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:
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.
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.
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:
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.
Jacquiline Mugo will be joining the 2021 Fogarty HATTP postdoctoral cohort. She will be defining 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 defining 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 occurrence of SCAR to FLTD reported to be as high as 13%.
SCARs are associated with increased mortality and healthcare costs, 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 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 is currently completing her PhD in Bioinformatics. She also holds a BSc (Hons) Mathematics (University of Nairobi), and an MSc Mathematical Sciences (Stellenbosch University). She will be supervised by Associate Professor Jonathan Peter.
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.
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.
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.
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.
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 was awarded a Fogarty HATTP Clinician Scientist PhD Fellowship in April 2019. He will be developing mathematical models to predict the likelihood of particular clinical diagnoses and outcomes.
Ashar will be developing clinical prediction models (CPMs) in the area of HIV-associated TB. His project has two principal aims: the use of CPMs for prognosis in HIV-infected patients with confirmed or suspected TB and the use of CPMs for diagnosis of HIV-associated TB in inpatients and outpatients. In particular, he will aim to develop CPMs using elements that are readily available in resource-limited settings.
CPMs combine data—from a patient’s history, examination, and investigations—to predict the probability of a diagnosis or outcome. CPMs may be more accurate than clinical judgement, since they integrate multiple pieces of information simultaneously. Ashar’s models may ultimately be made available through a website calculator or within an app for a smartphone device, which could be used at the bedside to assist health professionals with everyday decision-making.
Ashar holds an MBChB (University of the Witwatersrand) and an MPH (Harvard University). He is currently a medical registrar in the Division of Dermatology at Groote Schuur Hospital. He previously conducted research into reproductive health during his medical internship and the role of diet in skin cancer during his MPH. He’s also conducted several meta-analyses in the field of dermatology during his time as a medical registrar. Ashar is supervised by Prof. Gary Maartens and co-supervised by Prof. Graeme Meintjes and Dr David Barr.
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 was awarded a Fogarty HATTP Clinician Scientist PhD Fellowship in early 2019. Simon is reading for a PhD titled “Evaluation of six concise host-blood tuberculosis mRNA signatures in HIV-infected and HIV-uninfected South African adults”, to be completed in 2021. He will establish whether host, virological, signature design, and/or environmental factors affect the performance of the mRNA signatures; and will adapt and validate the signatures for use with finger-prick blood samples with a view to development of a point-of-care test.
In 2017, 36% of TB cases were undiagnosed, unreported, or untreated (1). There is a need for earlier TB case identification, using novel non-sputum-based diagnostic tests (2). These tests must be efficacious in the HIV-infected population, which is at high risk of Mycobacterium tuberculosis infection and progression to TB disease. A blood-based triage test could help shorten the time to treatment initiation, or even facilitate initiation of preventive therapy before symptoms emerge. Host-blood transcriptional profiling has recently been used to discover mRNA signatures capable of discriminating active TB disease from M. tuberculosis infection, other disease states, and healthy individuals. Simon will evaluate six concise PCR-based TB signatures with utility to diagnose prevalent TB and predict incident TB in both HIV-infected and -uninfected persons.
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). Simon is supervised by South African Tuberculosis Vaccine Initiative (SATVI) Director Prof. Mark Hatherill, and is co-supervised by Prof. Tom Scriba (SATVI Deputy Director: Immunology & Laboratories).
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.
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).
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’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).