M. Claassens, University of Namibia - Hotspots, hospitals and households: enhanced drug-resistant tuberculosis case finding in Namibia (H3TB)

BACKGROUND
Each year over half a million individuals develop multidrug-resistant (MDR) tuberculosis (TB), a type of TB caused by organisms that are resistant to the two most effective anti-TB drugs, rifampicin and isoniazid. Although this is only 5% of the total TB burden, it consumes over 50% of the TB budget in many high TB burden countries and is a major threat to plans to eliminate TB. To prevent ongoing transmission of MDR-TB, infectious cases must be identified early, diagnosed and put on treatment. Frequently, patients wait a long time before they seek care, by when they have infected many others. By actively searching for MDR-TB cases, in places where they are likely to be found, individuals can be found more effectively. The best methods of finding patients are currently unclear. Whole genome sequencing (WGS) is a relatively new technology that can tell us the genetic 'fingerprint' of organisms. By looking at small changes between the organisms in different patients, you can tell how related the organisms are and consequently in which order, and when, transmission likely took place. If this is combined with methods to map the social networks of patients to see where they live, socialise, work and carry out their daily lives, geographical transmission hotspots can be identified and targeted as places in which active case finding of MDR-TB patients may be effective. Other ways of finding new TB patients are a) screening close and household contacts of TB patients and b) screening visitors to TB hospitals. Both groups are at increased risk of having TB themselves.

RESEARCH QUESTIONS
1. Can transmission hotspots be identified using a combination of WGS and social network mapping?
2. How effective are three active case finding strategies for identifying MDR-TB cases, namely targeting transmission hotspots, close contacts, and hospital visitors?
3. If active case finding were scaled nationally, what would be the impact on the MDR-TB epidemic and would it be cost effective?

PROPOSED RESEARCH
We plan to work in two regions of Namibia and over a two-year period identify all MDR-TB cases that are diagnosed (about 300 cases). We will carry out WGS on the isolates from individuals to evaluate relatedness and transmission dynamics. We will contact and interview the patients, collecting clinical, epidemiological and social network data. We will combine WGS and social network data to identify geographical sites where transmission could take place. We will carry out feasibility studies to evaluate three methods of active case-finding. These will be through the targeting of the transmission hotspots, through screening of close and household contacts of MDR-TB patients and through evaluation of visitors to MDR-TB hospitals. These feasibility studies will involve qualitative research in which we interview patients and staff, to find out how acceptable the interventions are, as well as quantitative research, where we measure the proportion of cases that are identified and how much the activities cost. The final part is to use mathematical models to determine what would be the impact on the national burden of MDR-TB if these different strategies for case finding were employed, in terms of transmission reduction and reducing the overall burden of new MDR-TB cases. We would also evaluate the cost and cost effectiveness of these approaches.

WHO IS INVOLVED IN THE RESEARCH
The research will be carried out in Namibia by Dr. Claassens and a team of researchers at the University of Namibia. This team will be supported by the PI of the project, Dr. James Seddon, and the team in Borstel, led by Prof. Stefan Niemann. Imperial College London will support the Namibian research team.

POTENTIAL BENEFITS
If it is possible to identify transmission hotspots and if targeting case finding to these locations is effective and cost effective, this could prove to be an important strategy that might be employed to fight the MDR-TB epidemic.

BACKGROUND
Poor case management, pharmacokinetic variability and on-going transmission have fostered the MDR-TB epidemic leading to a global estimated number of >500,000 new MDR-TB cases per year. Namibia is a high TB burden country with an incidence rate of 446/100,000 in 2016; ~11,000 new cases per year. 3.9% of new cases and 8.7% of previously treated cases have MDR-TB. Whole genome sequencing has been applied to interrogate the complete genetic code of M tuberculosis and can be used to infer relationships between identified strains.

OBJECTIVES
1) Characterise the MDR-TB epidemic, in terms of clinical, epidemiological, geospatial, social network and laboratory data, in order to identify transmission hotspots
2) Evaluate the feasibility of targeted case finding intervention strategies
3) Develop a transmission model to investigate the impact of case finding intervention strategies on MDR-TB incidence.

METHODS
Individuals with GeneXpert MTB/RIF rifampicin-resistant samples and a positive M tuberculosis culture from two regions in Namibia will be included in a transmission hotspot identification study. Clinical, epidemiological, geospatial, social network and laboratory data (GeneXpert MTB/RIF, culture, drug sensitivity tests) will be collected and whole genome sequencing performed. The results in conjunction with a systematic review and meta-analysis will inform the design of case finding interventions which will be evaluated through a mixed-methods feasibility study at high transmission areas (hotspots, households and hospitals). Data from these studies and the TB programme will be used to develop a transmission model, including a health economics component.

IMPACT
The project will strengthen MDR-TB diagnosis, surveillance and control, inform case finding policy in Namibia and regionally, inform resource allocation by identifying high transmission areas and create preliminary data to design a large-scale MDR-TB case finding intervention.

WHO WILL BENEFIT FROM THE RESEARCH?
Our work will be of interest to academic partners, including project staff, but also health service partners and policy-makers. Other beneficiaries will include members of the communities from which the data were captured, business partners such as the Namibian Institute of Pathology (NIP), as well as members of the public with an interest in research, science and TB. These include:

1. MDR-TB patients, their families and other close contacts
2. Communities with high MDR-TB burdens
3. Healthcare workers caring for MDR-TB patients
4. Policy-makers
5. Clinical, epidemiological and social scientists at Imperial and UNAM, including project staff
6. The wider academic community
7. Industry involved in MDR-TB diagnostics, e.g. NIP
8. Ministries of Health and National TB Programmes
9. Advocates for MDR-TB
10. Members of the public with an interest in research, science and TB

HOW WILL THEY BENEFIT?
1. The H3TB project has the potential to make a dramatic difference to the lives of MDR-TB patients, their families and other close contacts. If we could identify transmission hotspots and improve case finding, we could address community transmission.
2. Community members will benefit from our research when feasible interventions are implemented and reduce TB incidence in their communities, thereby improving their health and wellbeing.
3. Healthcare workers will better understand MDR-TB transmission, allowing them to target interventions more directly and permit more effective activities.
4. Health service partners and policy-makers (local, national and international) will indirectly benefit from our research through the discovery of cost-effective interventions, which could be piloted and, if shown to be effective, scaled-up.
5. The project staff will benefit by working on the project through the development of their own skills in TB research, including planning, implementing, analysing and writing-up of results. In addition, they will collaborate with a group of multidisciplinary experts (clinical epidemiologists, statisticians, modellers) which will contribute to their academic development in TB research, as well as increase their capability and research networks.
6. Local and international colleagues will be able to use our methods in their own projects and compare our results with theirs, in order to broaden the scientific base from which decisions can be made.
7. Our business partner, the NIP, will benefit through our collaboration when we use updated guidelines from the World Health Organization to determine laboratory algorithms, using the latest sputum examination techniques. This will encourage the NIP to employ these techniques in their own research and service delivery.
8. Findings of the H3TB project may reduce the burden of MDR-TB, reducing costs to National TB Programmes, and which could be redirected to other priorities.
9. Advocates for MDR-TB could use the findings of our project to communicate the message that enhanced case finding could make a drastic difference to community transmission and incidence.
10. Members of the public will indirectly benefit from our research by being given the opportunity to actively engage with researchers through traditional and social media, in order to stimulate dissemination and dialogue. In this way, we will be able to formulate additional ideas and hypotheses by getting inputs from a wider range of audiences, including service deliverers as well as researchers and scientists from other disciplines.

Realistic timescales for the benefits to realise will be during the five-year timespan of the H3TB project especially for benefits regarding the project staff, local and international colleagues, the NIP, and members of the public. Long-term benefits (during and after the completion of the project) will include those relating to health service partners, policymakers and community members.