By: Herman Kosasih, Myrna Evanda Adeline

With 2 billion infected people, 10 million new cases, and 1.5 million deaths yearly, tuberculosis (TB) remains one of the most significant infectious causes of morbidity and mortality worldwide and is the number one cause of death among those infected with HIV. Major research needs span from basic research to identify biomarkers that accurately predict outcomes of active and latent TB to clinical research to measure the efficacy and effectiveness of new tools and strategies for TB. To meet this need, the US National Institutes of Health (NIH) is working with interested governments to provide a platform for coordinated and collaborative approaches to tuberculosis research. These partnerships comprise a consortium called RePORT International.

Starting with just two members, India and Brazil, in 2013, RePORT added Indonesia and South Africa in 2015, China and The Philippines in 2017, and just recently, the Republic of Korea. Each country conducts TB studies that reflect national research goals but are coordinated through the utilization of common standards and practices, including a RePORT International Common Protocol with corresponding case report forms and a manual of operations developed in collaboration with investigators in the various consortia. Data and biospecimen repositories are being developed in each country to store their own data and samples. This platform sets the stage for future combined or comparative data analyses and is an invaluable resource for in-country and cross-national collaborations between bench and clinical researchers.

Since its establishment, RePORT has conducted six annual meetings where every country reports the progress of TB studies and scientific contributions. The 6th annual international meeting in Cape Town, South Africa, is from September 7-8, 2022. The representatives from Indonesia, Dr. Erlina Burhan from the site Persahabatan Hospitals and Dr. Myrna from Dr. Soetomo, Hospital, were invited to give their oral presentations. Dr. Erlina Burhan (the principal investigator of our Tuberculosis research of INA-RESPOND on Drug Resistance (TRIPOD)) presented the latest update on this study, including the first manuscript that has just been accepted for publication in AJTMH where it describes drug resistance patterns and the proportion of drug resistance in naive & previously treated subjects, and several manuscripts on preparation (performance of AFB vs. Xpert compared to sputum culture, the seroprevalence of histoplasmosis among TB sub-jects, factors associated with TB treatment outcomes), and future plans on data analysis and specimen evaluation (e.g., Mtb and NTM genome sequencing). Dr. Myrna, one of 10 selected young investigators, described a preliminary analysis on the use of plasma CA-125 for monitoring two-months treatment response in MDR-TB patients.

On the second day of the RePORT meeting, September 8, 2022, dr Myrna presented an abstract entitled Plasma CA-125 as a tool for monitoring two-months treatment response in MDR-TB patients: a preliminary analysis. Plasma Ca-125 was chosen as alternative monitoring in the second month of MDR-TB treatment because sputum culture is time-consuming and cannot be done in patients who do not produce sputum. Several studies suggested that cancer or carbohydrate antigen-125 (CA-125) may be used as an alternative for monitoring treatment response as it is associated with the activity and severity of pulmonary TB.

Twenty-five TRIPOD Study MDR-TB subjects from Kariadi Hospital, consisting of 20 negative and five positive sputum cultures two months post-treatment, were selected. Plasma Ca-125 levels at baseline and 2-month treatment were measured and analyzed. As a result, at baseline, subjects in PG had higher median baseline plasma CA-125 than subjects in NG. At two months post-treatment, the median plasma CA-125 was significantly higher in PG than NG. This preliminary analysis reveals that plasma CA-125 might be a potential biomarker in predicting positive sputum culture two months post-treatment in MDR-TB patients. CA-125 levels, when combined with clinical response, chest X-rays, and sputum cultures, might promote better treatment response monitoring.

Before the two-day annual meeting, data managers from each country completed a highly productive 2-day “data harmonization pre-meeting”. It was the first time they met each other in person after extensive discussion virtually. During this meeting, they discussed a technical framework for Phase 1 collaboration, reviewed new data and software for Phase 2, shared operational updates and lessons learned, and established milestones and goals for the first three projects (epidemiology, adherence, and biomarkers protocols). The mapping for phase 1 data is targeted to complete by December 2022. Researchers from all countries are encouraged to start thinking of new study ideas that can use this dataset.

Since several consortiums such as Brazil, India, and South Africa are mature, their researchers and researchers from universities/institutes collaborating with these consortiums presented advanced ongoing studies and/or impressive scientific outputs. Dr. James Seddon from Stellen-bosch University in South Africa described the importance of biomarkers study in childhood tuberculosis and including biomarkers in clinical management algorithms. This is because children and adults show differences in immunology, the spectrum of TB disease, the spectrum of other diseases and co-infection, triage vs. treatment decision, and the samples used. Dr. Rein Houben from the London School of Hygiene & Tropical Medicine described how to diagnose sub-clinical tuberculosis disease, which is positive bacteriologically but without symptoms, how the outcomes are, and its role in the transmission in the community. Studies about sub-clinical TB in different epidemiological settings across life stages and the development of biomarkers for sub-clinical TB diagnosis and treatment outcomes are examples of important RePORT studies in the future.

Dr. Stephanus Malherbe from Stellenbosch University presented the preliminary results of a study on biomarkers to predict TB treatment outcomes conducted in China and South Africa. This study found that low base-line lesion as a biomarker does not sufficiently offset the risk of reduced treatment duration or poor adherence. Still, high baseline lesion validated a poor prognostic factor, especially cavity volume and character. Large-scale host and bacterial biomarker discoveries such as whole blood RNAseq and Luminex on serum are ongoing. Dr. Adrie Steyn from Africa Health Research Institute explained the mechanism of bedaquiline, which targets the energy metabolism of the pathogen to induce cell death and its potential for resistance. Dr. Morten Ruhwald, the Director of the TB program of FIND, Switzerland, describes the pipeline of TB Diagnostics, which remains the weakest link in the cascade of care. He reported that new instruments and sampling strategies are promising to bring the diagnostics close to the patients. Imaging and CXR/CAD are currently in rapid development, but we do not yet understand this technology’s full potential.

Prof. Grant Theron from Stellenbosch University, South Africa, informed us that PreFIT is preparing a cohort of more than 4000 subjects who have contact with positive TB cases. These subjects are observed for 12 months, sputum-based microbiology in all who can expectorate and/or symptomatic is collected, and CXR at the end of follow-up is examined. This cohort is very important to discover promising biomarkers for active TB since existing tools such as TST or IGRA have poor predictive value and are not feasible for near point-of-care in high-burden settings. This cohort also provides the opportunity to validate findings from earlier studies that used a similar study design.

Other interesting lectures include ‘How sputum culture methods to influence the detection of genotype diversity and transmission link’ (Prof Bhavesh Kana, Centre of Excellence for Biomedical TB Research), ‘Protein signature in TB’ (Novel Chegou, Stellenbosch University), ‘Aerosolization of Mycobacterium Tuberculosis via Tidal Breathing’ (Ryan Dinkele, University of Cape Town), ‘Mycobacterium Tuberculosis Sequencing’ (Tyler Brown, MD, Massachusetts General Hospital), and ‘Host Blood Transcriptomic Biomarkers of TB: Diagnosis, Prognosis, and Treatment Response’ (Simon Mendelsohn).

Besides Dr. Myrna from Indonesia, this annual meeting also invites nine other young investigators to present their studies orally. Two speakers from Brazil presented their work on tuberculosis and diabetes (Transcriptional and Inflammatory Changes Associated with Glycosylated Hemoglobin Levels in persons with Tuberculosis and Diabetes by Artur T.L Queiroz, and Tuberculosis Treatment Out-comes of Diabetic and Non-Diabetic TB/HIV Co-infected Patients by Beatriz Barreto-Duarte). Two speakers talked about TB drugs (Population Pharmacokinetics of Linezolid and Moxifloxacin in Patients with Multidrug-resistance Tuberculosis by Juan Eduardo Resendiz-Galvan from India, and Treatment outcomes with a shorter all-oral regimen for rifampicin-resistant TB in a programmatic setting which is an interim analysis from the SHIFT-TB cohort by Jacob AM Stadler from South Africa). Besides Dr. Myrna from Indonesia, three other speakers also talk about biomarkers (Early Microbiologic Surrogate Markers of Pulmonary Tuberculosis Treatment Outcomes by Mandar Paradkar from India, Identification and Validation of Specific miRNA Biomarkers in Pleural Effusion for Diagnosis of Tuberculous Pleurisy by Jing Dong from China, and Peripheral Blood Kynurenine, Tryptophan and indoleamine 2,3-dioxygenase Expression for TB diagnosis by Heena Ranchod from South Africa). The importance of ‘Mycobacterium Tuberculosis Infection among Children and Adolescent Contacts of Pulmonary Tuberculosis Cases in Brazil’ was raised by Mariana Araujo Pereira, whereas ‘Mechanisms Regulating Distinct Immuno Pathologies in High and Low transmission Mycobacterium Tuberculosis Infections’ was discussed by Vaishnavi Kaipilyawar.

Attending this meeting, I believe we have not used this cross-consortium partnership to maximize scientific output. Besides anti-histoplasmosis Abs and CA-125 examination, our publications are all based on routine TB diagnostic tests despite collecting various specimens at different time points. The main obstacle for Indonesia is the requirement of material transfer agreement approval which is not a problem for the three countries with advanced TB research, such as South Africa, India, and Brazil. Besides specimen testing, we may also ask for technical and scientific advice from other consortiums as one of RePORT’s missions is to develop TB research capacity and infrastructure. We also need to find more information regarding the opportunity to request funding for activities related to enhancing infrastructure and human resources for TB clinical trials, which Dr. Peter Kim informed us of. Since the next RePORT annual meeting will be conducted in India next year, we still have time to prepare scientific outputs that will contribute significantly to regional and global TB knowledge.

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