Brazilian Response to Global End TB Strategy : The National Tuberculosis Research Agenda

Afranio Kritski[1],[2], Draurio Barreira[3], Ana Paula Junqueira-Kipnis[1],[4], Milton Ozorio Moraes[5], Maria Martha Campos[1],[6], Wim Mauritz Degrave[7], Silvana Spindola Miranda[1],[8], Marco Aurelio Krieger[1],[9], Erica Chimara[1],[10], Carlos Morel[11], Margareth Pretti Dalcolmo[1],[12], Ethel Leonor Noia Maciel[1],[13], Maria do Socorro Nantua Evangelista[3],[14], Teresa Scatena Villa[1],[15], Mauro Sanchez[1],[16], Fernanda Dockhorn Costa[3], Inacio Queiroz[17], Martha Maria Oliveira[1],[11], Ruy Souza Junior[3], Jose Roberto Lapa e Silva[1],[2] and Antonio Ruffi no-Netto[1],[18]


INTRODUCTION
The Global End Tuberculosis (TB) Strategy, endorsed by the World Health Assembly in May 2014, aims to reduce TB deaths and incidence in all countries to levels currently observed in high-income countries. This can be achieved via reducing mortality, improving early diagnosis, providing more effective treatment, monitoring possible mycobacterial resistance, and expanding contact tracing and infection control (1) (2) . The strategy is based on three pillars: integrated, patient-centered care and prevention (Pillar 1); bold policies and supportive systems (Pillar 2); and intensified research and innovation (Pillar 3) (3) . Achieving these ambitious goals within countries currently devastated by TB-in other words, whose citizens suffer significant morbidity and mortality from TB-will require substantial expansion of TB-related research (i.e., Pillar 3) within these countries (3) (4) (5) .
In November 2014, the World Health Organization (WHO) designated Brazil as one of the few model countries that already have substantial TB research capacity and could achieve these goals rapidly. Furthermore, it highlighted the importance of the existing Brazilian TB Research Network (Rede TB), which has been working closely with the National TB Program (NTP) of the Ministry of Health (MoH) over the last 10 years. Rede TB is a non-governmental non-profit organization (www. redetb.org) that aims to improve TB control via focusing on integrated research activities through collaborative actions involving researchers, students, health professionals, industry, civil society, and the government (6) (7) (9) , Global Plan to End TB (10) ), we reviewed the National TB Research Agenda. The aim of this technical report is to present the results of the actions that led to the establishment of the National TB Research Strategy Plan, which was launched in November 2015. In June 12, 2015, a summary of the key ongoing activities, gaps, and priorities in TB research established for each research platform were presented in a meeting organized by Rede TB, FIOCRUZ, and the NTP in Rio de Janeiro. The general recommendations and priorities for each platform noted in this meeting were consolidated as key steps for developing and implementing a National TB Research Strategy Plan, which are here further disseminated for use by national and international stakeholders.

GENERAL RECOMMENDATIONS
Considering that the "Global End TB Strategy" does not merely attempt to address a biomedical public health problem, but also a development challenge, achieving it must go beyond mere development of TB programs. The following recommendations have been made towards achieving the Global End TB Strategy: 1. Promote the creation of a national TB research committee that will foster the inclusion of Pillar 3 (research) of the Global End TB strategy (2) and Stop TB Partnership's Global Plan (2016-2020) (10)  3. Promote exchange experience between junior and senior scientists from international research groups 4. Provide training courses for fundamental and translation scientists pursuing interaction between academia and industry.
5. Improve the interaction between Brazilian groups carrying out translational studies, especially those performing cohort studies or clinical research.

Research priorities
1. Develop new vaccines using new biotechnologic methods such as knockouts, knockdown, or the CRISPR-Cas-9 (clustered regularly interspaced short palindromic repeats-CRISPR-associated nusclease 9) approach. 2. Investigate host-pathogen interaction targeting new genetic, molecular, immunological, or metabolic markers, through the following: • Large-scale approaches using omics techniques such as genetic epidemiology (e.g., evaluate single nucleotide polymorphisms (SNPs) in candidate genes or genome-wide associated studies). • Projects with a large-scale population with the disease phenotype or well-characterized endophenotypes. • Gene expression studies of molecular markers in the blood or other clinical samples, which can result in identification of molecular signatures and gene maps that can be used to define a risk score for progression to disease in contacts. • Developing a robust database of clinical data, including metabolomic and proteomic analyses of serum or urine samples and data on the activation (or deactivation) of the immune response (e.g., interferon gamma release assay [IGRA] with new specific mycobacterial antigens). • Studies on the genetics of the pathogen useful for epidemiological surveillance aimed at infection control, evolution of resistance, or monitoring the virulence states of specific strains. • Large-scale experimental model studies of pathogen growth in specific culture conditions or infections that assist in the understanding of pathogenesis mechanisms, such as ESX-1, which surrounds protective immune cells and reprograms host cells or enzymes (Zimp) that control the tissue physiology of the patient. • Collecting data that consolidates the studies mentioned above, and evaluating how different strains can activate the immune response or jointly evaluating the genetics of the host and pathogen.

DRUG DEVELOPMENT AND PRODUCTION PLATFORM
Strategies to correct gaps 1. Create a coordination research group on drug development that pursues increased collaboration among labs to better utilize the available knowledge of different groups.

Provide training courses for fundamental and translational
scientists pursuing effective interaction between academia and industry.
3. Create collaborations with Brazilian research groups to provide highly representative and well-evaluated isolate lineages of drug-sensitive and drug-resistant Mtb. These activities should pursue the molecular characterization and creation of a reference biobank of mycobacterial strains using genomics and sequencing for use in the testing cycle for the development of new molecules.
4. Evaluate possible technology transfer for large-scale chemical synthesis with countries such as India or China.
5. Increase the interaction of Brazilian research groups with recognized foreign centers for chemical synthesis and toxicological assays in animal models with rodents and (especially) non-rodents.
6. Create collaborations with international groups with experience in pharmacokinetics and toxicokinetics pursuing joint proposals and exchanging of senior and junior scientists.
7. Increase international collaboration pursuing the production of fixed-dose combinations of drugs for TB among children.
8. Improve the interaction between Brazilian groups that are carrying out translational studies, especially those performing cohort studies or clinical research.

Research priorities
1. Develop pre-clinical studies evaluating new drugs against specific molecular targets for drug-sensitive and drugresistant Mtb.
2. Amplify the screening for target compounds in different environments (e.g., sea, soil).
3. Identify new targets through screening, including high throughput screening (HTS) with natural products and high content screening (HCS) with relevant enzyme assays.

Strategies to correct gaps
1. Create an inter-group support system to develop capacity of operational and health system research coordination at different sites.
2. Increase number of research sites qualified to perform operational research and capable of participating in multicenter projects.
3. Implement quality management system for identified sites.

Designate training sites for operational research (human research and biosafety)
5. Identify international partnerships, with a focus on cofinancing strategies 6. Improve the investment in infrastructure including renovation of laboratory spaces and equipment.

Research priorities
1. Evaluate the services and health care system performance at different health care levels (primary, secondary, and tertiary) in TB control in the general and vulnerable populations (i.e., those with HIV/AIDS, diabetes, or other chronic comorbidities; inmates; people living in international border regions; indigenous people; drug users; and health professionals) focusing on the following topics: • Analysis of more effective access strategies for TB diagnosis and treatment in vulnerable subjects. • Impact analysis of direct and indirect costs for TB patients and for the National Health System in different regions. • Impact of latent TB treatment on disease incidence, both regionally and locally. • Comparison of the performance of innovative approaches to pulmonary TB triage using signs and symptoms. • Impact of diabetes, smoking, and drug addiction on TB, TB/HIV, and MDR-TB control activities. • Analysis of the health unit adoption of the TB Infection Control Recommendations described in the National TB Guidelines (11) . • Evaluate impact of provision of directly observed treatment in the organization of TB services and follow-up of vulnerable TB cases. • Identify the most effective strategies used by services that result in a positive impact in adherence to TB treatment. • Analyze TB patients' access to secondary and tertiary referral centers. • Analyze hospital needs (e.g., beds, complexity of workups, intensive care units) for TB cases with and without social deprivation. • Analyze the quality of care of TB services in primary care. • Evaluate the contribution of traditional healers and the role of traditional medicine in the strengthening and contextualization of TB control actions in the native and culturally differentiated communities. 3. Spatial analysis of avoidable hospitalizations and mortality from TB and social inequalities in various territories.
• Identification of TB distribution considering environmental aspects and social inequalities.
4. Evaluation of policy transfer, technologies, and care practices in the health system for TB control.
• Evaluate the factors that contribute to the development and expansion of new diagnostic technology: Who is involved and affected by innovation and change? How they are bound? Who supports and who opposes or resists innovations?

Strategies to correct gaps
1. Increase number of research sites qualified to perform impact assessment of the incorporation of new technologies and are capable of participating in multicenter projects. 2. Implement quality management system for identified sites. 3. Create training research programs to evaluate the impact of new technologies in the unified health system (Tripartite will help in the development of the TB Research Agenda within the National Health Agenda). 4. Improve investment in infrastructure including renovation of laboratory space and equipment. 5. Acquire financial support via state and national funding agencies. 6. Identify a transfer mechanism such that states and municipalities that incorporate technology assessment in their budgets receive more funds from the central government. 7. Identify international partnerships, with a focus on cofinancing strategies.

Research priorities
1. Perform a clinical impact and economic analysis (costeffectiveness and budget impact) on the following: • Recombinant PPD in the diagnosis of latent TB in different regions of the country. • Xpert MTB/RIF or INH assay, the upcoming Alere q assay, and other molecular tests developed domestically (e.g., QuantStudio 3 real-time PCR system) for use at different health care levels (primary, secondary, and tertiary). • Phenotypic methods (using liquid culture or not) in the detection of MDR and XDR TB in Brazil (i.e., MGIT 960 with TB eXiST software, kit SIRE Nitratase®, TB Scott/Ogawa-Kudoh swab cultures). • Xpert MTB/RIF assays in Brazil that consider different populations (mainly the general population, health professionals, people living with HIV/AIDS, children, persons deprived of liberty, and indigenous populations living in urban areas).
• TB control decentralization for primary care in Brazil. • Use of bedaquiline for treating pre-XDR or fullblown XDR TB on a national scale. • New treatment regimens for latent TB in different regions of Brazil.
• Implementation of quality management system in the research laboratories (collaborating centers) and services (LACENS). • Digital health approaches for TB control, such as use of mobile phones or Skype to support TB screening, diagnosis, and treatment. • Incentives provided for anti-TB treatment.
• Use of TB-Web/SINAN/SIM/SITE-TB systems for TB, TB/HIV, and DR-TB surveillance.

Analysis of:
• The clinical and economic impact of the directly observed treatment for TB in vulnerable populations. • The impact of communication interventions, advocacy, and social mobilization carried out by forums, networks, committees, and NGOs working to fight TB in Brazil. • The impact of actions developed through coordination between civil society and management of states/provinces and municipalities. • Impact on TB control of the relationship between leadership activists and health services managers, locally, regionally, and nationally. • The association between the health care services characteristics and the successful treatment of TB patients. • The association between the characteristics of health care services and TB case detection. • Incorporation of a fixed-dose combination of a drug named 4:01 (RHZE) in Brazil.

COMMUNITY ENGAGEMENT PLATFORM
Strategies to correct gaps 1. Promote a national discussion among TB/TB-HIV activists on research engagement and generate a legitimate community research agenda.
2. Create a permanent educational and incentive platform for community engagement to promote community participation in research based on the following: • Permanent education (diagnostics, treatment and research literacy) and • Funding to establish and support community advisory boards (CABs) and ethics committee participation.
3. Create and maintain a platform and accessible database on research for common users.
4. Promote regular consultation among the various sectors, including the community, academia, health services, and the government and congressmen (e.g., TB Front on National Congress), on research development and the TB agenda.

Research priorities
1. Evaluate strategies to increase interaction between community advocates, researchers, and health professionals on topics such as access to services, quality of service delivery, patient support, and adherence issues.
2. Evaluate the efficacy of different strategies against stigma and discrimination against people with TB from the view of people affected.
3. Assess and document communication interventions, advocacy, and social mobilization carried out by forums, networks, committees, and NGOs working in the fight against TB.
4. Evaluate policy relations between community organizations and TB programs at the three levels of health care (primary, secondary, and tertiary).

Evaluate the efficacy of compulsory hospitalization for TB
in Brazil by engaging patients' perspective.

Strategies to correct gaps
1. Perform an inventory of public health laboratories and collaborating centers conducting TB activities of the established capacity and existing quality management activities.
2. Review policy for public health laboratories and collaborating centers (linked to universities and research institutes) seeking allocation of financial and human resources to implement the much-needed quality management system. 3. Support by mentors for paper publications and results presentation at national and international meetings.

Strategies to correct gaps
The platform should use the successful experiences from the International Clinical, Operational and Health Services Research Training Award project and those strategies presented above, along with others not until now: 1. Shared funding between agencies in Brazil and abroad will allow new collaborations, including research capacity building.
2. More intensive use of the Science without Borders (SwB) program from the Brazilian government. The main goals of the SwB are to increase the presence of students and scientists in international institutions, encourage young talents and highly qualified researchers from abroad to work in Brazil, and facilitate the internationalization of universities.
3. Extension of the Brazilian experience in research capacity building in African Lusophone countries and in Latin American countries.