. Spectrum—using narrow-spectrum antibiotics to reduce collateral damage to the microbiome, and broad-spectrum antibiotics to allow for interventions even when the diagnosis is not complete
2. Transmission—avoiding pathogen spread by treating patients effectively
3. Enablement—making other medical interventions possible (e.g., surgery)
4. Diversity—using a range of treatment options to reduce drug-resistance selection pressures
5. Insurance—having a backup in the event of a new, sudden, or significant increase in drug resistance

From a funding perspective, each of these benefits is associated with billions or even trillions of dollars’ worth of population- or social-level value,

and it is difficult for the current market to reimburse the researchers for those forms of value, said Outterson. In the antimicrobial space, the result is that traditional market pricing mechanisms do not appropriately incentivize novel antimicrobial development, thus undermining the entire sector. For example, 7 of 18 new antimicrobials approved by the U.S. Food and Drug Administration (FDA) since 2010 have been either associated with bankruptcy or withdrawn from marketing applications in Europe, generally owing to the pharmaceutical companies’ position that the forecasted profit margins in Europe do not justify the costs of a second market authorization. To provide context with the sales of other pharmaceutical products, Outterson shared that the annual U.S. sales for all branded antibacterials approved by FDA since 2010 total around $720 million in the United States, which is less than the U.S. annual revenue generated by the most profitable single oncology drug.¹⁵

Building New Therapeutic Development Business Models to Catalyze Development

In the face of this economic problem, the antimicrobial industry has been considering changing its business models in ways that could potentially benefit the TB community, said Outterson. Major funding organizations typically support either basic research coupled with early discovery or late-stage clinical development; CARB-X has tried to bridge that binary divide. He acknowledged that the TB drug development effort has the advantages of more coordinated pipelines and strategically set target product profiles to guide development, but there is an opportunity to work collaboratively across funding and research silos and reward the development of antimicrobials—including TB drugs—based on their social value. He suggested making such an argument by encouraging resource allocation based on clinical baseline needs and strategic planning between outbreaks, rather than allocating resources during emergencies to combat microbial threats when they arise. Rather than competing for funding streams, experts from different disciplines of microbial threats could be encouraged to discuss their common needs and the broader social values of innovation.

Outterson also suggested that governments could finance antimicrobial innovation through a “subscription” business model, whereby an established amount of government funding is steadily available to drug developers regardless of the actual market demand for new antibiotics. In addition to increasing financial incentives for companies, this would help to maintain a robust research, development, and manufacturing ecosystem capable of supporting supply chain redundancies and remaining resilient to perturbations in market demand.

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¹⁵ The recently published article found sales to be $714.3 million in the U.S. for branded, on-patent antibacterials. See Outterson et al. (2022).

Outterson concluded by connecting the new Advanced Research Projects Agency for Health (ARPA-H) to his call for collaboration, suggesting that it could serve as a platform for sharing practical experiences—for example, regarding how to operate at scale effectively or prioritize candidates within a pipeline. He noted that ARPA-H is likely to receive roughly $3 billion dollars in appropriations from Congress to fund health product development through a model similar to the Defense Advanced Research Projects Agency’s model for funding technical and engineering innovation. He noted that efforts to break down silos between infectious disease disciplines will help to capitalize on future opportunities.

DISCUSSION

Considerations in Improving Diagnostic Capacities

Castro asked about the feasibility and potential level of support from WHO and the global community for replacing rapid PCR test kits for COVID-19 with a multiplexed version capable of testing for both COVID-19 and TB. This approach could enable widespread screening of patients with respiratory symptoms, while potentially helping to recover funding and renew case-finding efforts in TB-endemic areas, he suggested. Rubin replied that it might be possible to repurpose the COVID-19 rapid tests to include TB, but it would require dealing with technical issues related to specimen preparation for TB testing. Specifically, it would be challenging to reconcile sample processing for the two diseases in the same test kit, given that the current standard diagnostic specimen type is sputum for TB and nasal swab or saliva sample for COVID-19. Castro then asked about the status of commercializing a nonsputum POC test for TB. Emini said that it may be feasible to couple PCR testing for COVID-19 and TB using oral samples—bypassing the sputum-processing issue—but further major challenges would arise in breaching the organisms’ structures to access their genomes because the causative agents for TB and COVID-19 are very different. He noted that the evidence base and diagnostic algorithms for detecting the presence of bacteria or volatile biomarkers in exhaled breath samples are under development, but those tests are not yet close to clinical application.

Keshavjee responded to a comment about the 2012 buy-down agreement, which was intended to improve countries’ access to the tests and spur market demand. However, it unintentionally decoupled price determination from production volume,¹⁶ which required negotiating the price of the new

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¹⁶ For an analysis of the buy-down, see Branigan (2020).

GeneXpert cartridges down to $5 per test.¹⁷ Keshavjee explained that this resulted in limited uptake of the GeneXpert test, which precluded widespread community screening and heightened the reliance on smear microscopy for diagnosing TB, though it has lower sensitivity (WHO, 2011). Community screening conducted through AI-aided X-ray screening, which would cost less than $1 per person, followed by a confirmatory genetic test (e.g., GeneXpert, TrueNAT) could be a more diagnostically accurate and cost-effective strategy, he added. An economically priced diagnostic test would make the expansion of large-scale community diagnostic testing capacity feasible.

Economic Considerations and Implications for Program Design

Rubin asked whether price is generally a driving factor in front-end development or a later consideration once a product reaches market. Emini replied that although price is often considered up front, it is affected by multiple variables—chiefly, volume and competition. He offered the example of a buy-down, in which negotiation can modulate the volume of goods, but in the absence of competition, a single supplier would still control the price. The BMGF led a buy-down initiative for HIV self-testing in a number of African countries, where a system was built to introduce competition into the market. Consequently, the initial buy-down helped to lower product prices early on and to generate data showing the effect of HIV self-testing, while competition between multiple suppliers kept prices low over time.

While price-control systems hold promise, a concern is that prices for new TB drug combination regimens may not be able to compete with the low cost of the classic combination treatment of isoniazid, rifampicin, and pyrazinamide, Emini cautioned. He reiterated that a major challenge in improving TB treatment outcomes is finding a way to balance the price that the market will bear with the cost that society is asked to bear, which is an important prospective consideration for program and intervention development. Key questions include how the drugs will be used, who will pay for them, and what balance is optimal from both the societal and market perspectives, he added.

Outterson acknowledged Emini’s distinction between cost of goods and price, adding that the introduction of social value as a consideration further distinguishes that difference and, moreover, can shift a company’s focus from deriving revenue from market mechanisms to other reimbursements for its activities, including research and development (R&D). This concept, known

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¹⁷ Organizations involved in negotiating the 2012 buy-down agreement included the BMGF, the U.S. President’s Emergency Plan for AIDS Relief, the U.S. Agency for International Development, and Unitaid; see http://www.stoptb.org/wg/new_diagnostics/assets/documents/News_XpertPrice_21Aug12.pdf (accessed August 18, 2021).

as “delinkage,” is exemplified by the subscription-style funding model of the PASTEUR Act, which delinks a company’s reward from sales volume, unit sales, and unit price. Outterson pointed out that delinkage is not a market mechanism; instead, it recognizes that “the market doesn’t function to deliver social value when you’re doing it through individual transactions on individual patients, so it’s the difference between patient-level and population-level reimbursement.” He added that the interventions discussed at the workshop could be made broadly available at little to no cost to the public if there were a way to appropriately reward companies.

Outterson added that the ultimate cost of goods is a consideration early on in the preclinical development life cycle at CARB-X; the optimizations for cost structure and adaptive research into product characteristics (e.g., stability, shelf life) are initiated closer to clinical trials. This type of optimization work receives special funding from the UK government. In circumstances of limited competition—such as the period of market exclusivity for patent-protected drugs—CARB-X has had success in contractually mandating global stewardship and access principles at the start of funding, he added.¹⁸

Bridging Silos and Shifting Paradigms

Rubin observed that the TB control community appears divided into two camps: one focused on developing new tools and interventions, the other on implementing them. He noted that the path from development to implementation is not always fluid, pointing out that CARB-X and the BMGF have tried to approach this translational medicine challenge by envisioning the target characteristics and usability of the end product early on. Rubin also pointed out that while breakthroughs and innovations could transform current programs, many underused interventions and tools for TB elimination are available right now. He called for movement forward in both areas by improving the implementation of existing tools while also working to develop better tools for the future.

Paradigm Shift to Improve Implementation of Existing Tools

Keshavjee remarked upon opportunities to create large effects with small changes to current TB programs. To illustrate, he suggested the policy changes of (1) shifting to community-level screening combined with commitments to contact tracing for prophylaxis and (2) establishing a mechanism for coordinated, rapid clinical trial studies, similar to some of the efforts made during the COVID-19 pandemic.

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¹⁸ Outterson noted that this is a concept that CARB-X adapted from their funders, including the BMGF and the Wellcome Trust.

Castro inquired about institutional changes or implementation arrangements needed to effectively support the search-treat-prevent strategy. Keshavjee suggested that TB control programs could reconfigure their principles and operations to frame TB as a social disease, rather than a disease of individuals.

This reconfiguration could lead TB control programs to extend beyond providing DOTS therapy for positive cases to creating household screening systems, he said. Although the household screening model would require more staffing, testing resources, and medications, especially in resource-limited settings, Keshavjee maintained that this would facilitate a step toward expanding TB control programs into general health care delivery platforms equipped to address other common diseases (e.g., diabetes, hypertension). An additional benefit of this type of robust, on-the-ground health care system would be immediate increased capacity for uptake and deployment of new treatments, vaccines, or diagnostic tests. This could also contribute to fostering innovations by providing rollout assurances and market access, he added.

Castro asked if studies of human–systems interactions might be incorporated alongside platform development to improve the end-user experience, reduce waste, and improve efficiency and effectiveness. Keshavjee responded that any treatment model has a behavioral economics component. For example, the conditional cash transfers described by Kim have a twofold benefit: stimulating local economies and encouraging participation in public health efforts to eliminate disease. He acknowledged that these methods have not been used widely in controlling TB, but they represent an opportunity for programmatic improvement by taking community contexts into account. He suggested that each TB program should be asking, “How do you actually interact with [people] and the community in a way that people will want to get screened, and people will want to take treatments?”

Paradigm Shift to Articulate the Biosecurity and Social Values of Tuberculosis Elimination

Keshavjee made the case that the lack of community health care delivery capacity for diagnosis, screening, and treatment constitutes a biosecurity emergency. To address this issue, he suggested calling for funding agencies to support comprehensive health programs rather than tying their funding to specific diseases or activities. Related workshops and organizations might have a role in conveying this need to stakeholders. Keshavjee cited evidence from a colleague’s forthcoming study, which estimated that each missed (i.e., untreated) TB patient in India—assuming each person infects an additional 1.5 people annually over 5 years—costs the national economy $6,000. Cassell noted that such economic data can bolster compelling policy arguments for TB control.

Monique Mansoura, executive director of global health security and biotechnology at the MITRE Corporation, reflected on the cost of inaction for TB and potential competing health care needs in a community. She asked about the evidence base on the cost-effectiveness and synergistic outcomes associated with addressing TB and another prevalent disease (e.g., diabetes). Keshavjee shared two examples from TB programs that are also screening for diabetes and hypertension: the Resource Group for Advocacy and Community Health (REACH) in India and Advance Access & Delivery in Durban, South Africa.^19,20 Both programs have detected high rates of diabetes among people testing positive for TB in addition to significant rates of hypertension. Both conditions are generally easy and affordable to treat compared to TB, he noted, so it is relatively manageable for TB control field teams to take on treatment services for diabetes and hypertension in addition to their TB-related work. Keshavjee was hopeful that in the future, these programs would operate from unified funding streams, supply chains, and equipment for the treatment of many other health conditions that are currently disconnected.

Castro asked how to balance the competing needs for vertical programs and disease-specific objectives with broad, integrated health systems. He added that instead of viewing silos as structures to be dismantled, he sees them as centers of excellence that need to be connected. Outterson framed the social value of eliminating disease threats as the basis for integrated health systems and a bridge connecting different silos of expertise. For instance, the social value of elimination could be used to inform prioritization and balance objectives in funding decisions. He contrasted the rapid successes of the response to COVID-19, in which a large amount of capital was spent in a short period of time on a focused objective—possible, in part, because of the broadly perceived high value of elimination—with a hypothetical scenario in which that same level of effort and funding were spread out over a 20-year period. The latter case would be seen as a failure, but is actually similar to the approach taken for many other infectious diseases including TB. Outterson proposed that this type of health system strengthening could be thought of as broad-spectrum defenses against unknown or unknowable microbial threats. He remarked,

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¹⁹ More information about the REACH TB Network is available from https://www.reachtbnetwork.org (accessed December 15, 2021).

²⁰ More information about Advance Access & Delivery is available from http://www.advanceaccessanddelivery.org (accessed December 15, 2021).

Closing Remarks

In closing, Cassell entreated the audience and participants to work toward developing the goals laid out by Kim in the opening presentation. To illustrate the urgency of addressing TB, she offered the statistic that roughly 500,000 people fall ill with MDR TB every year, yet that number has not changed since the very first WHO report on MDR TB more than 20 years ago. In addition, this statistic is difficult to interpret given that the actual burden of TB was likely higher than reported. A previous workshop proceedings from the Institute of Medicine states that only one half of one percent of patients diagnosed with MDR TB were being treated (IOM, 2012). Given that TB is spread via aerosol, the actual number of MDR TB cases in 2022 is likely significantly higher. Cassell emphasized that determining the social value of ending TB is an important task that may require innovative economic research and policy making to be achieved.