Poor case management, pharmacokinetic variability and on-going transmission have fostered the drug-resistant tuberculosis (DR-TB) epidemic leading to a global estimated number of >500,000 new multidrug resistant (MDR) TB cases per year, of which roughly 10% are extensively drug resistant (XDR). Namibia is a high TB burden country with an incidence rate of 446/100,000 in 2016; about 11,000 new cases per year. 3.9% of new cases and 8.7% of previously treated cases have MDR-TB. Whole genome sequencing (WGS) has recently been applied to interrogate the complete genetic code of Mycobacterium tuberculosis (Mtb) strains. WGS can be used to infer relationships between identified strains as well as determine genomic variations involved in resistance development.

The specific aims of the H3TB study are to: (i) characterise the DR-TB epidemic, in terms of clinical, epidemiological, geospatial, social network and laboratory data, to identify transmission hotspots in three regions of Namibia, (ii) evaluate the feasibility of targeted case finding intervention strategies to improve DR-TB control in highly affected populations and (iii) develop a transmission model to investigate the potential impact of the case finding intervention strategies on DR-TB incidence in Namibia.

A prospective surveillance study started in January 2020, which includes all DR-TB cases in Namibia, and which will nest H3TB. Data collection tools and other study implementation tools have been designed and implemented. The study team is working in close collaboration with the National Institute of Pathology, where all DR-TB cases from the country are registered, to ensure all possible cases are captured. This is important for the identification of transmission hotspots.

After HREC and MOHSS approval, individuals with GeneXpert® MTB/RIF rifampicin-resistant samples and a positive Mtb culture from three regions in Namibia will be included in a transmission hotspot identification study. Preliminary data have shown that DR-TB clusters exist in these regions. Clinical, epidemiological, geospatial, social network and laboratory data (GeneXpert® MTB/RIF, culture, drug sensitivity tests) will be collected. WGS capacity has been established at the UNAM research laboratory, where WGS will be performed on the samples of H3TB participants; results will be validated at the Research Center Borstel in Germany. These study 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 conducted at high transmission areas (hotspots, households and hospitals). Data from these studies and the TB programme will be used to develop the model which will include a health economics component.

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

Inclusion Criteria:

• All cases diagnosed with drug-resistant TB in Namibia, in three regions of Khomas, Otjozondjupa and Ohangwena will be included for the first outcome. For the second outcome, all household members of DR-TB cases will be included; all hospital visitors to DR-TB cases will be included and community members at transmission hotspots will be included.

Exclusion Criteria:

• Anyone who does not give consent to participate.

For the first outcome, the study population is all DR-TB cases in three regions of Namibia, diagnosed by the National Institute of Pathology (GeneXpert Ultra Rifampicin resistant) over 18 months.

For the second outcome, all household contacts of DR-TB cases in the three regions is the study population, as well as DR-TB patients' hospital visitors and community members at transmission hotspots.

Data will be shared after the acceptance for publication of the main findings from the final dataset by researchers' efforts if a data transfer agreement is made between the custodians of the data (the H3TB study team) and other researchers, that: (i) data will be used only for research purposes, (ii) proper technological measures will be used to ensure data security, (iii) no effort will be made to identify study participants, (iv) data will be destroyed after the agreed analyses and (v) the data source will be acknowledged.

The sequencing data will be made available on ReSeqTB or a similar platform. The other data will be stored locally at UNAM in a tailored database and made available by researchers' efforts. These data include individual-level information on health status (e.g., TB and HIV infection status) which cannot be made publicly available.

Once the primary analyses are complete, manuscripts submitted and final reports submitted to funding agencies.