General Medicine & Global Health (GMGH) is a university-based research group at the Cape Heart Institute of the University of Cape Town and at the Department of Internal Medicine of the University Hospital Zurich/University of Zurich, established in 2019 by Associate Professor Friedrich Thienemann. Our mission is to improve global health through research, education and health services in partnership with institutions in our communities in Africa.

We study the convergence of non-communicable and infectious diseases in order to better understand the interaction of both with the aim to optimise current therapies to improve treatment outcomes. Our focus is on the world's biggest killers tuberculosis (TB), HIV/AIDS, cardiovascular and lung diseases, and diabetes – all major causes of morbidity, mortality, poverty, and inequality in low- and middle-income countries.

In order to achieve the above, we aim to strengthen local research capacity through training, collaboration, networking, good governance, effective leadership, support and mentoring with the goal to produce research excellence and to develop the next generation of global leaders in health. Our team develops regular health education programs to uplift our communities to live healthier lives.

The GMGH research lab is based at the Institute of Infectious Disease and Molecular Medicine (IDM) and is led by Professor Reto Guler. The Guler lab aims to identify targets for pathogen and host-directed drug therapy for TB; this includes the identification of statins and host non-coding RNAs as host-directed drug therapy for TB and the role of epigenetics in host immunity to TB. Further research includes investigating Minor Groove Binders as novel anti-mycobacterial agents and non-ionic surfactant vesicles as a drug delivery system for TB.

GMGH is a joint research group between the University of Cape Town, the University of Zurich and the University Hospital Zurich.

 

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Logo University Hospital Zurich (USZ)

 

Group members

Research projects

StatinTB

Protocol title: Preventing TB relapse and chronic lung disease: A proof-of-concept, double-blinded, randomized, placebo-controlled trial to evaluate the safety and efficacy of atorvastatin to reduce inflammation after TB treatment completion in HIV-infected and HIV-uninfected adults measured by FDG-PET/CT.

The primary objective is to compare persistent lung inflammation measured by total lung glycolysis on FDG-PET/CT after 12 weeks of 40 mg atorvastatin and placebo. If successful this trial will have proven that statins as Host Directed Therapy can be safe and effective adjunctive therapy to TB treatment in general. Further efficacy trials can be undertaken to translate the results into reduced TB relapse rates and reduced post-TB chronic lung disease. ClinicalTrials.gov Identifier: NCT04147286

Visit the StatinTB website.

ExtendTB

Protocol title: Extended follow-up of patients with cardiopulmonary sequelae after successful treatment of pulmonary tuberculosis: a 24-months observational cohort study.

Long-term morbidity and mortality after successful tuberculosis (TB) treatment, including cardiovascular sequelae, are increasingly recognized, but data remain limited. We are currently enrolling participants for the StatinTB trial, which evaluates the safety and efficacy of atorvastatin in reducing inflammation post-TB treatment in both HIV-infected and uninfected adults. Approximately 200 participants will undergo cardiovascular magnetic resonance imaging (CMR), with half showing no lung inflammation on PET/CT and half with extensive inflammation. Those with persistent inflammation will be randomized to receive 40 mg atorvastatin daily or placebo for 12 weeks, followed by a repeat CMR to assess its impact on cardiac health. Under the ExtendTB protocol, participants will have further follow-up, including CMRs at 1 and 2 years post-TB treatment, and additional tests if abnormalities are detected. This extended follow-up aims to provide deeper insights into the long-term cardiopulmonary sequelae after TB treatment. The study is funded through an NIH grant.

PAN-TB

Protocol title: A Phase 2b/c, Multi-Arm, 2-Stage, Duration Randomized Trial of the Efficacy and Safety of Two to Four Months Treatment with Regimens Containing Bedaquiline,OPC-167832, and Sutezolid, Plus Either Pretomanid or Delamanid, in Adults with Pulmonary Tuberculosis.

Successfully treating TB can be complex and challenging. New regimens with little to no drug resistance – known as pan-TB regimens – create a simpler and more effective treatment pathway for all people diagnosed with TB. The Project to Accelerate New Treatments for Tuberculosis (PAN-TB) is the first collaboration of philanthropic, non-profit and private-sector organizations that aims to accelerate the identification of promising pan-TB regimens and conduct research through phase 2b/2c clinical trials. These pan-TB regimens will be designed to have improved safety and tolerability, a shorter duration, and simpler to use than existing treatment options. The collaboration is evaluating two novel drug regimens each comprising five antibacterial agents: bedaquiline, delamanid, pretomanid, quabodepistat (formerly known as OPC-167832), and sutezolid.

Visit the PAN-TB website.

Tuberculosis vaccine phase 3 trial (M72/AS01E)

Protocol title: A Phase 3, randomized, double-blind, placebo-controlled, multicenter, clinical trial to assess the prophylactic efficacy, safety, and immunogenicity of the investigational M72/AS01E-4 Mycobacterium tuberculosis (Mtb) vaccine when administered intramuscularly on a 0,1-month schedule to adolescents and adults.

Prof. Friedrich Thienemann and Dr Sandra Mukasa were previously part of the TB-018 consortium and completed the Phase 2b trial, where the investigational M72/AS01E-4 Mtb vaccine demonstrated approximately 50% protection (49.7%; 95% confidence interval [CI]: 2.1–74.2) against developing laboratory-confirmed pulmonary tuberculosis (TB) over 36 months. The results are published in the NEJM. This protection was observed in adults who were positive for the interferon gamma release assay (IGRA) and negative for human immunodeficiency virus (HIV). This Phase 3 trial is designed to confirm the vaccine's efficacy in IGRA-positive, HIV-negative individuals and to gather safety and immunogenicity data in both IGRA-positive and IGRA-negative adolescents and adults, including those living with HIV (PLHIV).

Visit the Gates MRI website. 

 

PredictTB

PredictTB is a five-year project financed by a variety of international funders and implemented by American, African, Asian and European partners, that aims to shorten the treatment times of TB in drug-sensitive patients through individualized therapy. Coordinated by Prof. Clifton Barry from the US National Institutes of Health and Prof. Gerhard Walzl from Stellenbosch University in South Africa. The consortium implemented a prospective, randomized, no inferiority phase 2b clinical trial, enrolling and following up 620 patients with drug-sensitive pulmonary TB in five collaborating sites in Cape Town, South Africa and four sites in Henan Province, China. Over the five years, the project team will evaluate a set of criteria to reduce TB treatment times using data from scans, assays and cultures to evaluate inflammation and lung pathology, to test for the sustained presence of bacteria and to determine which patients are eligible for shortened treatment. In a sub-study, we investigate the potential of lung MRI to better understand complex lung lesions in TB (virtual biopsy study). ClinicalTrials.gov Identifier: NCT02821832

Visit the PredictTB website.

Cardiac Imaging After Tuberculosis (CIA-TB): understanding post-Tuberculosis sequelae

Protocol title: Cardiac assessment using cardiac MRI to better understand long-term morbidity and mortality after successful tuberculosis treatment (Cardiac Imaging After TB, CIA-TB)

The main focus of national TB control programs has been the DOTS strategy – directly observed treatment, short-course – which was an integral part of the End TB strategy by the World Health Organization. "DOTS quickly makes the infectious cases non-infectious and breaks the cycle of transmission". To achieve this, DOTS ensures that every TB patient achieves treatment success within a six-month course of TB treatment; at the end of this treatment, patients are currently discharged from their TB clinics as "cured" or "treatment completed". But TB is a lifelong disease: long-term morbidity and mortality after successful TB treatment are increasingly recognised with associated long-term functional impairment. To date, most research has focused on pulmonary function and data on cardiovascular long-term sequelae following TB treatment is lacking. In CAI-TB we investigate cardiac inflammation, fibrosis and function using cardiovascular magnetic resonance imaging (CMR) and coronary CT (CCT) after TB treatment.

HIV & Heart

From a global perspective, cardiovascular disease in HIV may result from cardiac involvement upon presentation of opportunistic infections in the presence of advanced immunosuppression, be a consequence of HIV-induced immune activation or derive from antiretroviral therapy-associated dyslipidemia and insulin resistance. HIV-associated cardiomyopathy and HIV-associated pulmonary hypertension are the most common cardiac manifestations of HIV. This study is investigating cardiovascular disease in a healthy HIV-infected cohort in Cape Town using Echocardiography and cardiac biomarkers.

HREC REF: 337/2013

PAPUCO: The African Pulmonary Hypertension cohort study

Epidemiology, aetiology, management and outcome data for various forms of pulmonary hypertension (PH) in Africa are scarce. A prospective, multinational cohort registry of 220 consecutive patients (97% of African descent) from nine specialist centres in four African countries. The antecedents, characteristics and management of newly diagnosed PH plus 6-month survival were studied. We are currently investigating the contribution of HIV to the burden of PH in Africa and are in the planning of PAPUCO II. Co-Principal investigators are Prof. Karen Sliwa-Hahnle and Prof. Friedrich Thienemann.

HREC REF 337/2013

Non-coding RNA in tuberculosis  

Protocol title: Targeting non-coding RNAs as host-directed drug therapy for tuberculosis

Tuberculosis (TB) kills more than one million people each year globally. Therefore, there is an urgent need to develop new, alternative drug treatments. In this study, we aim to identify host factors and pathways that are subverted by Mycobacterium tuberculosis (Mtb) to increase its persistence and survival within macrophages. Using genome-wide transcriptome analysis in Mtb-infected macrophages using the powerful CAGE technology, we have previously identified differentially expressed ncRNAs (miRNAs and lncRNAs) in M1/M2 polarized macrophages. Our identified ncRNAs are likely to represent novel targets by Mtb to evade host protective killing functions that permit the bacteria to survive within macrophages. Our aim is to functionally validate these differentially expressed ncRNAs in Mtb-infected human PBMCs, using chemically engineered antisense oligonucleotides (gapmers). Our objective is to validate our identified ncRNAs and associated pathways in human PBMCs infected in-vitro with Mtb. Differences in pathogen burden, phagosomal maturation, autophagy, host cytokine responses and killing effector functions will investigate the involvement of the selected ncRNAs in possible host protective or detrimental response against TB. The most promising ncRNAs will be further validated for their target genes by computational approaches and other methods, including dual-luciferase reporter assay and RNA immunoprecipitation. The expected outcomes are to identify new host drug targets to combat TB. Such results are expected to have a critical positive translational impact. As such, targeting these new host ncRNAs as a therapy to efficiently eliminate Mtb is less likely to induce multi-drug resistance than conventional antibiotic treatments. This study is a collaboration with colleagues at the National Institutes of Health (NIH).

Spinal TB X

Protocol title: Comparing gene expression profiles of adults with isolated spinal TB to disseminated spinal TB identified by 18FDG-PET/CT at time of diagnosis, 6- and 12-month follow-up: classifying clinical stages of tuberculosis and monitoring treatment response.

Tuberculosis (TB) is one of the top ten causes of death worldwide with approximately 10 million cases globally and 1.2 million deaths. Sub-Saharan Africa carries the highest burden of TB. South Africa has one of the highest HIV and TB rates worldwide with an HIV prevalence rate in adults of 19% and a TB case notification rate of 615/100,000 in 2019. Over many years, focus has been paid to pulmonary TB and extrapulmonary TB (EPTB) has received only little attention even though it accounts for almost a quarter of all TB cases. The diagnosis of EPTB remains challenging simply because sample collection requires invasive procedures in the absence of a blood-based diagnostic test. Spinal TB (spondylitis or spondylodiscitis caused by mycobacterium tuberculosis) - often known as Pott`s disease - accounts for up to 10% of EPTB and affects young children, people with HIV-coinfection and the elderly, and often leads to lifelong debilitating disease due to devastating deformation of the spine and compression of neural structures. Little is known with regards to the extent of the disease and isolated TB spine as well as a disseminated form of TB spine have been described. The latter presents with a spinal manifestation plus dissemination to other organs such as the lungs, pleura, lymph nodes, the GIT or urinary tract or even the brain.
In our Spinal TB X cohort, we aim to describe the clinical phenotype of spinal TB using whole-body PET/CT identify a specific gene expression profile for the different stages of dissemination and compare our findings to previously described signatures for latent and active pulmonary TB. A blood-based test for spinal TB would lead to earlier diagnosis and treatment in all settings globally and improve treatment outcomes of this devastating disease. This prospective cohort study is a joint project between the Department of Medicine and the Division of Orthopaedic Surgery and is led by Prof. Friedrich Thienemann and Prof. Michael Held. Dr Julian Scherer from the University Hospital Zürich is the PhD student on this project.

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Graduates

  • Lorna Gcanga, Postdoctoral Fellow
  • Bongani Motaung, Phd Student
  • Shandre Pillay, PhD Student
  • Solima Sabeel, PhD Student