Leadership and Planning for the Community of Public Health Workers and Partners in Ending TB—Past and Present

Jim Yong Kim, vice president and partner at Global Infrastructure Partners, focused on the value of strong community-based public health systems and the critical role of leadership. Kim illustrated these concepts by sharing his experience in Peru working with Partners In Health. He recounted the resistance that his team faced when attempting to treat multidrug-resistant (MDR) TB patients because of the global health community’s perception that the treatment needs of MDR TB might draw attention away from the standard, “directly observed treatment, short-course” (DOTS) program. While the resulting policy of not treating MDR TB cases has changed since that time, Kim shared that he encountered similar initial resistance when advocating for treating HIV infections in some low- and middle-income countries in Africa.

Kim noted that although the approach to TB and, more broadly, global health has changed over the past 20 years, some constants remain. The declarations he heard from many in the public health community during the current pandemic—for example, that it was “too late or too complicated” to conduct widespread contact tracing and stop the spread of COVID-19 in the United States—mirrored the resistance he experienced in Peru and Africa. Kim countered that view by bringing attention to the significant pandemic-related economic loss projected in a recent publication in the Journal of the American Medical Association. He cited the authors’ claim that the estimated $16 trillion economic loss represents reasonable justification for the United States to spend $100 billion per year in building public health system capacities, including testing and contact tracing systems (Cutler and Summers, 2020). Kim emphasized that:

one of the lessons we have learned over and over again is that to beat this virus, of course we need vaccines, therapeutics, and diagnostics. But to deliver all those interventions, we need a public health ground game that is equal to the task.

As a result of the COVID-19 pandemic, Kim anticipated, more funding support will become available for infectious disease threats; however, “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. According to Kim, public health leaders and programs in the TB community have an opportunity to take a central role in building new public health systems that can stop TB, COVID-19, and other infectious disease threats yet to come.

In response to a question from Cassell on the role of development banks in accomplishing this goal, Kim said his colleagues at the World Bank are responding to needs expressed by countries for public health systems that are equipped for a full range of health threats, including chronic and non-infectious diseases. In doing so, development banks are now looking for models of more horizontal health systems like community health worker (CHW) programs because those are more broadly useful and could therefore have a higher return on investment than vertical programs (e.g., programs that focus only on TB). The TB community, he believes, is uniquely qualified to take a leadership role in these horizontal programs, given their experience with the implementation of case finding, contact investigations, treatment adherence promotion, and infection control and prevention measures as part of DOTS. Kim offered the example of a program that Partners In Health developed in Massachusetts to highlight the benefits of CHW engagement. This program evolved from early contact tracing efforts and demonstrated several unique benefits, as follows:

• Proximity and relationship to patients in the community that contribute to various health care interventions (e.g., supporting isolation, vaccination outreach, delivering treatments).
• Ability to reach isolated communities.
• Horizontal integration of multiple disease programs that appeal to global investors.
• Economic stimulus—individuals who might otherwise be unemployed during a disease outbreak can remain in the workforce and the salary is returned to the local economy through spending.

In wrapping up, Cassell asked about the relationship between metrics to assess global health preparedness and the access and sustainability of financing for such programs. Kim shared his belief that leadership is critical and that the bottleneck is not a lack of money, pointing to the economic stimulus measures taken by the United States and other countries. He explained that multilateral organizations can accomplish impressive feats when there is agreement among the leadership. But in the absence of leadership alignment, the systems in place and available funding can be rendered irrelevant. The challenge, he said, lies in using the current opportunity of the COVID-19 pandemic—the attention and new capital associated with it—to build better systems and establish strong baseline capacities that are resilient to changes in leadership.

Current Progress on Global TB Elimination Goals and Opportunities for Moving Forward

Salmaan Keshavjee, director of the Harvard Medical School Center for Global Health Delivery and chair of the Steering Committee of the Zero TB Initiative,³ addressed the status of efforts to achieve the goals set out by WHO and UNHLM on TB. He began by sharing recent statistics from WHO that indicate the current progress is not on track to meet the goals set by UNHLM in 2018 (see Box 1).

BOX 1

Progress on Reducing the Global TB Burden from the WHO Global Tuberculosis Report Presented by Salmaan Keshavjee.

Citing the 2018 Lancet report from the Global Burden of Disease Tuberculosis Collaborators (GBD Tuberculosis Collaborators, 2018), Keshavjee pointed out that the annualized incidence rate for drug-sensitive and drug-resistant TB declined by only 1.3 percent and 2.1 percent, respectively, between 2006 and 2016. During the same period, the annualized incidence rate for extensively drug-resistant (XDR) TB increased by 7.9 percent. Furthermore, during COVID-19, 70 percent of the officers from Global Fund implementing countries reported a decrease in the number of TB patients receiving treatment, and 88 percent reported a reduction in TB case notification.⁴

Despite these statistics, Keshavjee reiterated his belief that TB elimination is possible and referred to the “search–treat–prevent” epidemic control strategy. This strategy, which has existed since the 1960s but has yet to be implemented globally, could be applied toward reducing the global disease burden of TB and act as a platform for diseases such as COVID-19, he said. The knowledge and practice of each component in the search–treat–prevent strategy date back to the early- to mid-20th century. For example, the “search” portion refers to active case finding around small numbers of cases or community screening in epidemic settings, both often performed with mobile X-rays. “Treat” pertains to the best practice of administering the correct medicines with the fewest side effects over the shortest possible treatment period. Finally, “prevention” refers to efforts aimed at stopping transmission of TB infections, but also preventing infections from turning into active disease.

One preventive approach that has risen to prominence recently with the COVID-19 pandemic involves the use of respirators, ventilation, and upper room ultraviolet germicidal lighting as effective transmission control measures. However, Keshavjee acknowledged that these have been difficult to roll out in resource-limited settings and there are limited data on the application of these methods toward TB prevention. On the other hand, he shared a finding from a study conducted by the U.S. Public Health Service (Kaplan et al., 1972) that a pharmaceutical-based approach involving the combination of treating active disease, screening household contacts, and prophylactically treating contacts for infection could reduce community transmission of TB to nearly zero because:

now we know that the idea of latent versus active [disease] is a binary that doesn’t really exist. It’s actually a continuum. And sometimes people that don’t really appear to have clinically active disease are actually shedding bugs.

Keshavjee estimated that, because 8–10 percent of people exposed to someone with an active case of TB will progress to active disease within 2 years, based on the current case incidence rate for TB, 20–30 million of these contacts could benefit from prophylactic treatment each year. While this number may seem daunting, he also pointed out the logistical feasibility of reaching the close contacts of patients already receiving treatment for active TB.

For each component of the search–treat–prevent strategy, Keshavjee highlighted new tools and opportunities that have recently emerged or been expanded:

• Search
  • Application of artificial intelligence (AI) to X-ray diagnosis
  • Genetic testing for case confirmation and drug susceptibility information
  • Culture capacity
• Treat
  • Short-course regimens for drug-sensitive TB that reduced the treatment time from 6 to 4 months
  • All oral treatment regimens for drug-resistant TB
  • Opportunities for behavior economics–based innovations to support patients to finish treatment (e.g., food, cash transfer programs)
• Prevent
  • Short-course preventive treatment regimens for drug-sensitive TB (e.g., 1 month of isoniazid or rifapentine, or 3 months of once weekly isoniazid and rifapentine)
  • Treatment regimens for MDR and XDR TB (e.g., bedaquiline, ongoing clinical trial using levofloxacin)
  • Opportunities to leverage existing treatment regimens toward increasing coverage of preventive therapy

Seeing an opportunity to build on past successes where the use of the search–treat–prevent strategy accelerated TB elimination—including in Alaska and New York City (Golub et al., 2005; Kaplan et al., 1972); Tomsk, Russia (Keshavjee et al., 2008); and Karachi, Pakistan (Dowdy et al., 2013)—Keshavjee called for renewed commitment to comprehensiveness in designing TB elimination initiatives.

He further pointed out that by extending the capabilities and deepening the reach of clinics into communities, TB programs can essentially become community-based delivery platforms for a wide range of diseases—including endemic infectious diseases, non-communicable diseases (e.g., diabetes, heart disease, and mental illness), and emerging infectious diseases like COVID-19. Establishing effective TB control systems, Keshavjee explained, is synergistic with efforts to bolster global biosecurity and pandemic preparedness because the capacities required for TB control (e.g., community-wide case finding to stop transmission, patient support and remote monitoring during treatment, ventilation and germicidal lighting for infection control) are widely applicable to many different health care priorities.

Keshavjee closed by reiterating the importance of the comprehensive search–treat–prevent approach, noting the need for catalytic investments to support communities and programs for implementation. He also laid out a research agenda to improve this strategy, including faster POC tests, more effective vaccines for different indications, and immunomodulators to complement the antibiotics arsenal. His final comment entreated the TB community to build more than just a TB program, and instead aim for a community-based platform for better health care delivery overall.

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

Eric Rubin, editor-in-chief of the New England Journal of Medicine, reviewed key learnings and opportunities from the COVID-19 pandemic regarding diagnostics, therapeutics, and vaccines for TB. First, the scale-up of diagnostic testing based on polymerase chain reaction (PCR) during the pandemic holds promise for similar technologies being applied to pulmonary TB and perhaps other TB syndromes, Rubin said. Although other rapid, cheap, POC diagnostics have been developed, Rubin explained, implementation rates have been low.

Regarding therapeutics, Rubin pointed out the relative lack of progress during the COVID-19 pandemic. This is attributable to both the lengthy therapeutic development timeline and the small existing pipeline for coronaviruses, he explained. Additionally, while more than 200 clinical trials were listed for COVID-19 therapeutics at the time of this workshop, many of them have been withdrawn, had repetitive trial designs, or had small sample sizes unlikely to yield useful results. One lesson Rubin took from this experience is the value of coordination and thoughtfulness in the clinical trials enterprise to avoid redundancy. In contrast, the pipeline for TB drugs is more robust than that for coronavirus drugs, and researchers are experienced in designing and embarking on cost-efficient clinical trials due to limited funding.

Rubin lauded the rapid advances in vaccine development during the COVID-19 pandemic. The success and widespread use of new technologies like mRNA and adenovirus vector vaccines have broadened opportunities for antigen exploration and reduced the reliance on expensive adjuvants, he said. However, pointing to a previous vaccine trial as an example, Rubin noted that the TB case incidence tends to be lower than that of COVID-19 in the midst of a global outbreak, contributing to a smaller effect size and adding to the difficulty in conducting vaccine trials. Finally, Rubin pointed out that the identification of biomarkers that correlate with protection remains a critical knowledge gap in both TB and COVID-19 research.

New Technologies and Remaining Gaps in TB Diagnostics

Soumya Swaminathan, chief scientist of WHO, acknowledged that the impact of COVID-19, in terms of unreported and untreated cases, is likely to be felt on TB and other diseases for a long time. She added that, given the known challenges in TB diagnosis in children, the impact on the pediatric population is likely to be even greater.

However, Swaminathan also noted that many countries have begun to revitalize their TB programs, with some conducting joint activities with their COVID-19 response. She pointed out a number of innovations in sample types and collection methods for POC or self-administered tests that have been developed for COVID-19 and hold promise for translation to TB. These include improvements in polyester swabs and new sampling protocols that use mouthwashes, oral swabs, or absorbent strips in facemasks. The ability to use easy-to-obtain samples such as saliva for diagnosis, she explained, could improve access to decentralized testing, allowing for large testing facilities in the community, mobile testing sites, broader reach of CHWs, and pharmacy available self-testing kits.

On POC diagnostics, Swaminathan acknowledged biomarker-based tests currently under clinical evaluation and review, including the second-generation lateral flow lipoarabinomannan assay using urine samples. These tests hold promise for people living with HIV/AIDS, and may have the potential to be expanded as a POC test for all TB cases. WHO plans to convene a Guideline Development Group in 2022 to review the clinical evidence for these tests, she said. On the other hand, Swaminathan noted, multi-disease diagnostic platforms such as GeneXpert and Truenat, among others, could be more robust, used more broadly in family health centers, and expanded in multiplex capabilities in order to achieve better cost and efficiency. She offered hope that the wider use of molecular technologies will reduce the reliance on suboptimal tools like smear microscopy.

Digital tools have also seen accelerated development during the COVID-19 pandemic, Swaminathan said. For example, smartphone apps have been used for education, risk communication, referrals, and contact tracing. She suggested these applications could be repurposed and used for TB. Swaminathan also expressed hope for the integration of TB and COVID-19 diagnostic tools such as cough analyzers that use AI and digital stethoscopes to diagnose COVID-19, or automated X-ray interpretation (which has been applied to TB in the past but saw accelerated use during the pandemic), particularly if combined with portable X-ray units.

Swaminathan distinguished an opportunity that the COVID-19 pandemic has modeled for the efforts to combat TB: the capacity to rapidly collect and analyze large volumes of genomic sequencing data.

COVID-19, you know, came in a digital era. So there’s real-time data sharing, big platforms, user AI application analysis. We expect minute-by-minute updates on the data visualizations and informing, communicating with the public, directing public health response. But 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.

Swaminathan cautioned that, for TB, there is an increasing knowledge gap in the genetic sequence-based detection of drug resistance to antibiotics outside of rifampicin. Swaminathan discussed ongoing efforts at WHO to collaborate with partners and countries around the world to build a catalog of “over 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, 2021). By contrast, researchers have amassed nearly 2.5 million whole-genome sequences for SARS-CoV-2 in less than 2 years since the onset of the COVID-19 pandemic, Swaminathan said. Particularly, because of COVID-19 variants, there is new interest and investment in enhancing sequencing capacities in many countries. Investments in robust data systems and data integration will be important not only for TB, she noted, but also for many other diseases.

Swaminathan believes that WHO could take on a central role in convening stakeholders to design data-sharing platforms, similar to the database for COVID-19 that currently contains data on more than 350,000 individual patients from more than 60 countries. Swaminathan pointed out the need to balance the dynamic and collaborative nature of this multilateral data platform with safeguarding the confidence and interests of researchers from the Global South. In addition, WHO will convene a Guideline Development Group for next-generation sequencing for TB in 2022. She connected the genetic sequencing advancements seen during the COVID-19 pandemic to implications for TB diagnostics, pointing out that coupling data from next-generation sequencing to drug resistance will allow researchers to identify the most relevant mutations for each drug, such that future molecular tests can provide updated susceptibility information at the time of diagnosis.

Swaminathan summarized the emerging innovations from the COVID-19 pandemic into “three major new domains that we have seen the potential for the point-of-care biomarkers in rapid diagnostic tests, multi-disease platforms, and next-generation whole-genome sequencing.” She remarked that it will not be possible to achieve TB elimination goals without robust diagnostic tests. Furthermore, Swaminathan framed this as “forming a part of the pandemic planning and preparedness and coverage, … that’s [the reason for focusing on] multi-disease, multi-platform technologies and the attention to databases that cover cost cutting across diseases.” Finally, Swaminathan 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

In summary, Swaminathan reiterated the challenges and opportunities in advancing TB diagnostics:

1.

Meeting global TB elimination goals is doubtful without new and more effective diagnostic tools; this is a neglected and underfunded research area.

2.

Digital tools will play a key role in the future, but more research is needed to accurately measure their impacts on health outcomes.

3.

Data sharing poses an important opportunity, but effective governance may be needed to ensure trust, confidentiality, and responsible use.

4.

The three major domains that have seen advances during the COVID-19 pandemic are:

a.

POC biomarker and other rapid diagnostic tests.

b.

Multi-disease platform diagnostics.

c.

Next-generation genetic sequencing.

5.

Global multilateral mechanisms similar to the Access to ACT-A may serve as a model for developing and ensuring equitable access to address TB needs.

Improving Treatment Regimens and Vaccine Development

Emilio Emini, director of the HIV and TB program at the Bill & Melinda Gates Foundation (BMGF), spoke about the challenges and opportunities related to developing effective TB therapeutics and vaccines.

The Collective Social Value of Infectious Disease Interventions

Kevin Outterson, co-director of the Boston University Health Law Program and founding executive director of the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X),¹³ spoke about the policy and economic considerations for building new antibiotic development business models, and potential translatable lessons for ongoing efforts in TB. He observed that organizations, funding streams, government agencies, and scientific communities associated with infectious diseases are separated by strong disciplinary boundaries drawn around diseases of focus. The result is that “there [are] funding streams for AMR [antimicrobial resistance], there [are] funding streams for tuberculosis, funding streams for HIV. And it becomes something of a zero-sum game in which we compete.” However, Outterson suggested that it could be mutually beneficial for these groups to learn from and share common experiences with each other.

Taking a strategic view, Outterson said, can be difficult in models for the cooperative production of public goods (e.g., treatments and interventions for infectious disease outbreak preparedness and response). Instead, he suggested it might be valuable to adopt a broader view in defining the value of these interventions. As an example, CARB-X encourages the framing of antibiotics as a “safety net” that enables modern medicine and creates favorable risk–benefit calculus for now common medical procedures like C-sections, knee replacements, and cancer treatments. Outterson further noted that, similar to TB interventions, the value of effective antibiotics often cannot be traced to a single patient. He gave the example of a forthcoming study that found the second leading cause of death for cancer patients is infection, and outlined five benefits he identified from the health economics literature about the population-level benefits of effective antimicrobial therapy:

1.

Spectrum: Narrow-spectrum antibiotics reduce collateral damage to the microbiome, and broad-spectrum antibiotics allow for interventions even when diagnosis is not complete.

2.

Transmission: Avoiding pathogen spread by treating patients effectively.

3.

Enablement: Making other medical interventions such as surgery possible.

4.

Diversity: Range of treatment options reduces drug resistance selection pressures.

5.

Insurance: Having a backup in the event of a new, sudden, or significant increase in drug resistance.

Based on this understanding, Outterson explained the challenge of funding these interventions:

Each of these … things we’re talking about [has] billions or trillions of dollars’ worth of value attached to them. But they are population-level value, social-level value…. It’s really difficult for the market now to reimburse the researchers for this social value.

The result in the antimicrobial space, Outterson said, is that traditional market pricing mechanisms do not appropriately incentivize novel antimicrobial development. He explained that “the sector, not just a couple companies or a couple drugs … is being undermined.” This is evident in how 7 out 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 because the company believes that the forecasted profit margins in Europe do not justify the costs of a second market authorization. Putting the sales figure into perspective with other pharmaceutical products, Outterson shared that the annual sales are approximately $720 million in the United States for all branded antibacterials approved by FDA since 2010, which is less than the revenue generated by most single oncology drugs in the United States.¹⁴

This economic problem has encouraged the antimicrobial industry to think about ways to change the business models, Outterson said, which could be helpful for the TB community. He described how major funding organizations typically support either basic research and early discovery, or late-stage clinical development. CARB-X filled the role that bridged the two sides. Although Outterson acknowledged that the TB drug development effort has more coordinated pipelines and strategically set target product profiles to guide development, there is an opportunity to work collaboratively across funding and research silos and make the argument that “antimicrobials, including tuberculosis drugs, must be rewarded based on their social value.”

One way to make that argument might be to encourage the allocation of resources based on clinical baseline needs and strategic planning between outbreaks, he suggested, rather than allocating resources in emergencies to combat microbial threats as they arise. Instead of competing for funding streams, experts from different disciplines of microbial threats could coordinate to discuss common needs and the broader social values of innovation.

Outterson also suggested a “subscription” model for government funding of antimicrobial innovation in which a set level of government funding is steadily available to drug developers regardless of the actual market demand for new antibiotics. This would increase financial incentives for companies and, more importantly, maintain a robust research, development, and manufacturing ecosystem that can support redundancies in the supply chain and remain resilient to perturbations in market demand.

Finally, Outterson connected the new Advanced Research Projects Agency for Health (ARPA-H) to his call for collaboration, including the sharing of practical experiences such as how to operate at scale effectively or prioritize candidates within a pipeline. ARPA-H is likely to receive roughly $3 billion in appropriations from Congress to fund health product development through a model similar to the one used by the Defense Advanced Research Projects Agency (DARPA) in funding technical and engineering innovation. Outterson believes that steps taken toward breaking down silos among infectious disease fields will be helpful in capitalizing on future opportunities, such as the one presented by ARPA-H.

Considerations in Improving Diagnostic Capacities

Castro opened the discussion with the workshop speakers with a question about the feasibility of replacing rapid PCR test kits for COVID-19 with a multiplexed version that can test for COVID-19 and TB, which could enable widespread screening of patients with respiratory symptoms while potentially recovering funding and case-finding in TB-endemic areas. In addition, Castro wondered whether WHO and the global community might support this effort. Rubin pointed to the technical challenge in reconciling the sample processing for the two diseases in the same test kit. The current standard specimen type for TB diagnosis is sputum, whereas COVID-19 tests rely on a nasal swab or saliva sample. Although it may be technically possible to repurpose the COVID-19 rapid tests to include TB, Rubin explained, “a considerable amount of work [would need to go] into the specimen preparation if you were going to apply it to TB.” Castro followed up by asking about the status of commercializing a non-sputum POC test for TB. Emini added that it may be feasible to couple PCR testing for COVID-19 and TB using oral samples, bypassing the issue with processing sputum, but that because the causative agents for TB and COVID-19 are very different, significant challenges remain in breaching the organisms’ structures to access their genomes. In terms of detecting the presence of bacteria or volatile biomarkers in exhaled breath samples, Emini said the evidence base and diagnosis algorithms are still under development and that these tests are not yet near clinical application.

Responding to a comment about the 2012 buy-down agreement that raised the need to negotiate the price of the new GeneXpert cartridges down to $5 per test,¹⁵ Keshavjee explained that the buy-down was intended to improve countries’ accessibility to the tests and spur market demand, though it unintentionally decoupled price determination from production volume.¹⁶ This limited uptake of the GeneXpert test precluded widespread community screening and led to reliance on smear microscopy (a diagnostic test with about 50 percent sensitivity), he elaborated. A more effective, though less efficient, way of community testing could be an AI-aided X-ray screening followed by a confirmatory genetic test (e.g., GeneXpert, Truenat), Keshavjee said. He proposed that a target price of $1 per test would be economical and suitable for large-scale community diagnostic testing capacity.

Economic Considerations and Implications for Program Design

Following the discussion on the cost of diagnostic tests, Rubin asked Emini and Outterson whether price is a driving factor in front-end development or if it is a later consideration once a product reaches market. Emini believes that although price is often considered up front, it is affected by a number of variables—with two of the most significant being volume and competition. In the case of a buy-down, he explained, even while negotiation can modulate the volume of goods, a single supplier would still control the price in the absence of competition. Emini offered the example of another buy-down initiative that BMGF led for HIV self-testing in a number of African countries, where a system was built to introduce competition into the market. As a result, he explained, the initial buy-down helped to lower product prices early on and generate data to show the impact of HIV self-testing, while competition between multiple suppliers kept prices low over time.

While price-control systems hold promise, Emini shared his concern that prices for new drug combination regimens may not be able to compete with the low cost of the classic HRZ combination treatment (isoniazid, rifampin, and pyrazinamide). He pointed out that the challenge in improving TB treatment outcomes articulated earlier by Outterson—how to balance the price that the market will bear with the cost that society is asked to bear—represents an important prospective consideration for program and intervention development:

How are we going to use them? Who is going to pay for them? What makes sense from both a societal and a market perspective?

Outterson acknowledged the distinction that Emini described between cost of goods and price, and added that the discussion of social value further distinguishes a difference and shifts the focus from a company deriving revenue from market mechanisms to other reimbursements for its activities, including research and development. This is known as “delinkage,” Outterson explained, and the subscription-style funding model of the Pioneering Antimicrobial Subscriptions to End Up surging Resistance (PASTEUR) Act is an example of delinking the reward for the company from sales volume, unit sales, and unit price. He pointed out that delinkage is not a market mechanism, but instead 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.” If there is a way to appropriately reward the company, he said, the interventions discussed here could be made broadly available at little or no cost to the public.

Outterson added that although the ultimate costs of goods are a consideration early on in the preclinical development life cycle at CARB-X, optimizations for cost structure and adaptive research into product characteristics, including stability and shelf life, are initiated closer to clinical trials. These optimizations receive special funding from the UK government. He also added that in conditions where there is limited competition, such as the period of market exclusivity for patent-protected drugs, CARB-X has found success in contractually mandating global stewardship and access principles at the start of funding. This is a concept that CARB-X adapted from its funders, including BMGF and the Wellcome Trust.

Bridging Silos and Paradigm Shifts

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

Paradigm Shift to Improve Implementation of Existing Tools

Keshavjee agreed, adding that there are opportunities with current TB programs where small changes could create a large impact. One example he suggested was a shift to community-level screening combined with commitments to contact tracing for prophylaxis. Another policy change suggested by Keshavjee was a mechanism for coordinated, rapid clinical trial studies, similar to some of the efforts seen during the COVID-19 pandemic.

Castro invited Keshavjee to comment on 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 consider TB as a social disease rather than a disease of individuals. Beyond providing DOTS therapy for positive cases, this reconfiguration would lead TB control programs to create household screening systems, he said. Although this new model would require more staffing, testing resources, and medications, Keshavjee believes this shift could be 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 robust, on-the-ground health care system, Keshavjee pointed out, is enhanced immediate capacity for uptake and deployment of new treatments, vaccines, or diagnostic tests. This could contribute to fostering innovations by providing roll-out assurances and market access, he said.

Castro wondered how studies of human-systems interactions might be incorporated alongside platform development in order to improve end-user experience, reduce waste, and improve efficiency and effectiveness. Keshavjee responded that there is a behavioral economics component to any treatment model. As an example, he expounded on the conditional cash transfers mentioned by Kim in the opening presentation, which have a two-fold benefit in stimulating local economies and encouraging participation in public health efforts to eliminate disease. Keshavjee acknowledged that these methods have not been used widely in controlling TB, and represent an opportunity for programs to improve by considering community contexts and 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 Value of TB Elimination

Keshavjee made the case that the lack of community health care delivery capacity for diagnosis, screening, and treatment is a biosecurity emergency. He suggested that this could be addressed by calling for funding agencies to support comprehensive health programs, instead of tying funding to specific diseases or activities. Keshavjee believes that related workshops and organizations might have a role in conveying this need to stakeholders. Keshavjee cited evidence from a colleague’s forthcoming study that calculated each 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 these types of economic data can be part of compelling policy arguments for TB control.

Monique K. Mansoura, executive director of global health security and biotechnology at The MITRE Corporation—in bringing together reflections on the cost of inaction for TB and potential competing health care needs in a community—asked about the evidence base on cost-effectiveness and synergistic outcomes of addressing TB and another prevalent disease (e.g., diabetes).

Keshavjee shared two examples in which TB programs are also screening for diabetes and hypertension: the Resource Group for Advocacy and Community Health in India, and Advance Access and Delivery in Durban, South Africa. Both programs have discovered high proportions of diabetes among those testing positive for TB, he said, in addition to significant rates of hypertension. Both diabetes and hypertension are easily and affordably treatable compared to TB, Keshavjee said, so TB control field teams are finding it relatively manageable to tack on treatment services for these two conditions to their normal TB-related duties. Keshavjee said he hoped that in the future, these programs will operate from unified funding streams, supply chains, and equipment for the treatment of many currently disconnected health conditions.

Castro asked Outterson how the competing needs for vertical programs and disease-specific objectives can be balanced with broad, integrated health systems. Castro also 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. The social value of elimination, he speculated, could be used to inform prioritization and balance objectives in funding decisions. He contrasted the rapid successes of the response to COVID-19, where a large amount of capital was spent in a short period on a focused objective (possible in part because of the broadly perceived value of elimination), with a hypothetical scenario where that same level of effort and funding are spread out over a 20-year period. The latter case, Outterson pointed out, would be seen as a failure, but is in fact similar to the approach taken for many other infectious diseases—including TB.

Finally, following up with the examples Keshavjee cited, Outterson proposed that this health system strengthening could be thought of as “broad-spectrum defenses to unknown or unknowable microbial threats,” adding that:

The preparedness value of that is immense, and it crosses all silos, because it’s not a preparedness system to surveil for any of our particular diseases, it should be something that surveils for all infectious diseases, and … even chronic diseases that aren’t infectious.

Closing Remarks

In closing, Cassell entreated the audience and participants to work toward developing the goals Kim laid out 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, and that number has not changed since the very first WHO report on MDR TB more than 20 years ago. She shared her belief that determining the social value of TB eradication is an important task yet to be completed that may require innovative economic research and policy making. ◆◆◆