At commemorations of World Tuberculosis Day 2019 this March, there was a palpable new sense of optimism that the global fight against tuberculosis (TB) could eventually be won. Awareness has grown that TB is the world’s deadliest infectious disease, afflicting 10 million and killing 1.6 million globally in 2017.[i] Government leaders are demonstrating a renewed political will about committing the resources necessary to end the global TB epidemic. World TB Day 2019 marked six months after the United Nations High-level Meeting on TB in September 2018—a good occasion to reflect on recent progress and the road ahead.
Ending the global TB epidemic will require grappling with many underlying challenges. A paramount challenge is identifying and caring for the estimated 4 million people annually who become ill with active TB but who are not diagnosed, treated, and monitored by national public health programs. TB is the leading cause of death among people living with HIV, resulting in one-third of AIDS deaths. Inadequate or ineffective treatment of drug-sensitive TB can lead to the development of drug-resistant TB, which affected over half a million people in 2017. Only 20 percent of people with multidrug-resistant TB (MDR-TB) were treated in 2017, and only half of those patients were cured, contributing to ongoing transmission. Children are particularly vulnerable to TB because they have few diagnostic and treatment options. A quarter of the world’s population has latent TB infection, which can develop into active infectious TB in about ten percent of infected people, but there are no diagnostic tests available to identify which individuals will develop symptomatic TB disease. While there is much that can be done to expand access to existing diagnostics and treatment regimens, the epidemic will not be ended without new therapeutics, diagnostics, and vaccines.
TB research and development (R&D) has been underfunded for many decades, leaving health care workers to fight the disease with many antiquated tools. In recent years there has been a slow increase in the resources and attention devoted to TB R&D, leading to gradual advancement of medical products through the development pipeline. But to accelerate the pace of R&D, investments from public, private, and philanthropic entities must increase significantly. Stop TB Partnership has estimated that US$2 billion in annual global research investments are required to end the global TB epidemic by 2030.[ii] While global funding for TB R&D reached a new high of $772 million in 2017, according to Treatment Action Group (TAG), the investment still falls far short of the global need.[iii] The current level of productivity in TB R&D indicates that the moment is ripe for an infusion of resources to accelerate outcomes and ensure access to new medical products for the patients who most need them. There have been many exciting research developments announced just in the past six months with great hope and optimism for patients—as long as issues around access are addressed.
There is a significant unmet need for vaccines against TB and treatment options for the most drug-resistant forms of TB. The only existing TB vaccine, the bacille Calmette-Guérin (BCG) vaccine, has limited effectiveness in children but not against the primary manifestation of disease in adults. In September 2018, GlaxoSmithKline and Aeras published promising results from a phase 2b trial of the M72/AS01E vaccine conducted in Kenya, South Africa, and Zambia. The vaccine demonstrated 54% efficacy in preventing progression from latent TB infection to active TB disease in HIV-negative adults.[iv] These results have injected new optimism into the TB vaccine field, and development is ongoing. In early March 2019, TB Alliance announced that the U.S. Food and Drug Administration had granted Priority Review to its new drug application for the novel TB drug pretomanid tested as part of a regimen with bedaquiline and linezolid for the treatment of extensively drug-resistant TB (XDR-TB) and MDR-TB that has failed prior treatment.[v] In ongoing phase 3 clinical trials in South Africa, the bedaquiline / pretomanid / linezolid regimen cured 89% of the first 75 enrolled participants after six months of treatment. This is a marked improvement over the current standard treatment of 18-20 months for MDR-TB and the more extensive, individualized, and often experimental treatment needed for XDR-TB.
As noted earlier, there are no diagnostic tests to identify which individuals with latent TB infection will develop active TB disease. However, it is known that some people are at higher risk of developing TB, including people living with HIV and household contacts of those with TB disease. TB preventive therapy is recommended for these individuals, but for a long time the standard of care was 6-9 months of daily isoniazid, which resulted in discontinuation of therapy and liver side effects for some patients. Recently, shorter and more tolerable preventive therapy regimens have been developed, including a once-weekly dose of isoniazid and rifapentine for 12 weeks, but there were questions about interaction of this regimen with antiretroviral HIV therapy. In early March 2019, researchers released results of a Unitaid-funded trial in South Africa demonstrating that once-weekly rifapentine / isoniazid could be given safely to HIV patients taking dolutegravir while maintaining effectiveness of dolutegravir, a WHO-recommended first-line treatment.[vi] Based on these results, Unitaid and the Aurum Institute are introducing once-weekly rifapentine / isoniazid preventive therapy in 12 high-burden countries, prioritizing people living with HIV, children under five, and household contacts of TB patients.[vii]
TB research and development is already improving patient care and better options are progressing through the pipeline. The exciting momentum in R&D must be maintained. TAG has spearheaded a proposal urging governments to devote a small percentage of their current R&D expenditure to TB. According to TAG’s analysis, if countries invested at least 0.1% of their annual R&D spending on TB research, the $1.3 billion annual funding gap would be closed.[viii] This proposal has been endorsed by stakeholders and many government leaders as a way for each country to contribute to TB R&D based on the country’s demonstrated research capacity. Only three countries met or exceeded the target in 2017: South Africa, the Philippines, and New Zealand.[ix]
South Africa and the Philippines represent middle-income countries with a high TB burden that are investing in research to improve the health of their citizens. Other high-burden middle-income countries should follow the lead of South Africa and the Philippines and aim to invest 0.1% of their R&D spending on TB. The creation of six regional TB research networks over the last four years—the West African Regional Network for TB control, the European Tuberculosis Research Initiative, the BRICS TB Research Network, the Central African Regional Network for TB control, the TB Research Cooperation Network in Eastern Europe and Central Asia, and the future Asian-Pacific TB Research and Innovation Network—is a promising avenue for countries to collaborate and amplify the effect of their research investments.[x]
Many high-income countries are global research leaders and are needed to play prominent roles in developing innovative tools against TB. The United States is by far the leading public-sector funder of TB R&D, investing $313.5 million in 2017, almost ten times more than the second-ranked public funder. Yet even the U.S. government could do more to meet the 0.1% target, as it only achieved 70% of that target goal.[xi] Canada placed fifth on TAG’s list of top government funders in 2017, reaching 73% of its target funding amount. Although Canada has a low incidence of TB, there are periodic outbreaks and the total number of TB cases has gradually increased since 2014.[xii] TB disease in Canada disproportionately impacts a few vulnerable populations including the Inuit who live in the Northern Arctic regions. The Canadian government in 2018 committed to eliminate TB among the Inuit by 2030, but it is evident that more effective, safer, and less cumbersome treatment, diagnostic, and vaccine options would reduce the burden on patients and the health care system. In 2017, Canada took steps to provide access to once-weekly rifapentine / isoniazid to communities with high rates of TB. Innovative TB medical products are needed in low-incidence and high-incidence countries alike to support patient-centered care for TB patients and advance toward global TB elimination. If world leaders are serious about the commitments made to ending the global TB epidemic at the UN High-level Meeting in September 2018, investments in TB R&D must match the rhetoric.
[i] World Health Organization (WHO), Global Tuberculosis Report 2018 (Geneva: WHO, 2018), http://apps.who.int/iris/bitstream/handle/10665/274453/9789241565646-eng.pdf?ua=1
[ii] Stop TB Partnership, The Global Plan to End TB 2016-2020. Geneva: 2015. http://www.stoptb.org/assets/documents/global/plan/globalplantoendtb_theparadigmshift_2016-2020_stoptbpartnership.pdf
[iii] Treatment Action Group. Tuberculosis Research Funding Trends, 2005–2017. New York: December 2018. http://www.treatmentactiongroup.org/sites/default/files/tb_funding_2018_final.pdf
[iv] O. Van Der Meeren, M. Hatherill, V. Nduba et. al. N Engl J Med 2018;379:1621-34. DOI: 10.1056/NEJMoa1803484
[v] TB Alliance. “TB Medicine Pretomanid Enters Regulatory Review Process in the United States.” March 8, 2019. https://www.tballiance.org/news/pretomanid-enters-FDA-review
[vi] Kelly E. Dooley et. al. Safety & PK of weekly rifapentine/isoniazid (3HP) in adults with HIV on dolutegravir. Conference on Retroviruses and Opportunistic Infections, March 2019. http://www.croiconference.org/sessions/safety-pk-weekly-rifapentineisoniazid-3hp-adults-hiv-dolutegravir
[vii] Scale-up of TB prevention among people living with HIV possible, reveals new study. Africa Science News. March 9, 2019. http://africasciencenews.org/scale-up-of-tb-prevention-among-people-living-with-hiv-possible-reveals-new-study
[viii] Treatment Action Group. Setting Country-Specific TB R&D Funding Targets. New York: 2017. http://treatmentactiongroup.org/sites/default/files/Country-specific%20TB%20R%26D%20funding%20targets_updated%202Nov2017_Final.pptx
[ix] Treatment Action Group. Tuberculosis Research Funding Trends, 2005–2017. New York: December 2018. http://www.treatmentactiongroup.org/sites/default/files/tb_funding_2018_final.pdf
[x] World Health Organization, Meeting for advancing TB research through multi-country research networks, 25 October 2018. https://www.who.int/tb/features_archive/advancing-TB-research/en/
[xi] Treatment Action Group. Closing the Gap in Tuberculosis Research and Development Funding: Actions for U.S. Government Executive Agencies (2019) http://www.treatmentactiongroup.org/sites/default/files/TAG_GERD_brief_exec_v4.pdf and Closing the Gap in Tuberculosis Research and Development Funding: Actions for U.S. Congress (2019) http://www.treatmentactiongroup.org/sites/default/files/TAG_GERD_brief_leg_v5.pdf
[xii] Theresa Tam, Chief Public Health Officer Spotlight on Eliminating Tuberculosis in Canada, March 2018. https://www.canada.ca/en/public-health/corporate/publications/chief-public-health-officer-reports-state-public-health-canada/eliminating-tuberculosis.html