2024 cohort

 

Herman Bagula: Fogarty HATTP Masters Fellow

Dr Bagula earned his undergraduate medical degree at the University of Cape Town. He then completed his internship at Steve Biko Hospital and community service at Kalafong Hospital. 

Recognising the importance of public health in addressing broader health challenges, he pursued a Master's degree in Public Health at UCT. He then returned to Groote Schuur Hospital where he currently serves as a medical registrar in the Department of Internal Medicine.


 

 

Dr Haroon Moolla

Haroon Moolla: Fogarty HATTP PhD Fellow

Haroon Moolla is a senior research officer at the University of Cape Town’s Centre for Infectious Disease Epidemiology and Research. He holds an honours degree in actuarial science, a medical degree, and a masters in public health from the University of Cape Town. He was a clinician and registrar in public health medicine and is currently a senior epidemiologist and mathematical modeller for the International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA) Collaboration and the HIV Modelling Consortium in the United Kingdom.

Haroon was awarded a Fogarty HATTP PhD Fellowship in April 2024 for his project “Addressing HIV care interruptions to help achieve the “End TB” strategy in South Africa”. TB incidence and TB-related mortality are strongly associated with HIV. It is estimated that approximately 55% of incident TB cases and 70% of TB-related deaths in South Africa between 1990 and 2019 were attributable to HIV. Antiretroviral therapy (ART) is therefore critical for improving TB outcomes at a population level. Unfortunately, South Africa struggles with ART coverage, largely due to high rates of treatment interruption. ART coverage is the biggest gap in the 95-95-95 UNAIDS targets.

Haroon’s research will investigate the associations between ART interruptions and TB incidence and mortality using real world data from the Western Cape Provincial Health Data Centre. The impact of interventions to minimise ART interruptions on the epidemiology of TB will be projected using the Thembisa model (a compartmental HIV and demographic model calibrated to South African data sources using a Bayesian approach). These projections will support future HIV and TB policy decisions.

The PhD will be undertaken within the School of Public Health’s Division of Epidemiology and Biostatistics, under the supervision of A/Prof Leigh F. Johnson and Prof Mary-Ann Davies.


 

 

Bianca Sossen

Bianca Sossen: Fogarty HATTP PhD Fellow

Bianca has been awarded a Fogarty HATTP PhD Fellowship for the 2024 cohort for her project Non-sputum-based rapid diagnostics for HIV-associated tuberculosis. Tuberculosis (TB) is a leading infectious cause of death worldwide and in people living with HIV (PLHIV), TB is the leading cause of death, hospitalization and inpatient mortality. PLHIV often die before a diagnosis is made or soon after treatment is started. Reliance on the typical sputum sampling in PLHIV can lead to both missed and delayed diagnoses.  There is thereby an urgent, unmet need for rapid and accurate diagnostic tests that can be performed in non-sputum-based samples. With her PhD, Bianca will complete the following projects on a non-sputum-based diagnostic tool that is not yet routinely available: (i) Assess the diagnostic accuracy and diagnostic yield of urine Xpert ultra (Urine-XPU) in adult inpatients and outpatients living with HIV, (ii) conduct a systematic review and meta-analysis of the diagnostic accuracy and diagnostic yield of Urine-XPU, (iii) compare the time to initiation of TB treatment between a period where Urine-XPU is available to a period before – in patients living with HIV who are admitted to hospital medical wards, (iv) compare ten-week mortality between a period where Urine-XPU is available to a period before – in patients living with HIV who are admitted to hospital medical wards, and (v) assess and describe the user’s experiences, challenges, knowledge and views around the implementation of both Urine- XPU and the currently-available DetermineTM TB LAM Ag assay (AlereLAM), by means of a semi-structured questionnaire.

Overall, Bianca plans to generate and summarize evidence and knowledge on non-sputum-based diagnostics, and specifically Urine-XPU, to allow for stakeholders and policymakers to consider its role within diagnostic algorithms for HIV-associated TB. These projects will hopefully allow for a greater number of PLHIV, at great mortality risk, to be able to benefit from non-sputum-based rapid diagnostics.

Bianca holds an MSc in The Control of Infectious Diseases from the London School of Hygiene and Tropical Medicine, which was supported by a Chevening Scholarship. She also holds an MBChB from UCT and a Diploma in HIV Management from CMSA. Her prior work has also focused on non-sputum-based diagnostics in PLHIV, as well as on the natural history of TB disease. Bianca is undertaking this PhD in the UCT Department of Medicine under the supervision of Professor Graeme Meintjes.


 

Head-and-shoulders photograph of Jacquline Mugo

Jacquiline Mugo: Fogarty HATTP Postdoctoral Research Fellow

Jacquiline Mugo has joined the 2024 Fogarty HATTP postdoctoral cohort and will be working under Prof. Jonny Peter. Her research will define pharmacogenomic risk factors associated with severe cutaneous adverse reactions (SCARs) in HIV-uninfected, HIV-infected, and HIV-TB co-infected populations in South Africa and the molecular and cellular signatures of antigen-driven T cells at the site of SCAR reactions.

SCARs are serious, treatment-limiting cutaneous immune-mediated adverse drug reactions that are overrepresented in Africa due to the common offending drugs being first-line anti-TB drugs (FLTD) and cotrimoxazole, with the occurrence of SCAR to FLTD reported to be as high as 13%. They are associated with increased mortality, healthcare costs, and long-term morbidity and are a global priority, particularly in the context of additional immunosuppression with HIV and TB co-infection. Research into SCAR in African TB and HIV-endemic settings remains neglected, with limited genetic or other biomarkers for prevention and no targeted therapies available to direct clinical care or prevent TB and HIV-associated immune-mediated adverse drug reactions (IM-ADRs). Jacquiline’s research aims to improve the safety and effectiveness of treatments for HIV and TB in African populations through the identification of biomarkers and novel therapeutics that allow a personalized approach to predict, prevent, diagnose, and treat IM-ADRs.

Jacquiline submitted her PhD in 2023. In her PhD, she mainly focused on the development of computational methods to analyse disease population genetics data. Few methods are able to analyse complex data from populations with multiple ancestry (admixed populations), and generally only from admixed populations that result from the interbreeding of two or three genetically isolated populations (2-way or 3-way admixed individuals). Increasingly, individuals are mixing and interbreeding, resulting in populations with up to 5-way admixture. In her PhD, Jacquiline developed a novel association method (JasMAP), which considers the ancestry contribution of the parental populations and is tailored to multi-way admixed populations. The tool was applied to TB data from a South African multi-way admixed population and uncovered novel genetic associations. As part of her research, she also developed a simulation tool (FractalSIM) that generates realistic human genetic data for admixed populations, incorporating recombination, mutation, random mating, disease models, admixture, and natural selection. Simulated data generated using the tool was used to assess other disease association methods.

Jacquiline holds an MSc in Mathematical Sciences (Stellenbosch University) and a BSc (Hons) in Mathematics (University of Nairobi).

References:

  1. Jacquiline W Mugo, Emile R Chimusa and Nicola J Mulder. Data Simulation to Optimize the GWAS Framework in Diverse Populations. (2023) medRxiv 2023.10.26.23297606; doi: https://doi.org/10.1101/2023.10.26.23297606
  2. Jacquiline W Mugo, Emile R Chimusa and Nicola J Mulder JasMAP: A Joint Ancestry and SNP Association Method for a Multi-way Admixed Population. (2023) medRxiv 2023.10.26.23297617; doi: https://doi.org/10.1101/2023.10.26.23297617
  3. Shatha Alosaimi, Noëlle van Biljon, Denis Awany, Prisca K. Thami, Joel Defo, Radia Hassan, Imane Allali, Christian D Bope, Jacquiline W Mugo, Gaston K Mazandu, Nicola J. Mulder and Emile R Chimusa; Simulation of African and non-African low and high coverage whole genome sequence data to assess variant calling approaches, Briefings in Bioinformatics 2020 Dec 21:bbaa366. doi: 10.1093/bib/bbaa366. Epub ahead of print. PMID: 33341897

2023 cohort

 

 

Rephaim Mpofu

Rephaim Mpofu: Fogarty HATTP Clinical PhD Fellowship

Rephaim Mpofu is a medical doctor and clinical pharmacologist, currently based in the Division of Clinical Pharmacology at the University of Cape Town. He has been awarded a Fogarty HATTP Clinical PhD Fellowship for his research project, titled “The clinical pharmacology of tenofovir prodrugs among Southern Africans living with HIV”. His research is focused on the pharmacological safety profile of tenofovir prodrugs used in the management of HIV. His main research aims include assessing the impact of tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF) on renal and bone toxicity in individuals with HIV, as well as potential drug-drug interactions between TAF and rifampicin that are used in the treatment of tuberculosis.

Tenofovir-based antiretroviral therapy (ART), particularly tenofovir disoproxil fumarate (TDF), has been associated with an increased risk of bone and renal toxicity in individuals living with HIV. However, the underlying mechanisms and factors contributing to these toxicities in the Southern African population are not fully understood, highlighting the need for further investigation. People living with HIV also have an increased risk of osteoporosis and fragility fractures, with TDF use being a potential contributing factor. The specific pathophysiological mechanisms linking TDF to bone toxicity, particularly through renal dysfunction, require clarification, and longer-term studies are necessary to assess the effects of newer prodrug formulations, such as tenofovir alafenamide fumarate (TAF), on bone mineral density in African populations. The potential drug interactions between TAF and rifampicin, a commonly used anti-tuberculous medication, also remain uncertain. Clarifying the safety and efficacy of co-administering TAF with rifampicin would provide valuable insights into optimizing treatment regimens for individuals with HIV who require concurrent tuberculosis treatment, avoiding unnecessary modifications that could disrupt patient care and increase logistical challenges. He aims to answer these questions by assessing the pharmacokinetic, pharmacodynamic, and pharmacogenomic factors influencing the safety of these tenofovir prodrugs using data from completed clinical trials that were conducted in South Africa.

Rephaim completed his Fellowship in Clinical Pharmacology with the Colleges of Medicine of South Africa (CMSA). He also holds Master of Medicine (MMed, UCT) and Bachelor of Medicine and Surgery (MBChB, UCT) degrees, as well as a diploma in the management of HIV (CMSA). He has previous experience as a Principal investigator at the Perinatal HIV Research Unit with the WITS Health Consortium. His PhD will be supervised by A/Prof Phumla Sinxadi and Prof. Gary Maartens.


 

pchoshi

Phuti Chosi: Fogarty HATTP Postdoc Fellow

Phuti Choshi completed her PhD in 2023 titled the immunopathogenic mechanisms of severe cutaneous adverse reactions (SCARs) to first line anti-tuberculosis drugs – under the supervision of Prof Jonathan Peter, Prof Rannakoe Lehloenya and Prof Elizabeth Phillips (Vanderbilt University). Her research elucidated pathogenic mechanisms underlying life threatening reactions to anti-TB drugs, particularly in persons living with HIV. Main findings from her PhD include, i) an optimised ELISpot assay to detect anti-TB drug specific T cells – with invitro diagnostic utility potential upon further standardisation; ii) HLA-B*44:03 risk allele associated with rifampicin induced SCAR; iii) pathogenic T cells clones driving the reaction; iv) a hyperactive and dysregulated immune state potentially contributing to increased SCAR susceptibility in HIV/TB co-infection. She is currently a postdoctoral fellow in the Department of Medicine, Division of Allergology and Clinical Immunology, supported by HATTP Fogarty postdoctoral fellowship.


 

Zaayid Omar

Zaayid Omar: Fogarty HATTP Fellow

Zaayid Omar was awarded a Fogarty HATTP Fellowship for project costs in support of his PhD thesis investigating the association between tuberculosis and myocardial fibrosis in persons with HIV in South Africa.

There is a high prevalence of tuberculosis in South Africa, particularly amongst persons with HIV. TB infection has been associated with poorly regulated immune responses including systemic inflammation, which can precede clinically evident active TB. Currently, it is unknown what the contribution of these TB states, certain of which are associated with systemic inflammation, is to the development of myocardial fibrosis and heart failure among persons with HIV.

His project will utilize markers of tuberculosis, including interferon gamma release assay and testing of RNA pathways associated with progression from latent to active tuberculosis, to explore and characterise the association between tuberculosis and myocardial fibrosis, as measured by extracellular volume fraction on cardiac magnetic resonance imaging.

Zaayid is a clinical researcher at the Wellcome Centre for Infectious Diseases Research in Africa. He holds a MBChB degree from Stellenbosch University and is currently pursuing a PhD in Medicine at the University of Cape Town.


 

Tafadzwa Chimbetete

Tafadzwa Chimbetete: Fogarty HATTP Basic Science PhD Fellow

Tafadzwa Chimbetete was awarded a Fogarty HATTP PhD Fellowship in May 2023 for his project “Characterizing the skin immune microenvironment in normal and diseased SCAR skin across different strata of HIV-related immunosuppression and immune reconstitution”. His research will describe changes in normal and diseased skin microenvironment amongst persons living with HIV (PLHIV), with special focus on cutaneous adverse drug reactions (CADRs) to allow for spatial mechanistic insights of immune cell phenotypes and interactions. For his study, it is hypothesized that advanced immune suppression and immune reconstitution seen in PLHIV are the main drivers of severe tissue specific immune responses– and using high dimensional transcriptomics and immune profiling analysis will allow us to elucidate these tissue-specific immune networks driving different disease phenotype.

Many inflammatory conditions occur in the skin of PLHIV, with disease-specific examples including papular pruritic eruption (PPE) (1). PLHIV have up to a 100-fold increased risk of immune-mediated adverse reactions to drugs (2). The skin immune microenvironment has specialised epithelium, antigen presenting cells (APCs), and tissue-resident memory (TRM) T-cell populations; and immunophenotyping in blood has not elucidated mechanisms of skin diseases. In-depth study of site-of-disease samples with single-cell resolutions and spatial orientation are increasingly recognised to be the only route to identifying relevant biomarkers, and disease drivers of inflammatory skin pathologies in the future (2-4). However, at present, there is neither a transcriptomic or immunological atlas of normal or diseased skin in PLHIV in sub-Saharan Africa – this is the major gap that Tafadzwa’s work is looking to address. Overall, Tafadzwa hopes to develop a new understanding of HIV-associated immune dysregulation in the skin and hope to identify potential biomarkers that could lead to new treatments.

Tafadzwa holds an MSc Medicine degree with distinction, in Clinical science and Immunology from UCT. He characterized the immunological profile of the skin in DRESS and SJS/TEN reaction to first-line anti-tuberculosis drugs in HIV-infected patients. He is undertaking his PhD in the Division of Allergology and Clinical Immunology (UCT) under the supervision of Associate Professors Jonathan Peter and Rannakoe Lehloenya and is supported by another Fogarty fellow - Phuti Choshi.

References

  1. Chimbetete T, Buck C, Choshi P, Selim R, Pedretti S, Divito SJ, et al. Hiv-Associated Immune Dysregulation in the Skin: A Crucible for Exaggerated Inflammation and Hypersensitivity. J Invest Dermatol (2023) 143(3):362-73. Epub 20221220. doi: 10.1016/j.jid.2022.07.035.
  2. Peter J, Choshi P, Lehloenya R. Drug Hypersensitivity in Hiv Infection. Current opinion in allergy and clinical immunology (2019) 19(4):272-82.
  3. Kim D, Kobayashi T, Voisin B, Jo JH, Sakamoto K, Jin SP, et al. Targeted Therapy Guided by Single-Cell Transcriptomic Analysis in Drug-Induced Hypersensitivity Syndrome: A Case Report. Nat Med (2020) 26(2):236-43. Epub 2020/01/22. doi: 10.1038/s41591-019-0733-7.
  4. Schabitz A, Hillig C, Mubarak M, Jargosch M, Farnoud A, Scala E, et al. Spatial Transcriptomics Landscape of Lesions from Non-Communicable Inflammatory Skin Diseases. Nat Commun (2022) 13(1):7729. Epub 20221213. doi: 10.1038/s41467-022-35319-w.

 

katlego motlhaoleng

Caroline Katlego Motlhaoleng: Fogarty HATTP Fellowship

Caroline Katlego Motlhaoleng has been awarded a Fogarty HATTP fellowship to support project cost for her PhD in Medicine study at the University of Cape Town. Katlego’s PhD study is titled “Optimizing intensified TB case finding in people living with HIV in PEPFAR-supported districts in South Africa.’’

Tuberculosis (TB) is a leading cause of death in people living with HIV (PLHIV).  Finding the missing PLHIV with TB is essential to reduce morbidity and mortality caused by TB. This strategy is enshrined in South Africa’s National Strategic Plan for HIV, TB and STIs 2017-2022. It is also a critical component of the WHO End TB Strategy, which, together with the United Nations (UN) Sustainable Development Goals (SDGs), commits to end the global TB epidemic by 2030.

With her study, Katlego proposes to investigate the effectiveness and adoption of a new policy to find the missing PLHIV with TB and link them to appropriate care. The proposed study has the potential to enhance an understanding of health professionals' adoption of new policies and provide information about the most effective strategies to optimize TB case finding during program implementation.

Katlego is a TB/HIV Public Health Specialist at the US Centers for Disease Control and Prevention (CDC) South Africa, where she provides technical guidance for the development, implementation, and monitoring of the President's Emergency Plan for AIDS Relief (PEPFAR) funded TB/HIV program activities.

She holds a Master of Public Health (MPH) from the University of Pretoria and a Bachelor of Arts in Nursing Science specializing in Health Services Management and Health Sciences Education (BCur) from the University of South Africa (UNISA). She is supervised by Professor Gary Maartens.


 

Astrid Kühn: Fogarty HATTP Masters Fellow

Astrid Kühn joined the 2023 Fogarty HATTP Fellowship cohort in January 2023. They were awarded support for their Masters project entitled: “Monocyte activation, circulating leukocyte-platelet aggregates and sequestration in patients with HIV-associated tuberculosis: associations with disease severity and mortality.”

Despite major improvements in the treatment of HIV-associated tuberculosis (HIV-TB) over the past decade, mortality in certain patient groups remains unacceptably high.1 This is especially in patients ill enough to be hospitalized with severe HIV-TB, and the causes for this high mortality remain to be elucidated.

In a prospective cohort of hospitalized patients with severe HIV-TB, it was previously reported that mortality is associated with activation of the innate immune system, with simultaneous anti-inflammatory changes. These immunological changes are similar to those seen in bacterial sepsis.2 In the same patient population, a hypercoagulable state was seen with activation of the endothelium, which was associated with mortality.3 Disseminated intravascular coagulation (DIC) was a common finding in these patients.3 It was found that patients with severe HIV-TB co-infection display lower proportions of circulating leukocyte-platelet aggregates. These differences were more distinct in patients who died as well as in patients with Mycobacterium tuberculosis blood stream infection (Mtb-BSI), and correlated with sepsis severity.

The current study hypothesizes that the lower proportions of circulating leukocyte-platelet aggregates reported, may reflect sequestration of leukocyte- platelet aggregates in the microcirculation, resulting in DIC and micro-thrombosis. Astrid will use a combined approach of immunohistochemistry analysis of post-mortem tissue samples as well as immunologic analysis of whole blood of prospectively recruited patients and controls. These factors may contribute to tissue damage and multi-organ failure culminating in the pathology seen.

Astrid holds a Bachelor of Medical Science (Hons) in Applied Anatomy and a Bachelor of Science in Integrated Human Anatomy and Physiology and Biochemistry, both studied at the University of Cape Town. Their supervisors are Dr Saskia Janssen (TASK Postdoctoral Fellow) and Associate Professor Dirk Lang (Head of Division: Cell Biology, UCT).

References

1. Odone A, Amadasi S, White RG, Cohen T, Grant AD, Houben RM. The impact of antiretroviral therapy on mortality in HIV positive people during tuberculosis treatment: a systematic review and meta-analysis. PloS one 2014; 9:e112017.

2. Janssen S, Schutz C, Ward A, et al. Mortality in Severe Human Immunodeficiency Virus-Tuberculosis Associates With Innate Immune Activation and Dysfunction of Monocytes. Clin Infect Dis. 2017 Jul 1;65(1):73-82

3. Janssen S, Schutz C, Ward AM, et al. Hemostatic Changes Associated With Increased Mortality Rates in Hospitalized Patients With HIV-Associated Tuberculosis: A Prospective Cohort Study. J Infect Dis. 2017 Jan 15;215(2):247-258. 


 

 

Maxine Höft: Fogarty HATTP Postdoctoral Research Fellow 

Maxine Höft joined the 2023 Fogarty HATTP postdoctoral cohort and the Burgers Lab in January 2023. She is currently investigating the long-term T cell memory responses towards SARS-CoV-2 in people living with HIV (PLHIV), supervised by Professor Wendy Burgers.  

As the world moves into long-term management of the COVID-19 pandemic, the need to understand the interactions between COVID-19 and HIV has been recognized by scientists and clinical practitioners, urging governments, funders and researchers to devote their resources and efforts to tackle both diseases simultaneously. Populations with high proportions of uncontrolled advanced HIV disease could contribute to the emergence of new SARS-CoV-2 variants that are highly transmissible and render the current vaccines less effective.  

There is evidence that some vaccines elicit suboptimal responses in PLHIV. While several studies describe antibody responses in this population, fewer have characterized T cell immunity or the durability of cellular memory in PLHIV following vaccination for COVID-19. Despite viral suppression by ART, incomplete CD4 T cell reconstitution, residual immune activation and persistent T cell exhaustion may compromise immune memory in PLHIV. Maxine aims to monitor long-term immunological memory in people living with HIV. Her research will focus on understanding the durability of T cell memory and identifying potential defects in cellular immunity in PLHIV. 

Maxine holds a PhD in Clinical Science and Immunology, awarded to her in 2022 within the Division of Immunology at the University of Cape Town.  Her PhD thesis encompassed the investigation of the immune response to Emergomyces africanus infection, a newly described dimorphic fungal pathogen affecting AIDS patients in South Africa. She established immunocompetent and immunocompromised in vivo infection models allowing her to describe disease kinetics and measure fungal burden, dissemination, cellular recruitment to infected tissue and cytokine and antibody responses towards infection. Finally, she showed recognition and binding of antifungal C-type lectin receptors that play a role in immune cell activation and cytokine production. Her work has laid the foundation to better understand Emergomyces spp. infection and the study has added valuable insight into disease kinetics and fungal clearance mechanisms.  

Maxine also holds an MSc (Biochemistry), BSc Honours (Microbiology) and BSc (Microbiology and Biological Sciences) all from Rhodes University.


 

Zinhle Cindi: Fogarty Postdoctoral fellowship

Zinhle Cindi joined the Fogarty HATTP PhD Fellow ranks in October 2018 and obtained her PhD in Clinical Pharmacology in 2023 from UCT. For her PhD, she investigated the pharmacogenetics and pharmacokinetics of dolutegravir and tenofovir among Southern Africans. Her project was a sub-study of the ADVANCE clinical trial. For her project it hypothesized that the pharmacogenetics of dolutegravir and tenofovir may affect drug exposure and toxicity, e.g., weight gain among people living with HIV in Southern Africa. The key research objectives addressed were:

1. The pharmacogenetics of dolutegravir plasma exposure among Southern Africans living with HIV. This study helps to identify genetic polymorphisms that may affect dolutegravir plasma exposure.1

2. The pharmacogenetics of tenofovir clearance among Southern Africans living with HIV. This study investigates genetic polymorphisms that affect tenofovir clearance.2

3. Genetic associations with weight gain among South Africans who initiated dolutegravir-containing and tenofovir-containing regimens. This study will help better define human genetics impact on the safety profile of dolutegravir and tenofovir.3

Zinhle has been awarded the Fogarty postdoctoral fellowship investigating “Using polygenic and integrated risk scores (PRS and IRS) to discover associations with contemporary HIV-relevant phenotypes” under the supervision of Professor Marylyn Ritchie (University of Pennsylvania) and Associate Professor Phumla Sinxadi (UCT). She will complete 12 months of her Post-doc training at the University of Pennsylvania.

References

  1. Cindi Z, Kawuma AN, Maartens G, Bradford Y, Venter F, Sokhela S, Chandiwana N, Venter F, Wasmann RE, Denti P, Wiesner L, Ritchie MD, Haas DW, Sinxadi P. Pharmacogenetics of Dolutegravir Plasma Exposure Among Southern Africans living with HIV. J Infect Dis. 2022; jiac174
  2. Cindi Z, Kawuma AN, Maartens G, Bradford Y, Sokhela S, Chandiwana N, Venter F, Wasmann RE, Denti P, Wiesner L, Ritchie MD, Haas DW, Sinxadi P. Pharmacogenetics of tenofovir clearance among Southern Africans living with HIV. Pharmacogenetics and Genomics
  3. Cindi Z, Maartens G, Bradford Y, Venter WDF, Sokhela S, Chandiwana NC, Haas DW, Sinxadi P. Genetic Associations with Weight Gain among South Africans who Initiated Dolutegravir-Containing and Tenofovir-Containing Regimens. J Acquir Immune Defic Syndr. 2021;87(3):1002–9

2022 cohort

 

Hannah May Gunter: Fogarty HATTP Clinical Fellowship

Hannah May Gunter has been awarded Fogarty HATTP project cost support for completing her Doctorate in Medicine as part of the Allergology and Clinical Immunology Division at the University of Cape Town, Groote Schuur Hospital. Her PhD thesis is titled ”Pharmacogenomics and Pharmacokinetics of Immune-mediated Adverse Drug Reactions to  Antituberculosis Treatment in a Tuberculosis-HIV Endemic Setting.’’

Life-threatening  immune-mediated adverse drug reactions (IM-ADRs) associated with first-line anti-TB drugs include severe cutaneous adverse drug reactions (SCAR), acute interstitial nephritis (AIN) and drug-induced liver injury (DILI). The majority occur in persons living with HIV (PLWH). There are no pharmacogenomic biomarkers in African populations in clinical practice for any of these IM-ADRs, making it an urgent unmet need.

With her project, Hannah proposes to determine genetic predictors of immune-mediated adverse drug reactions (IM-ADRs). The hypothesis -  that novel or known functional single nucleotide polymorphisms (SNPs) in relevant candidate ADME (absorption, distribution, metabolism, elimination) or immune tolerance genes, will be associated with interindividual differences in the pharmacokinetics of first-line anti-TB drugs, as well as the development of IM-ADRs.

Hannah is a Senior Lecturer in the Division of Clinical Pharmacology at UCT GSH. She is a medical doctor by training (MBChB) and holds a Fellowship of the College of Clinical Pharmacologists of South Africa at the Colleges of Medicine of South Africa, and a Masters in Medicine (MMed). Her MMed was on assessing causality in HIV-positive patients with a liver injury on antituberculosis and/or antiretroviral therapy.  Her PhD supervisors are Professor Jonny Peter and Associate Professor Phumla Sinxadi.


2021 cohort

 

rephaim-mpofu

Rephaim Mpofu: Fogarty HATTP Masters Scholar

Rephaim Mpofu has been awarded Fogarty HATTP project cost support for his MMed (Clinical Pharmacology) study “Renal toxicity associated with tenofovir administered as tenofovir disoproxil fumarate or tenofovir alafenamide fumarate in a South African population with HIV: a pharmacokinetic-pharmacodynamic analysis”. He will assess the pharmacokinetic-pharmacodynamic (PK-PD) effects of both forms of tenofovir (TFV) prodrug, when combined with emtricitabine (FTC) or dolutegravir (DTG), on nephrotoxicity in South African HIV-positive adults.

Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor widely used in antiretroviral therapy (ART) regimens in resource-limited settings. TDF use is associated with a decline in age-related kidney function and the development of kidney disease such as proximal tubulopathy.

The pathophysiology of TDF nephrotoxicity is incompletely understood but has been associated with higher plasma concentrations of TFV. Tenofovir alafenamide fumarate (TAF) is a newer prodrug of TFV, which achieves higher intracellular active drug concentrations, and lower plasma TFV concentrations. TAF is less nephrotoxic than TDF due to the lower plasma TFV exposure and because TAF does not penetrate well into renal tubular cells.

Most data on risk factors for TFV nephrotoxicity, including TFV PK parameters, are derived from studies conducted in high-income countries, with few data on women and Black African populations.

Rephaim will use data collected from the ADVANCE clinical trial to:

  • estimate and compare the TFV plasma area under the concentration-time curve (AUC) and minimal plasma concentrations (Cmin) parameters when administered as TDF or TAF using a population pharmacokinetic model;
  • assess the association between the TFV AUC and Cmin (administered as TDF or TAF), and treatment-emergent proximal tubular dysfunction; and
  • evaluate the association between the TFV AUC and Cmin(administered as TDF or TAF) and treatment-emergent glomerular dysfunction.

ADVANCE was an open-label, non-inferiority, controlled trial conducted in Johannesburg, South Africa which randomized ART-naïve participants into one of 3 arms: TDF-FTC-EFV, TDF-FTC-DTG, or TAF-FTC-DTG.

Rephaim is currently a clinical pharmacology registrar at Groote Schuur Hospital. He was previously a Principal Investigator at the Perinatal HIV Research Unit of the WITS Health Consortium. He holds an MBChB and a diploma in HIV Management, and is currently in the process of obtaining Fellowship of the College of Clinical Pharmacologists of South Africa at the Colleges of Medicine of South Africa. He is supervised by Prof. Gary Maartens.


 

Head-and-shoulders photograph of Raymond Moseki

Raymond Moseki: Fogarty HATTP Basic Science PhD Fellow

Moeketsi Raymond Moseki has been awarded a Fogarty HATTP Basic Science PhD Fellowship for his study titled “Molecular pathogenesis of tuberculosis associated immune reconstitution inflammatory syndrome”. Raymond will identify transcriptional biosignatures that are both predictive and diagnostic of tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS). In addition, he will investigate the effect of prednisone on transcriptional biosignatures associated with TB-IRIS, and compare dose-dependent responses to prednisone and Anakinra using an ex vivo peripheral blood mononuclear cell culture model.

Tuberculosis is the most prevalent cause of infectious morbidity and mortality in HIV-1 immunosuppressed patients. Early initiation of antiretroviral therapy saves lives but is associated with risk of paradoxical worsening of TB disease during co-treatment (TB-IRIS). TB-IRIS is the most common complication associated with ART and has a high incidence in some communities.

Our limited understanding of TB-IRIS pathology hinders the design of diagnostic and therapeutic interventions. Although low-dose prednisone effectively prevents TB-IRIS, its use in already severely immunocompromised individuals is not without risk. Safer therapeutic interventions are needed. Raymond hypothesizes that Anakinra, an IL-1 receptor blocker, will be a more efficacious (and potentially safer) treatment for TB-IRIS than prednisone.

Raymond’s study will be the largest transcriptomic investigation of TB-IRIS to date and will aid in identifying preliminary diagnostic and predictive molecular signatures, and new therapeutic treatment options.

Raymond holds BSc and BScMed (Honours) degrees from the University of the Free State, and an MSc Med from the University of the Witwatersrand (WITS). He was previously a medical research assistant in the Centre of Excellence for Biomedical TB Research at WITS. He is supervised by Prof. Graeme Meintjes.


 

Head-and-shoulders photograph of Mahmoud Abdelwahab

Mahmoud Abdelwahab: Fogarty HATTP Postdoctoral Research Fellow

Completed postdoctoral fellowship in March 2022

Mahmoud Abdelwahab joined the 2021 Fogarty HATTP postodoctoral cohort in early April 2021. He will use population pharmacokinetic (PK) models for rifampicin (RIF) and linezolid (LZD) to describe RIF and LZD exposure data derived from the LASER-TBM phase 2a trial.

LASER-TBM is a phase 2a multi-arm trial to evaluate the safety and tolerability of intensified antimicrobial therapy plus additional host-directed therapy compared with the standard of care for HIV-associated tuberculous meningitis (TBM). The trial randomized 100 adult participants in parallel to either standard of care or additional high dose RIF (35mg/kg) and LZD, with or without aspirin for 2 months. LZD was administered orally at 1200 mg daily for one month and reduced to 600 mg daily for the second month.

The combination of effective antimicrobial killing and control of the host response is a key strategy for the successful treatment and management of TBM.

Mahmoud will recalibrate existing population PK models to integrate rich plasma and cerebrospinal fluid (CSF) data from the LASER-TBM trial with the aim of:

  • describing the plasma and CSF PK of LZD and high-dose RIF, evaluating relationships between exposure, efficacy, and toxicity;
  • describing the unbound plasma RIF concentrations which will help characterization of dynamic relationships between serum and CSF protein levels and unbound (active) drug. This will define PK/pharmacodynamic targets, informing dosing for novel regimens; and
  • evaluating drug-drug interaction between LZD and RIF by quantifying the effect of high dose RIF on LZD clearance in plasma and CSF.

Mahmoud holds a Bachelor of Pharmaceutical Sciences degree from Helwan University, Egypt, and a PhD (Clinical Pharmacology) from UCT. He is supervised by Associate Professor Paolo Denti.


2020 cohort

 

Head-and-shoulders photograph of Hygon Mutavhatsindi

Hygon Mutavhatsindi: CIDRI-Africa/Fogarty HATTP Postdoctoral Research Fellow

Completed postdoctoral fellowship in March 2023

Current Position: Scientific Officer (May 2023 – Present) at Cape Town HVTN Immunology Laboratory.

Hygon Mutavhatsindi has been awarded Fogarty HATTP project cost support for his CIDRI-Africa postdoctoral fellowship “Investigation of the immunological signatures of the TB spectrum from infection to disease”. Hygon will investigate whether specific T cell features predict heightened susceptibility to development of tuberculosis (TB) disease using stored samples from well-characterised cross-sectional and longitudinal cohorts.

Tuberculosis infection manifests as a spectrum of states varying from adequate containment (latent infection) to active disease (1). Innovative imaging techniques have recently identified specific lung pathology characteristic of intermediate states of infection in latently infected individuals (2,3). Transition from one state of infection to another depends mostly on the immunocompetence of the host, but measurable indicators of immune protection remain unknown.

Hygon will identify these indicators by comprehensively characterising responses across phases of the TB spectrum, from latent infection, to subclinical and clinically active disease. He will make use of stored samples from active TB cases, healthy household contacts and HIV-infected household contacts of TB cases. All of the study participants have previously been screened using high resolution radiological imaging to track abnormal lung lesions indicative of subclinical or incipient TB, and followed for 18 months to determine disease outcome. Hygon will define the phenotypic and functional profiles of Mycobacterium tuberculosis-specific CD4+ T cell signatures that are associated with radiologically distinct TB disease activity stages. Comparing these signatures will allow him to identify specific phenotypes, pathways or mechanisms related to infection containment or increased TB risk and lead to a better understanding of how Mycobacterium tuberculosis-specific adaptive immune responses evolve across the TB spectrum.

Hygon holds a BSc (Biochemistry and Biology), BSc Honours (Biochemistry), MSc (Biochemistry) (all from the University of Venda), and a PhD (Molecular Biology) from Stellenbosch University. He is supervised by Dr Catherine Riou.

References

  1. Barry CE, 3rd, Boshoff HI, Dartois V, Dick T, Ehrt S, Flynn J, et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol. 2009;7(12):845-55.
  2. Esmail H, Lai RP, Lesosky M, Wilkinson KA, Graham CM, Coussens AK, et al. Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission and computed tomography. Nat Med. 2016;22(10):1090-3.
  3. Malherbe ST, Shenai S, Ronacher K, Loxton AG, Dolganov G, Kriel M, et al. Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure. Nat Med. 2016;22(10):1094-100.

 

Head-and-shoulders photograph of Tafadzwa Chimbetete

Tafadzwa Chimbetete: Fogarty HATTP Masters Scholar

Tafadzwa Chimbetete has been awarded Fogarty HATTP project cost support for his Masters study “The immunological profile of the skin in DRESS and SJS/TEN reactions to first-line tuberculosis drugs in HIV infected patients”. Tafadzwa will characterize the immune phenotype of skin from Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) immune-mediated drug reactions (IM-ADRs) in HIV infected patients.

Adverse drug reactions (ADRs) are unintended harmful reactions to medications. These reactions result in a high number of admissions to hospital: approximately 1 in 12 admissions to South African hospitals are ADR-related. Cutaneous adverse drug reactions are common, usually non-life threatening ADRs that involve the skin. However, severe cutaneous adverse drug reactions (SCARs), albeit uncommon, are potentially life-threatening and are associated with high morbidity and mortality. The most common SCAR clinical phenotypes globally are DRESS and SJS/TEN with prevalence of 4 per 10 000 and 1-7 per 1 000 000 respectively. The most common offending drugs in IM-ADRs in South Africa are first-line tuberculosis (TB) drugs (FLTD), antiretrovirals and cotrimoxazole.

Tafadzwa will use immunohistochemical and immunofluorescent techniques to enumerate T-regulatory and resident T-cell populations in the skin in SJS/TEN and DRESS reactions. These cell populations will be assessed across a range of conditions, including affected and non-affected skin, HIV positive and negative SCAR patients, FLTD-induced SCAR, and SCAR induced by other offending drugs. Contrasting these samples will provide valuable insights into the significance of differing immune cell subsets in the immunopathogenesis of drug-SCAR phenotypes as well as detail the influence of HIV-infection in these reactions.

Tafadzwa holds a BSc in Biochemistry and Physiology and BSc Honours in Physiology, both from Nelson Mandela University. He is supervised by Associate Professor Jonathan Peter.


 

Head-and-shoulders photo of Siphiwe Baloyi

Siphiwe Baloyi: Fogarty HATTP Clinical Science MMed Scholar

Siphiwe Baloyi is an MMed scholar who will be studying the diagnostic performance of the GeneXpert® MTB/RIF Ultra (Cepheid) assay on bone marrow aspirate samples in patients with suspected disseminated tuberculosis. Fogarty HATTP will be supporting Siphiwe by covering project costs.

Siphiwe holds an MBChB from the University of Pretoria and is currently a Haematopathology registrar at Groote Schuur Hospital. He aspires to become a Clinician Scientist and is exploring the possibility of expanding on his MMed project during a future PhD.

In his spare time, he tutors disadvantaged primary and high school children, impressing upon them the importance of inquisitiveness, persistence, learning, disruption and growth. He also takes an active role in undergraduate teaching. He is supervised by Prof. Graeme Meintjes.


2019 cohort

 

Head-and-shoulders photo of Avuyonke Balfour

Avuyonke Balfour: CIDRI-Africa/Fogarty HATTP Basic Science PhD Fellow

Avuyonke Balfour has been awarded a CIDRI-Africa Basic Science PhD Fellowship, with Fogarty HATTP support for project costs, for his study “The role of HIV and TB on frequencies and function of mucosal-associated invariant T (MAIT) cells”. Avuyonke will characterise the phenotypic and functional characteristics of MAIT cells donated by healthy controls, people with HIV, people with HIV-associated tuberculosis (TB) and people with active TB to better understand these cells’ contribution to host defence. MAIT cells are a subset of T cells which respond rapidly to infection by producing proinflammatory cytokines and cytotoxic molecules which lyse and kill infected cells.

Mouse models of TB have established that MAIT cells play a role in reducing bacterial load and increasing survival (1, 2). However, no studies in humans have directly shown the role of MAIT cells in protection against bacterial disease, and reports differ on the effect of HIV infection on the function of MAIT cells, with some studies reporting an impaired function (3) and others reporting a retained function (4).

Avuyonke hopes to bridge this gap and gain an in-depth understanding of MAIT cell response in Mycobacterium tuberculosis and HIV infection in humans. He will assess the effects of factors such as CD4 count, HIV viral load, antiretroviral treatment and TB treatment on MAIT cell frequencies and functional capacity using flow cytometry and Luminex. His work may contribute to the research pathway towards development of pre-infection vaccines.

Avuyonke holds BSc (Microbiology, Biochemistry and Chemistry) and BSc (Hons)(Biotechnology) degrees from Rhodes University, and completed his Master of Science at the University of Cape Town in 2019. He is supervised by Dr Muki Shey and Prof. Graeme Meintjes.

References

  1. Chua WJ, Truscott SM, Eickhoff CS, Blazevic A, Hoft DF, Hansen TH. Polyclonal mucosaassociated invariant T cells have unique innate functions in bacterial infection. Infect Immun. 2012;80(9):3256–67.
  2. Wang H, D’Souza C, Lim XY, Kostenko L, Pediongco TJ, Eckle SBG, et al. MAIT cells protect against pulmonary Legionella longbeachae infection. Nat Commun. Springer US; 2018;9(1).
  3. Leeansyah, E., Ganesh, A., Quigley, M. F., Sönnerborg, A., Andersson, J., Hunt, P. W., … Sandberg, J. K. (2013). Activation, exhaustion, and persistent decline of the antimicrobial MR1-restricted MAIT-cell population in chronic HIV-1 infection. Blood, 121(7), 1124–1135. https://doi.org/10.1182/blood-2012-07-445429
  4. Fernandez, C. S., Amarasena, T., Kelleher, A. D., Rossjohn, J., Mccluskey, J., Godfrey, D. I., & Kent, S. J. (2015). MAIT cells are depleted early but retain functional cytokine expression in HIV infection. Immunology and Cell Biology, 93(2), 177–188. https://doi.org/10.1038/icb.2014.91

 

Head-and-shoulders photo of Linda Boloko

Linda Boloko: Fogarty HATTP Clinical Science PhD Fellow

Linda Boloko joined the Fogarty HATTP Fellow cohort in late 2019, and will be pursuing his PhD. Linda hopes to develop directed therapies to reduce the high mortality of people with HIV-associated disseminated TB through his study “Investigating the pathophysiological mechanisms of HIV-associated disseminated TB with particular interest in immunological profiles and rapid diagnostics”.

Linda holds an MBChB and an MMed from UCT; his MMed project explored “The impact of HIV on 30-day survival amongst patients undergoing cardiac surgery at Groote Schuur Hospital in the antiretroviral era”. He has also participated in the Graduate Summer Institute of Epidemiology and Biostatistics Summer School, which took place at Johns Hopkins University. His PhD is supervised by Prof. Graeme Meintjes.


 

 

Ashar Dhana: Fogarty HATTP Clinical Science PhD Fellow

Graduation: March 2023

Update: Dr. Ashar Dhana was awarded a Fogarty HATTP Clinician Scientist PhD Fellowship in 2019. In 2023, he completed his PhD titled “The evaluation of different strategies to improve the diagnosis of tuberculosis in people living with HIV in resource-limited settings”. He was lead investigator for the 2021 World Health Organization HIV-associated tuberculosis screening guidelines, which formed part of his PhD work. Ashar’s research interests include systematic review, diagnostic test evaluation, and clinical prediction modelling

Ashar also holds an MBChB (University of the Witwatersrand), MPH (Harvard University), and MMED (University of Cape Town). He is currently a consultant dermatologist in the Division of Dermatology at Groote Schuur Academic Hospital, Cape Town. His PhD was supervised by Prof. Gary Maartens and co-supervised by Prof. Graeme Meintjes and Dr. David Barr.


 

Mmamapudi Kubjane: Fogarty HATTP Basic Science PhD Fellow

Graduation: July 2023

Update: Mmamapudi Kubjane, PhD (2023). She works as a Consultant Researcher at the Health Economics and Epidemiology Research Office, a division of the Wits Health Consortium, University of the Witwatersrand. Her work mainly focuses on modelling the epidemiological impact and cost-effectiveness of South African TB control programmes and supporting the development of the South African TB Investment Case. She is also a member of the South African TB Think Tank Executive Committee and leads the Epidemiology, Modelling and Health Economics Task Team (https://tbthinktank.org/about-us/). The TB Think Tank is a national network of TB experts who provide evidence-based advice to the National Department of Health on TB control policy and programmes. She has also been involved in mentoring students in the annual Clinic on Dynamical Approaches to Infectious Disease Data (https://www.ici3d.org/DAIDD/team/).

Mmamapudi Kubjane joined the Fogarty HATTP PhD fellowship programme in early 2019. She is reading for a PhD titled: “Modelling the South African tuberculosis epidemic: the historic impact of HIV; geographical differences, and the impact of current and future interventions”, which she will complete in 2020. Mmamapudi will evaluate how much of the TB epidemic in South Africa is due to HIV, what factors explain the differences in TB epidemiology across the provinces, and the possible impact of new TB strategies or improvements to existing TB control efforts.

The dynamical modelling study extends an established South African HIV model (Thembisa). The TB-HIV model will be calibrated to South African TB data sources including notified TB cases from the Electronic Tuberculosis Register, the number of TB deaths from vital registers and the anticipated TB prevalence from the National TB prevalence survey. The model will also incorporate additional data on gaps and delays in the South African TB treatment cascade.

This research will help understand provincial differences in TB epidemiology; how the TB treatment cascade has changed over time; how it varies across different provinces; and what improvements are needed. Results from this research also have the potential to inform national and provincial policy on effective intervention strategies to control TB.

Mmamapudi holds a BSc and BSc (Hons) in Mathematics, and a Master of Public Health in Epidemiology (all UCT). During her MPH she participated in research on the epidemiology of diabetes in a high HIV and TB burden setting. She is currently affiliated with the Centre for Infectious Disease Epidemiology & Research at UCT, where she is supervised by Dr Leigh Johnson and Prof. Andrew Boulle.


 

Simon Mendelsohn profile photo

Simon Mendelsohn: Fogarty HATTP Clinical Science PhD Fellow

Graduation: December 2022

Update: Dr Simon Mendelsohn was awarded a Fogarty HATTP Clinician Scientist PhD Fellowship in early 2019. In 2022, Simon completed his PhD titled “Evaluation of concise host-blood tuberculosis mRNA signatures in HIV-infected and HIV-uninfected South African adults”. He is currently a senior clinical researcher and investigator on TB vaccine and therapeutic clinical trials, and diagnostic observational studies at the South African TB Vaccine Initiative (SATVI) in the UCT Faculty of Health Sciences. Simon's research focuses on novel, non-sputum tests for diagnosing persistent Mycobacterium tuberculosis infection, pre-symptomatic TB disease, and biomarker-guided strategies for TB preventive and curative therapy.

Simon holds an MBChB (UCT), twin Master of Science degrees (Integrated Immunology, and International Health and Tropical Medicine, both University of Oxford), and a diploma in Tropical Medicine and Hygiene (Royal College of Physicians, London/University of Oxford). He previously participated in operational research evaluating the impact of HIV and TB public health interventions in Malawian prisons with Médecins sans Frontières (MSF, Doctors Without Borders). 

References

  1. WHO. Global tuberculosis report 2018. (2018) Geneva: World Health Organization. http://www.who.int/tb/publications/global_report/en/
  2. WHO. High-priority target product profiles for new tuberculosis diagnostics: report of a consensus meeting. (2014) Geneva: World Health Organization. http://www.who.int/tb/publications/tpp_report/en/

 

 

Isaac Singini: Fogarty HATTP Basic Science PhD Fellow

PhD awarded April 2021

Isaac Singini joined the group of Fogarty HATTP Basic Scientist PhD Fellows in early 2019; he will be developing statistical diagnostics for widely used joint models, and expects to complete his dissertation by the end of the year.

The statistical approach of standard time-to-event analysis with a composite outcome has recently been extended to jointly analyse longitudinal outcomes together with time-to-event outcomes. This is commonly known as joint modelling.

Case-deletion diagnostics for the joint model using Cook’s distance approach is motivated by the fact that in both longitudinal and survival outcomes there may be outlier or influential subjects/observations that influence model estimates.

Simply, an outlier is a subject/observation that is not consistent with the rest of the data under study, while an influential subject/observation causes noticeable change in parameters when excluded in estimation. Inclusion of influential subjects/observations in statistical models may lead to incorrect conclusions.

Isaac will evaluate the diagnostics he develops in simulation studies and using data from an HIV/TB pericarditis dataset.

Isaac holds a BSc (Statistics and Computer Science) from the University of Malawi, a post-graduate diploma (Medical Statistics) from the London School of Hygiene and Tropical Medicine, and an MSc (Medical Statistics) from the University of London. He has previously provided statistical expertise to projects at the Johns Hopkins Research Project—College of Medicine, University of Malawi. He is a visiting scholar at the Harvard T.H. Chan School of Public Health, MA, USA.  Isaac is supervised by Freedom Gumedze of UCT’s Department of Statistical Sciences.


2018 cohort

 

Phuti Choshi

Phuti Choshi: Fogarty HATTP PhD Fellow

Phuti Choshi was awarded a Fogarty HATTP PhD Fellowship in February 2018 for her project “HIV-associated tuberculosis: immunopathogenesis of drug hypersensitivity reactions”. Her research will elucidate pathogenic mechanisms underlying severe cutaneous adverse reactions (SCAR) to anti-TB drugs in persons living with and without HIV. The project has two main aims: characterisation of the nature of immune responses in anti-TB drug hypersensitivity reactions by phenotypic and functional analysis of drug-specific T-cells in peripheral blood and at the site of acute tissue damage; and identification of human leucocyte antigen (HLA) alleles associated with risk of anti-TB drug SCAR.

Her work could ultimately result in the development of methods to tailor TB treatment for South African patients via both pre-treatment screening and post-treatment analysis of adverse reactions. Her study will also investigate why anti-TB drug hypersensitivity reactions are more common in people living with HIV (1). HLA molecules shape the immune response to infection and non-self antigens; the system is highly polymorphic, and many HLA alleles occur in discrete geographic locations or populations (2). It is therefore important to identify the HLA alleles prevalent in South Africans—since ours is an understudied population (3)—and more specifically those associated with the occurrence of anti-TB drug SCAR. This will allow for screening of patients prior to initiation of anti-TB treatment. The methods used to identify drug-specific T-cells could be developed into in vitro and/or ex vivo assays to identify the offending drugs in patients who develop SCAR.

Phuti holds an MSc degree in clinical science and immunology from UCT. She investigated the interaction between neurons and T-cells in central nervous system tuberculosis to understand mechanisms associated with host-pathogen interaction and immune protection. She is undertaking her PhD in the Division of Allergology and Clinical Immunology (UCT) under the supervision of Associate Professors Jonathan Peter and Rannakoe Lehloenya, and Professor Elizabeth Phillips (Vanderbilt University).

References

  1. Knight L, Muloiwa R, Dlamini S, Lehloenya RJ. Factors associated with increased mortality in a predominantly HIV-infected population with Stevens Johnson Syndrome and Toxic Epidermal Necrolysis. PLoS ONE. (2014) 9(4):e93543.
  2. Holdsworth R, Diviney M. HLA typing in diverse populations. ISBT Science Series. (2017) 12:107–11.
  3. Tshabalala M, Mellet J, Pepper MS. Human Leukocyte Antigen diversity: a southern African perspective. Journal of immunology research. (2015) 2015.

 

Zinhle Cindi profile photo

Zinhle Cindi: Fogarty HATTP PhD Fellow

Zinhle Cindi joined the Fogarty HATTP PhD Fellow ranks in October 2018. She will be investigating pharmacokinetic exposure to the antiretrovirals dolutegravir and tenofovir alafenamide in participants enrolled in a randomised controlled trial.  She will determine associations between genetic polymorphisms and drug exposures and drug-related toxicities. Her project will also explore drug-drug interactions between these antiretrovirals and rifampicin-based anti-tuberculosis therapy.

Zinhle holds a BSc Microbiology, BSc Honours (Behavioural Genetics) (both University of the Free State), and an MSc (Medicine, Human Genetics) (University of Cape Town).

She obtained her MSc under the supervision of Prof. Collet Dandara on the subject of warfarin response in the South African Black and mixed ancestry population compared with the response in people of Eurasian ancestry. Zinhle determined that warfarin dose requirements differed between the two populations and population-specific dosing algorithms are therefore required.

She will be conducting her PhD under the supervision of Dr Phumla Sinxadi (Division of Clinical Pharmacology, UCT), Prof. Gary Maartens (Head of the Division of Clinical Pharmacology, UCT), and Prof. David Haas (Vanderbilt University, US).

In the future, Zinhle hopes to focus on health systems and implementation of pharmacogenomics research in relation to communicable diseases of relevance to South Africa.


 

Chacha Issarow

Chacha Issarow: Fogarty HATTP Postdoctoral Research Fellow

Completed postdoctoral fellowship in August 2019

Chacha  Issarow’s project “Developing a phylodynamic model to describe the evolution and transmission of rifampicin-resistant tuberculosis (RR-TB) in a high HIV prevalence setting in South Africa” will combine next generation sequencing (NGS) and clinical and demographic data to study RR-TB isolated from patients in Khayelitsha, Cape Town. His model will be used to infer the evolution of RR-TB strains over time in relation to HIV infection and the use of specific treatment regimens and drugs. He will also characterise highly transmissible and potentially rapidly evolving RR-TB strains.

Mycobacterium tuberculosis has a variety of different strains; some strains mutate rapidly and develop resistance to the drugs usually used to treat TB (such as rifampicin) (1). It is also thought that some drug resistant strains may be more likely to establish themselves in people living with HIV, and that antiretroviral therapy might induce mutations in M. tuberculosis (2). In Khayelitsha approximately 200 RR-TB patients are diagnosed every year, with approximately 70% also HIV infected. Given the strong association between HIV and TB, and potential association between HIV and TB drug resistance, greater understanding of the intersection between these pathogens with regard to evolution and transmission is needed.

Chacha obtained his PhD in Bioinformatics from UCT in 2016. He has previously investigated drug interactions in HIV-TB co-infection and their potential contribution to microbial resistance, and mathematical modelling of TB transmission. His post-doctoral work is supervised by Associate Professor Helen Cox (Division of Medical Microbiology, UCT), and falls within an existing collaboration between UCT, Stellenbosch University (SUN), and the Swiss Tropical and Public Health Institute (TPH). He will receive phylodynamics and bioinformatics training during several visits to the Swiss TPH in collaboration with Dr Tanja Stadler at Eidgenössische Technische Hochschule Zürich (ETH Zürich). This training will enable Chacha to analyse and manipulate genomic data using bioinformatics pipelines to produce complex phylodynamic models.  Visits to Switzerland and training workshops will be funded by an existing grant (Swiss/South Africa Research Award).

Chacha's Google Scholar profile

References

  1. Borrell S, Gagneux S. Strain diversity, epistasis and the evolution of drug resistance in Mycobacterium tuberculosis. Clinical Microbiology and Infection. (2011) 17(6):815–20.
  2. Wells CD, Cegielski JP, Nelson LJ, Laserson KF, Holtz TH, Finlay A, Castro KG, Weyer K. HIV infection and multidrug‐resistant tuberculosis—the perfect storm. The Journal of Infectious Diseases. (2007) 196(s1):S86–107.