Improving understanding of disease control implementation research through a mooc with participants from low- and middle-income countries: Evaluating participant reactions and learning.

The Special Programme for Research and Training in Tropical Diseases developed a massive open online course (MOOC) on implementation research with a focus on infectious diseases of poverty (IDPs) to reinforce the explanation of implementation research concepts through real case studies. The target MOOC participant group included public health officers, researchers and students. By reshaping institutions and building resilience in communities and systems, implementation research will allow progress towards universal health coverage and sustainable development goals. This study evaluates learners' knowledge in implementation research after completing the MOOC using anonymous exit survey responses. Of the almost 4000 enrolled in the two sessions of the MOOC in 2018, about 30% completed all five modules and the assessments, and were awarded certificates. The majority of the participants were early to mid-career professionals, under the age of 40, and from low- and middle-income countries. They were slightly more likely to be men (56%) with a Bachelor or a Master's degree. Participants were public health researchers (45%), public health officers (11%) or students (11%). On completion of the course, an exit survey revealed that 80.9% of respondents indicated significant improvement to strong and very strong implementation research knowledge. This evaluation clearly shows the usefulness of the MOOC on implementation research for reaching out to field researchers and public health practitioners who are facing problems in the implementation of control programmes in low- and middle-income countries.

Benefits and barriers in a clinical research competency development scheme for low- and middle-income countries.

BACKGROUND: The EDCTP-TDR Clinical Research and Development Fellowship (CRDF) scheme has offered one-year clinical research training placements for early- and mid-career researchers from LMIC since 1999. OBJECTIVE: Using the results of a 2018 external evaluation of the CRDF, the current article aims to identify the principal benefits for the main stakeholders of the CRDF scheme as well as the main barriers to accessing these benefits. METHOD: Data analysis was derived from an external evaluation of the CRDF scheme. Based on a logical framework approach, data for the external evaluation was collected through document review, interviews, focus groups, and questionnaires collected from the main stakeholder groups. The evaluation was structured along six main themes: relevance, effectiveness, efficiency, impact, sustainability, and equity. RESULTS: The current paper focuses on the expected benefits, unexpected benefits, and barriers to enjoying benefits of the scheme for key stakeholders. DISCUSSION: Expected benefits were aligned with the development of clinical research competencies, which is the objective of the scheme. Unexpected benefits centred on transferable professional skills in scientific leadership and knowledge translation. Barriers mainly were found around engagement with home institutions and the return and reintegration of fellows following the training period. CONCLUSIONS AND RECOMMENDATIONS: Recommendations include further engagement with and support for home institutions and developing a formal framework for the development of transferable professional competencies, including leadership and knowledge transfer competencies.

Strengthening the core health research capacity of national health systems helps build country resilience to epidemics: a cross-sectional survey.

Background:  TDR, The Special Programme for Research and Training hosted at the World Health Organization, has long supported Low- and Middle-Income Countries in strengthening research capacity through three training programmes: the Postgraduate Training Scheme (PGTS), the Clinical Research and Development Fellowship (CRDF), and the Structured Operational Research Training InitiaTive (SORT IT). In the advent of the COVID-19 pandemic, we assessed whether those trained through these programmes were involved in the COVID-19 response and if so, in which area(s) of the emergency response they were applying their skills. Methods: From the records for each training programme, we identified the individuals who had completed training during the relevant timespan of each programme: 1999-2018 for the CRDF scheme, 2015-2020 for PGTS, and 2009-2019 for SORT-IT. Between March and April 2020, we sent trainees an online questionnaire by e-mail. Results: Out of 1254 trained, 1143 could be contacted and 699 responded to the survey. Of the latter, 411 were involved with the COVID-19 response, of whom 315 (77%) were applying their acquired skills in 85 countries. With some overlap between programmes, 84% of those trained through CRDF were applying their skills in 27 countries, 91% of those trained through PGTS were applying their skills in 19 countries, and through SORT IT, this was 73% in 62 countries.  Skills were being applied in various areas of the emergency response, including: emergency preparedness, situation analysis/surveillance, infection control and clinical management, data generation, mitigating the effect of COVID on the health system, and research.  Depending on the type of training programme, 26-74% were involved in implementation, operational or clinical research. Conclusion: Research training programmes build research capacity and equip health workers with transferable core competencies and skillsets prior to epidemics. This becomes invaluable in building health system resilience at a time of pandemics.

Developing a framework of core competencies in implementation research for low/middle-income countries.

The field of implementation research (IR) is growing. However, there are no recognised IR core competencies in low/middle-income countries (LMICs), nor consistent curriculum across IR training programs globally. The goal of this effort is to develop a framework of IR core competencies for training programs in LMICs. The framework was developed using a mixed-methods approach consisting of two online surveys with IR training coordinators (n = 16) and academics (n = 89) affiliated with seven LMIC institutions, and a modified-Delphi process to evaluate the domains, competencies and proficiency levels included in the framework. The final framework comprised of 11 domains, 59 competencies and 52 sub-competencies, and emphasised competencies for modifying contexts, strengthening health systems, addressing ethical concerns, engaging stakeholders and communication especially for LMIC settings, in addition to competencies on IR theories, methods and designs. The framework highlights the interconnectedness of domains and competencies for IR and practice, and training in IR following the outlined competencies is not a linear process but circular and iterative, and starting points for training may vary widely by the project, institution and challenge being addressed. The framework established the need for a theory-based approach to identifying proficiency levels for IR competencies (ie, to determine proficiency levels for IR based on generalisable educational theories for competency-based education), and the relevance of various IR competencies for LMICs compared with high-income settings. This framework is useful for identifying and evaluating competencies and trainings, and providing direction and support for professional development in IR.

Tracking the career development of scientists in low- and middle-income countries trained through TDR's research capacity strengthening programmes: Learning from monitoring and impact evaluation.

The Special Programme for Research and Training in Tropical Diseases (TDR) co-sponsored by UNICEF, UNDP, World Bank and WHO has been supporting research capacity strengthening in low- and middle-income countries for over 40 years. In order to assess and continuously optimize its capacity strengthening approaches, an evaluation of the influence of TDR training grants on research career development was undertaken. The assessment was part of a larger evaluation conducted by the European Science Foundation. A comprehensive survey questionnaire was developed and sent to a group of 117 trainees supported by TDR who had completed their degree (masters or PhD) between 2000 and 2012; of these, seventy seven (77) responded. Most of the respondents (80%) rated TDR support as a very important factor that influenced their professional career achievements. The "brain drain" phenomenon towards high-income countries was particularly low amongst TDR grantees: the rate of return to their region of origin upon completion of their degree was 96%. A vast majority of respondents are still working in research (89%), with 81% of respondents having participated in multidisciplinary research activities; women engaged in multidisciplinary collaboration to a higher extent than men. However, only a minority of all have engaged in intersectoral collaboration, an aspect that would require further study. The post-degree career choices made by the respondents were strongly influenced by academic considerations. At the time of the survey, 92% of all respondents hold full-time positions, mainly in the public sector. Almost 25% of the respondents reported that they had influenced policy and practice changes. Some of the challenges and opportunities faced by trainees at various stages of their research career have been identified. Modalities to overcome these will require further investigation. The survey evidenced how TDR's research capacity grant programmes made a difference on researchers' career development and on south-south collaborations, by strengthening and localizing research capacity in lower income regions, and also showed there is more that needs to be done. The factors involved, challenges and lessons learnt may help donors and policy makers improve their future interventions with regard to designing capacity strengthening programmes and setting funding priorities.

Operational and implementation research within Global Fund to Fight AIDS, Tuberculosis and Malaria grants: a situation analysis in six countries.

BACKGROUND: Operational/implementation research (OR/IR) is a key activity to improve disease control programme performance. We assessed the extent to which malaria and tuberculosis (TB) grants from the Global Fund to Fight AIDS, Tuberculosis and Malaria ("Global Fund") include support for OR/IR, and discuss the implications of the current Global Fund operating mechanisms for OR/IR support. METHODS: The situation analysis focussed on malaria and TB, while HIV was excluded. Stakeholder interviews were conducted at the Global Fund secretariat and in six purposefully selected high disease burden countries, namely the Democratic Republic of the Congo, Ethiopia, India, Indonesia, Myanmar and Zimbabwe. Interviewed in-country stakeholders included the relevant disease control programme managers, project implementation partners, representatives from international organisations with a stake in global health, academic and governmental research institutions, and other relevant individuals such as members of the country coordination mechanism. Additionally, documentation of grants and OR/IR obtained from the Global Fund was reviewed. RESULTS: The Global Fund provides substantial resources for malaria and TB surveys, and supports OR/IR if such support is requested and the application is well justified. We observed considerable variations from one country to another and between programmes with regards to need, demand, absorption capacity and funding for OR/IR related to malaria and TB. Important determinants for the extent of such funding are the involvement of national research coordination bodies, established research agendas and priorities, human and technical research capacity, and involvement of relevant stakeholders in concept note development. Efforts to disseminate OR/IR findings were generally weak, and the Global Fund does not maintain a central OR/IR database. When faced with a need to choose between procurement of commodities for disease control and supporting research, countries tend to seek research funding from other donors. The Global Fund is expected to issue more specific guidance on the conditions under which it supports OR/IR, and to adapt administrative procedures to facilitate research. CONCLUSIONS: The importance of OR/IR for optimising disease control programmes is generally accepted but countries vary in their capacity to demand and implement studies. Countries expect guidance on OR/IR from the Global Fund. Administrative procedures specifically related to the budget planning should be modified to facilitate ad-hoc OR/IR funding. More generally, several countries expressed a need to strengthen capacity for planning, negotiating and implementing research.

Developing the ethics of implementation research in health.

Implementation research (IR) is growing in recognition as an important generator of practical knowledge that can be translated into health policy. With its aim to answer questions about how to improve access to interventions that have been shown to work but have not reached many of the people who could benefit from them, IR involves a range of particular ethical considerations that have not yet been comprehensively covered in international guidelines on health research ethics. The fundamental ethical principles governing clinical research apply equally in IR, but the application of these principles may differ depending on the IR question, context, and the nature of the proposed intervention. IR questions cover a broad range of topics that focus on improving health system functioning and improving equitable and just access to effective health care interventions. As such, IR designs are flexible and often innovative, and ethical principles cannot simply be extrapolated from their applications in clinical research. Meaningful engagement with all stakeholders including communities and research participants is a fundamental ethical requirement that cuts across all study phases of IR and links most ethical concerns. Careful modification of the informed consent process may be required in IR to permit study of a needed intervention. The risks associated with IR may be difficult to anticipate and may be very context-specific. The benefits of IR may not accrue to the same groups who participate in the research, therefore justifying the risks versus benefits of IR may be ethically challenging. The expectation that knowledge generated through IR should be rapidly translated into health policy and practice necessitates up-front commitments from decision-makers to sustainability and scalability of effective interventions. Greater awareness of the particular ethical implications of the features of IR is urgently needed to facilitate optimal ethical conduct of IR and uniform ethical review.

Efficacy and Safety of 'Fixed Dose' versus 'Loose' Drug Regimens for Treatment of Pulmonary Tuberculosis in Two High TB-Burden African Countries: A Randomized Controlled Trial.

BACKGROUND: There are limited data on the performance of the use of fixed-dose combination (FDC) TB drugs when used under programmatic settings in high TB-endemic countries. We evaluated the efficacy and safety of FDC versus loose formulation (LF) TB treatment regimens for treatment of pulmonary TB (PTB) in the context of actual medical practice in prevailing conditions within programmatic settings in five sites in two high TB-burden African countries. METHODS: A two-arm, single-blind, randomized clinical trial comparing FDCs with separate LFs involving 1000 adults newly diagnosed with culture positive PTB was conducted at five sites in two African countries between 2007 and 2011. Participants were randomized to receive daily treatment with anti-TB drugs given as either FDC or separate LFs for 24 weeks (intensive phase- 8 weeks of isoniazid, rifampicin, ethambutol and pyrazinamide; continuation phase- 16 weeks of rifampicin and isoniazid). Primary outcome measures were microbiological cure and safety at the end of six months' treatment; pre-specified non-inferiority margin for difference in cure rate was 4%. The primary efficacy analysis was based on the modified intent to treat (mITT) cohort comprising all randomized patients with a positive baseline culture result for TB and who received at least one dose of study treatment. Patients missing end of treatment culture results were considered failures. Further analyses were done in which mITT patients without an end of treatment (EOT) culture were excluded in a complete case analysis (mITTcc) and a per protocol cohort analysis defined as mITTcc patients who received at least 95% of their intended doses and had an EOT culture result. RESULTS: In the mITT analysis, the cure rate in the FDC group was 86.7% (398/459) and in the LF group 85.2% (396/465) (difference 1.5-% (90% confidence interval (CI) (-2.2%- 5.3%)). Per Protocol analysis showed similar results: FDC 98.9% (359/363) versus LF 96.9% (345/356), (difference 2.0% (90% CI: 0.1%- 3.8%)). The two arms showed no significant differences in terms of safety, early culture conversion and patient adherence to treatment. INTERPRETATION: The comparison of the two drug regimens satisfied the pre-specified non-inferiority criterion. Our results support the WHO recommendations for the use of FDC in the context of actual medical practice within health services in high TB-endemic countries. TRIAL REGISTRATION: ISRCTN Registry 95204603.

Research Capacity Strengthening in Low and Middle Income Countries - An Evaluation of the WHO/TDR Career Development Fellowship Programme.

Between August 2012 and April 2013 the Career Development Fellowship programme of the Special Programme for Research and Training in Tropical Diseases (World Health Organization) underwent an external evaluation to assess its past performance and determine recommendations for future programme development and continuous performance improvement. The programme provides a year-long training experience for qualified researchers from low and middle income countries at pharmaceutical companies or product development partnerships. Independent evaluators from the Swiss Tropical and Public Health Institute and the Barcelona Institute for Global Health used a results-based methodology to review the programme. Data were gathered through document review, surveys, and interviews with a range of programme participants. The final evaluation report found the Career Development Fellowship to be relevant to organizers' and programme objectives, efficient in its operations, and effective in its training scheme, which was found to address needs and gaps for both fellows and their home institutions. Evaluators found that the programme has the potential for impact and sustainability beyond the programme period, especially with the successful reintegration of fellows into their home institutions, through which newly-developed skills can be shared at the institutional level. Recommendations included the development of a scheme to support the re-integration of fellows into their home institutions post-fellowship and to seek partnerships to facilitate the scaling-up of the programme. The impact of the Professional Membership Scheme, an online professional development tool launched through the programme, beyond the scope of the Career Development Fellowship programme itself to other applications, has been identified as a positive unintended outcome. The results of this evaluation may be of interest for other efforts in the field of research capacity strengthening in LMICs or, generally, to other professional development schemes of a similar structure.

Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial.

BACKGROUND: WHO guidelines recommend early initiation of antiretroviral therapy (ART) irrespective of CD4 cell count for all patients with tuberculosis who also have HIV, but evidence supporting this approach is poor quality. We assessed the effect of timing of ART initiation on tuberculosis treatment outcomes for HIV-positive patients with CD4 counts of 220 cells per µL or more. METHODS: We did this randomised, placebo-controlled trial between Jan 1, 2008, and April 31, 2013 at 26 treatment centres in South Africa, Tanzania, Uganda, and Zambia. We enrolled HIV-positive patients with culture-confirmed tuberculosis who had tolerated 2 weeks of tuberculosis short course chemotherapy. Participants were randomly allocated (1:1) to early ART (starting after 2 weeks of tuberculosis treatment) or delayed ART (placebo, then starting ART at the end of 6 months of tuberculosis treatment). Randomisation was computer generated, with permuted blocks of size eight, and stratified by CD4 count (220-349 cells per µL vs ≥350 cells per µL). Patients and investigators were masked to treatment allocation until completion of 6-months' tuberculosis treatment, after which the study was open label. The primary endpoint was a composite of failure of tuberculosis treatment, tuberculosis recurrence, and death within 12 months of starting tuberculosis treatment in the modified intention-to-treat population. Secondary endpoints included mortality. The study is registered with controlled-trials.com (ISRCTN77861053). FINDINGS: We screened 13,588 patients and enrolled 1675: 834 assigned early ART, 841 delayed ART. The primary endpoint was reached by 65 (8·5%) of 767 patients in the early ART group versus 71 (9·2%) of 771 in the delayed ART group (relative risk [RR] 0·91, 95% CI 0·64-1·30; p=0·9). Of patients with a CD4 cell count of 220-349 cells per µL, 26 (7·9%) of 331 patients versus 33 (9·6%) of 342 reached the primary endpoint (RR 0·80, 95% CI 0·46-1·39; p=0·6). For those with 350 cells per µL or more, 39 (8·9%) of 436 versus 38 (8·9%) of 429 reached the primary endpoint (RR 1·01, 95% CI 0·63-1·62; p=0·4). Mortality did not differ significantly between treatment groups (RR 1·4, 95% CI 0·8-2·3; p=0·23). Grade 3 and 4 adverse events occurred in 149 (18%) of 834 patients assigned early ART versus 174 (21%) of 841 assigned delayed ART (p=0·37). 87 (10%) of 834 versus 84 (10%) of 841 had immune reconstitution inflammatory syndrome (p=0·56). INTERPRETATION: ART can be delayed until after completion of 6 months of tuberculosis treatment for HIV-positive patients with tuberculosis who have CD4 cell counts greater than 220 cells per µL. WHO guidelines should be updated accordingly. FUNDING: USAID, Zambia Ministry of Health, Tanzania Commission for Science and Technology, WHO-TDR.

Reduced antituberculosis drug concentrations in HIV-infected patients who are men or have low weight: implications for international dosing guidelines.

Reduced antituberculosis drug concentrations may contribute to unfavorable treatment outcomes among HIV-infected patients with more advanced immune suppression, and few studies have evaluated pharmacokinetics of the first-line antituberculosis drugs in such patients given fixed-dose combination tablets according to international guidelines using weight bands. In this study, pharmacokinetics were evaluated in 60 patients on 4 occasions during the first month of antituberculosis therapy. Multilevel linear mixed-effects regression analysis was used to examine the effects of age, sex, weight, drug dose/kilogram, CD4(+) lymphocyte count, treatment schedule (5 versus 7 days/week), and concurrent antiretrovirals (efavirenz plus lamivudine plus zidovudine) on the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) of the respective antituberculosis drugs and to compare AUC(0-12)s at day 8, day 15, and day 29 with the day 1 AUC(0-12). Median (range) age, weight, and CD4(+) lymphocyte count were 32 (18 to 47) years, 55.2 (34.4 to 98.7) kg, and 252 (12 to 500)/µl. For every 10-kg increase in body weight, the predicted day 29 AUC(0-12) increased by 14.1% (95% confidence interval [CI], 7.5, 20.8), 14.1% (95% CI, -0.7, 31.1), 6.1% (95% CI, 2.7, 9.6) and 6.0% (95% CI, 0.8, 11.3) for rifampin, isoniazid, pyrazinamide, and ethambutol, respectively. Males had day 29 AUC(0-12)s 19.3% (95% CI, 3.6, 35.1) and 14.0% (95% CI, 5.6, 22.4) lower than females for rifampin and pyrazinamide, respectively. Level of immune suppression and concomitant antiretrovirals had little effect on the concentrations of the antituberculosis agents. As they had reduced drug concentrations, it is important to review treatment responses in patients in the lower weight bands and males to inform future treatment guidelines, and revision of doses in these patients should be considered.

Biomarkers for tuberculosis disease activity, cure, and relapse.

New drugs, vaccines, and other therapies will be required to realise the goal of global tuberculosis elimination or control. This Review covers the important role biomarkers can have in accelerating drug development by providing validated surrogate endpoints that can bring enhanced statistical power to small short studies. Candidate biomarkers should differentiate people with active tuberculosis from healthy individuals, normalise with therapy, and reproducibly predict clinical outcomes in diverse patient populations. Although a large number of promising candidate biomarkers have been examined to date, few patients in these studies have reached clinically meaningful outcomes, and few of the studies have been conducted to international research standards. These markers must be further studied in tuberculosis treatment trials to evaluate the kinetics of the responses and their relation to long-term clinical outcomes. These studies will benefit from multidisciplinary collaborations including microbiologists, immunologists, clinicians, tuberculosis control personnel, and the pharmaceutical and biotechnology industry.

Immunity against HIV/AIDS, malaria, and tuberculosis during co-infections with neglected infectious diseases: recommendations for the European Union research priorities.

Infectious diseases remain a major health and socioeconomic problem in many low-income countries, particularly in sub-Saharan Africa. For many years, the three most devastating diseases, HIV/AIDS, malaria, and tuberculosis (TB) have received most of the world's attention. However, in rural and impoverished urban areas, a number of infectious diseases remain neglected and cause massive suffering. It has been calculated that a group of 13 neglected infectious diseases affects over one billion people, corresponding to a sixth of the world's population. These diseases include infections with different types of worms and parasites, cholera, and sleeping sickness, and can cause significant mortality and severe disabilities in low-income countries. For most of these diseases, vaccines are either not available, poorly effective, or too expensive. Moreover, these neglected diseases often occur in individuals who are also affected by HIV/AIDS, malaria, or TB, making the problem even more serious and indicating that co-infections are the rule rather than the exception in many geographical areas. To address the importance of combating co-infections, scientists from 14 different countries in Africa and Europe met in Addis Ababa, Ethiopia, on September 9-11, 2007. The message coming from these scientists is that the only possibility for winning the fight against infections in low-income countries is by studying, in the most global way possible, the complex interaction between different infections and conditions of malnourishment. The new scientific and technical tools of the post-genomic era can allow us to reach this goal. However, a concomitant effort in improving education and social conditions will be needed to make the scientific findings effective.