Creating an Evidence-Based Blueprint for Action
In the penultimate session of the workshop, several speakers, including session chairs, individually identified potential options for moving forward that emerged from the presentations and discussions, highlighting those that, in the individual speakers’ views, are supported by evidence. This chapter provides an integrated summary of the remarks made during that session, organized thematically into four broad areas of interest: pediatric DR TB, genomic tools and diagnostics, transmission, and drug supply and access. Speakers also addressed a fifth, cross-cutting theme: that of the opportunity to improve global awareness and the visibility of DR TB. Note that this summary should not be construed as reflecting consensus or endorsement by the workshop participants, the planning committee, the Forum, or the National Academies.
ADDRESSING DRUG-RESISTANT TB IN CHILDREN1
Children have a high risk of severe disease and death when infected with M.tb., said both Mercedes C. Becerra, Harvard Medical School, and Qian Gao, Professor, Shanghai Medical College, Fudan University, China. Bacteriologic confirmation of TB disease in children also is very difficult, even with invasive procedures. For that reason, the decision to treat a case of TB disease in a child as drug resistant often relies on a combination of
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1 This section is based on presentation by by Mercedes C. Becerra, Associate Professor, Department of Global Health and Social Medicine, Harvard Medical School, and Qian Gao, Professor, Shanghai Medical College, Fudan University, China.
clinical evaluation and known exposure to a source patient with DR TB. Cure rates in children exceeding 80 percent have been documented around the world using regimens that are tailored to the child’s susceptibility profile or to that of the source case, even in children who are coinfected with HIV.
Becerra and Gao listed several potential action items and resource needs that could help expose and address the “silent epidemic” of DR TB in children:
• Children with DR TB can be a key indicator to help guide a large-scale policy response. The identification of children with DR TB allows for the monitoring of gaps, needed drugs, and whether programs are accessing the support they need to deliver care to children.
• Adoption of 1-year targets for the treatment of DR TB in children at the global, country, and institutional levels could help improve treatment rates. Targets could be defined either in terms of absolute numbers or as a percentage of the treatment for drug-resistant patients. To complement these efforts, institutions and countries could improve reporting of how many children are being treated and how many are waiting for treatment.
• Tests diagnosing TB and identifying drug resistance that perform well in children need to be developed.
• Treatment regimens need to be optimized for pediatric disease. This can be done using both prospective and retrospective approaches. A wealth of clinical information is available from around the world, including information on children, but the right partners and analytic tools are needed to deal with retrospective data. Funding for this research also is needed.
• Drugs in child-friendly formulations are needed. In addition, more needs to be known about the pharmacokinetics and pharmacodynamics of old and new drugs to optimize dosing in children.
• Ongoing exchange needs to be supported and promoted among clinicians and researchers to share best practices and accelerate learning in real time; exchange needs to occur across countries and needs to overcome language barriers.
ADOPTING GENOMIC TOOLS TO MAP THE EPIDEMIC OF DRUG-RESISTANT TB AND ADDRESS DIAGNOSTIC CHALLENGES2
Whole-genome sequencing could reveal drug-resistant strains, compensatory mutations, highly transmissible strains, and other characteristics of the pathogen, said Sven Hoffner, WHO Supranational Tuberculosis Reference Laboratory and Swedish Institute for Communicable Disease Control; and Yanlin Zhao, China CDC. Molecular epidemiology could trace outbreaks, risk groups, and risk settings and thus contribute to infection control efforts. In addition, epigenetic studies could increase understanding of host–pathogen interactions.
Hoffner and Yanlin Zhao proposed the following areas of need for further consideration:
• New diagnostics need to be scaled up from pilot sites to the national level.
• Studies using molecular diagnostic tests need to be conducted to understand the mechanism of resistance and to develop reliable phenotypic DST.
• Development of test algorithms for the evaluation of new tests could ensure that poor-quality tests are avoided and reliable results are obtained.
• Trial sites need to be staffed with experienced and knowledgeable investigators, particularly in the BRICS countries.
• Plans for national laboratory networks need to take into account new diagnostic tests, human resource development, and infection control needs.
• The roles of microscopy, microbial culture, and molecular testing should be evaluated and optimized to allow for sensitive, specific, and timely detection of MDR and XDR TB.
• A central body should be in charge of the entire laboratory network, including private laboratories. Basic quality criteria and a licensing system should be established to ensure high-quality service throughout the national laboratory networks, especially in the more peripheral laboratories.
• A laboratory information system and a database of genetic analysis and clinical data should be developed to ensure effective data handling, improve test quality, and enhance timely reporting.
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2 This section is based on the presentations by Sven Hoffner, Director, WHO Supranational Tuberculosis Reference Laboratory; and Department for Preparedness, Swedish Institute for Communicable Disease Control; and Yanlin Zhao, Vice Director, National Center for Disease Control and Prevention; and Director, National Tuberculosis Reference Laboratory, China CDC.
• Resources are needed to implement more rapid tests as soon and as widely as possible.
BLOCKING TRANSMISSION OF DRUG-RESISTANT TB3
Although TB is an airborne disease, not enough attention has been given to transmission control, said Edward A. Nardell, Brigham and Women’s Hospital, Harvard Medical School; and Lixin Zhang, Deputy Director, Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology; and Inaugural Director, Drug Discovery Center for Tuberculosis, IMCAS. Community-based treatment is at least as effective as hospital-based treatment and, importantly, is more likely to reduce transmission. Patients who are on effective therapy quickly become noninfectious, even if they remain smear positive.
Nardell and Lixin Zhang made the following points:
• Hospitals and clinics need to uncover the prevalence in their respective settings of unrecognized TB or unrecognized drug resistance, as these cases are a key source of transmission.
• Routine active case finding through cough surveillance of all hospital admissions and other means is an effective approach to transmission control, especially if combined with molecular rapid testing for TB and for MDR TB. To stem transmission, cough detection needs to progress to diagnosis and effective therapy within a matter of days, not months. Individual tests, which could overcome the difficulty of obtaining sputum samples, are a promising new screening technology on which several companies are working.
• Environmental control and respiratory protection remain important until effective treatment starts and, on an ongoing basis, for patients with XDR TB. Architectural and engineering capacity to implement these controls and protections needs to be improved.
• The incidence of TB and of MDR TB among health care workers needs to be monitored at the institutional level, and efforts to improve reporting are needed as well. Health care workers need comprehensive employee health programs, including preventive therapy for TB.
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3 This section is based on the presentations by Edward A. Nardell, Associate Professor, Division of Global Health, Brigham and Women’s Hospital, Harvard Medical School; and Lixin Zhang, Deputy Director, Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology; and Inaugural Director, Drug Discovery Center for Tuberculosis, IMCAS.
• Transmission control, including the development of new technologies and approaches, is as important a focus of attention as new diagnostics and drugs.
REFORMING DRUG DISTRIBUTION AND ASSURING DRUG QUALITY4
The drug development pipeline at the preclinical development stages is almost completely empty. “You cannot address an infectious disease that generates resistance without having an ongoing pipeline,” said Barry R. Bloom, Harvard School of Public Health. In addition, new and more capable molecular diagnostics could greatly speed up diagnosis, which would be “a tremendous stride forward.” Bloom noted that these principles reinforce the need for basic, developmental, and operational research.
Bloom offered the following proposals for next steps:
• The most limiting factor in the supply of drugs is a lack of information. What will be the need? How many doses will be bought? How many doses will be used? How much should be produced? What are the lead times for producers? According to Bloom, TB forecasting needs to be linked with forecasting for other diseases and drugs, with input from experts in both the public and private sectors.
• The countries that are sources of the production of drugs and thus must try to forecast future needs will need to work with regulatory authorities to make improvements in the later stages of the drug supply chain—allowing quicker production and dissemination of quality drugs so they reach patients. This cooperation between countries and regulatory authorities would also ensure greater supplies, more producers, more competition, and lower prices.
• Better provision of anti-TB drugs also will require more funding than is available today. Increased funding through the Global Fund or other international mechanisms could help guarantee markets, provide continuity to producers, inform better forecasts, and increase the visibility of TB. However, many of the HBCs have “graduated” from the Global Fund grants, potentially lengthening the impact of this intervention.
• An up-front pooled capital fund would reduce the need for each country to negotiate separately with a large number of producers.
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4 This section is based on the presentation by Barry R. Bloom, Harvard University Distinguished Service Professor and Joan L. and Julius H. Jacobson Professor of Public Health, Department of Immunology and Infectious Diseases, Harvard School of Public Health.
Even expensive drugs can be cost-effective if they keep the MDR/ XDR disease from spreading. Moreover, up-front payments and guarantees could bring prices down.
• Drugs that are prequalified by WHO or stringent regional regulatory authorities should not have to go through an extended period of regulatory review within individual countries. Regional regulatory agreements can avoid the need for repeated validations by agencies in each country.
• Adequate funding needs to be applied for training in how to run supply chains, assess and assure quality, and comply with regulations; such training would be useful not only for TB drugs but for other drugs as well.
• Improved organization and leadership are needed to strengthen the supply of drugs for DR TB. Public–private partnerships could be a way to make expertise in the private sector available to the public sector.
Bloom also observed that successful community-based care of MDR TB patients, such as that implemented in South Africa and elsewhere, is very promising and could be generalized to many other countries.
INCREASING THE VISIBILITY OF DRUG-RESISTANT TB
Panelists also addressed the need for improved global awareness and visibility of the problem of DR TB. Millennium Development Goal 6 calls for combating HIV/AIDS, malaria, and “other diseases.” As Bloom said of TB, “When a disease which is this fatal and this threatening to the world is termed an ‘other’ disease … we have done a poor job of getting the message through.”
Information about DR TB needs to be simplified so that political leaders and members of the public can understand and act on it, said Bloom. As an example, he proposed a “marketing” strategy, proclaiming, “With the appropriate funds, leadership, and organization, we can save X number of lives every year and prevent Y number of lives from being infected with drug-resistant TB.”
Gao made a similar point in his remarks, noting that better treatment will require greater societal involvement, which in turn will require that MDR TB be acknowledged as a serious disease. TB and MDR TB are as much a social as a medical problem. “Without society paying attention to MDR TB, we cannot solve this problem,” he said. In that respect, countries could learn from the response to the HIV epidemic, whereby recognition of the magnitude of the problem led to a greater response than has been the case with DR TB.
