The Wellcome Trust will be running a course on “Working with Pathogen Genomes” in Cape Town from the 17th-22nd June 2018.
The deadline for applications is 2nd March 2018.
For more details please see: https://coursesandconferences.wellcomegenomecampus.org/events/item.aspx?e=708
On Monday 4 December, CIDRI-Africa hosted a UK Science delegation at the Khayelitsha Site B clinical research site. Professor Robin Grimes, Chief Scientific Adviser of the UK Foreign and Commonwealth Office, and John Wade-Smith, Africa Regional Head of Science and Innovation, were joined by colleagues Richard Atkinson and Mayibuye Magwaza from the British Consulate General in Cape Town to visit the research facilities. They were hosted by CIDRI-Africa’s Clinical Research Platform Lead Professor Graeme Meintjes and Projects Coordinator for Clinical Research Rene Goliath, along with a team of CIDRI-Africa researchers, Drs Friedrich Thienemann, Hanif Esmail, Sandra Mukasa and Amy Ward. Scientific studies conducted at the site were presented and a tour conducted of the core infrastructure supporting this work. The visitors play key roles in international science, innovation and diplomacy, and we are pleased to have had the opportunity to share with them the important health research being done at UCT and our many productive UK collaborations.
This workshop tackles the challenges of high-quality research study design and proposal development in the context of improving understanding and management of the major communicable and non-communicable diseases that beset Africa.
Deadline for applications: 12th January 2018
Following the Research Methods Workshop held at Walter Sisulu University in Mthatha, Eastern Cape, Dr Mbulelo Mntonintshi expressed an interest in extending his research ideas and collaboration with the University of Cape Town.
As developing research capacity in the field of Infectious Diseases was the main aim of the workshop, Dr Mntonintshi visited the University of Cape Town (UCT) on an invitation from Professors Graeme Meintjes and Robert J Wilkinson from the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) and the Institute of Infectious Disease and Molecular Medicine (IDM) from the 8th to the 19th November 2017.
Dr Mntonintshi explained his reason for the visit: “I am a Family Physician who qualified in May 2017 and a young researcher. I like to do clinical research that improves patient care in our setting. The UCT and NIH team hosted a research workshop at Walter Sisulu University (WSU) 3 months ago. We learnt a lot about research and how to apply for research funding.
During the workshop I met researchers who can help WSU to uplift the research standard and output. I asked them for guidance in research and they responded overwhelmingly and I was invited to UCT.”
During this time, he also attended the 7th Federation of Infectious Diseases Societies of Southern Africa Conference (FIDSSA) held in Cape Town from 9th to 11th November. He felt he learnt a lot during the conference.
He describes his experience of his time observing in the IDM laboratories: “At UCT I saw a research laboratory with sophisticated equipment. In UCT they keep research specimens in a minus 80 degrees freezer and store them for a long time. They have a machine that can count individual cells like lymphocytes and identify receptors. They said if we can organize transportation of specimens to UCT and maintain the cold chain they can do some tests for us in UCT. That can immediately uplift our research standard.”
He also had one hour sessions with about 10 researchers, each with individual expertise and experience and commented on how friendly and professional they were.
He also attended the IDM lunch hour seminars.
Following his visit to the Khayelitsha Clinic site, he commented: “I visited 2 of their research sites in Khayelitsha, one for HIV vaccine and another about HIV and TB. I was introduced to the whole team and they had time to show me what they do. Their research sites are of high standard. They adhere to ethical requirements, really reduce bias and are careful and dedicated about the work they do.”
“Professor Meintjes helped to develop my research project and showed me how to apply for funding. We have plans to do collaborative research between UCT and WSU. I am happy to have them on my side.”
Thanks from Dr Mntonintshi Mbulelo
Professor Graeme Meintjes with Dr Mbulelo Mntonintshi outside the CIDRI-Africa Office in the IDM
Prospective applicants should be researchers affiliated with either Sefako Makgatho Health Sciences University (SMU) or Walter Sisulu University (WSU).
Applicants may be clinically qualified researchers with or without a PhD, or non-clinical researchers who hold a PhD. Work leading to the degree of MMed for clinicians would be in scope.
Honorary Professor Robert J Wilkinson’s research leadership as Director of the Wellcome Centre for Infectious Diseases Research in Africa, based in the Institute of Infectious Disease and Molecular Medicine at the Faculty of Health Sciences, and as Senior Group Leader at the Francis Crick Institute in London, are highlighted in this report.
You can view the articles as follows:
Prestigious new Wellcome Centre for Infectious Diseases Research in Africa for UCT
Crick African Network to train top African Scientists
Sponsoring organisations: Western Cape Government Health Department, Wellcome Centre Infectious Diseases Research in Africa, University of Cape Town, MSF, City Health, City of Cape Town’s Solid Waste and Disaster Management and Environmental Health.
On October 25th, the Western Cape Government Health Department’s Khayelitsha Community Health Clinic together with the Wellcome Centre Infectious Diseases Research in Africa, University of Cape Town, MSF, City Health, City of Cape Town’s Solid Waste and Disaster Management and Environmental Health sponsored the Health Imbizo which focused on public engagement with the community of Khayelitsha. The Imbizo was open to all the public of Khayelitsha specifically those residing in Site B and approximately 250 were in attendance. During the Imbizo, the attendees shared their opinions, thoughts and suggestions for consideration for the improvement of services and better understanding of the functions of the different organisations present.
Facility manager of the Khayelitsha Community Health Clinic, Mr. David Binza; Wellcome Centre Infectious Diseases Research in Africa Community Liaison Officer, Ms. Zandile Ciko; Ward 18 Councillor, Ms. Ntomboxolo Koopman were on hand to open the Imbizo. Mr. Binza gave a brief background of the Health Imbizo concept. He explained how it was necessary for platforms of this nature to be occur as the community has to be aware of services provided by the different organisations and governmental departments working within Khayelitsha.
The Keynote speaker was Mr. Mzwanywa Ndibongo, Chairperson of the Khayelitsha Health Forum. Mr. Ndibongo spoke about the importance of having an open dialogue between organizations and the community. He emphasized that his work was to bridge the gap between these two very important groups and how developing a continuous impartial relationship amongst them was key for the progress of health related initiatives within Khayelitsha.
During the day, Imbizo participants had the opportunity to listen and engage with different speakers, sharing their experiences and developing recommendations for effective participation and service provision. Topics covered included current HIV and TB research initiatives, Access to services, Shortage of staff in clinics, Adherence to medication, Responsible water usage and various more. The participants had the opportunity to further engage with the different organisational representatives by visits their display and information tables. Following a structured program of presentations and information exchange, the audience and organisational representatives reached a consensus that an annual Health Imbizo was important to allow for a continuous dialogue and a standard of accountability and ownership for the development of health related services within Khayelitsha.
Phathuxolo Vinqishe, manning the Uhambo (HVTN 702) table. Uhambo is an HIV vaccine efficacy trial currently being conducted at the eKhayaVac Clinic Research Site.
Zandile Ciko, presenting an overview of the current research initiatives at eKhayaVac CRS and the Hubb at the Site B CHC.
Audience and participants listening to the presentations.
The core administrative team for the Fogarty HIV-TB Training Program at UCT: Jonny Peter, Sipho Dlamini, Kathryn Wood and Graeme Meintjes
The Fogarty HIV-associated Tuberculosis Training Program has been established at the University of Cape Town in partnership with Johns Hopkins University (JHU) and Vanderbilt University Medical Center (VUMC) in the US. The Program is funded by a 5-year grant from the Fogarty International Center of the US National Institutes of Health.
UCT has a well-established international reputation as a leader in the field of HIV-TB research. This Training Program aims to support the career development of the next generation of research leaders in this field at UCT. The vision of the Training Program is the establishment of a multidisciplinary, highly successful trainee cohort who are retained at UCT and function as a collaborative community (during and beyond their Fogarty training) so as to sustain the quantity, quality and impact of HIV-TB scientific output from UCT. To this end, 15 fellowships will be awarded over the 5 years to clinician researchers, basic scientists and epidemiologists, helping each to either obtain a PhD or undertake post-doctoral study towards research independence.
The five research focus areas prioritized for training are:
Personal Individual Development Plans with annual review will be a strong focus. The Program also includes periods in the US for certain fellows to obtain specific skills, short courses at UCT, distance learning via web-based courses, a schedule of research seminars for trainees, and an annual symposium. The Program will organise an annual seminar for medical students in 5th and 6th year to introduce them to HIV-TB research and discuss funding and career opportunities in this field.
The Program will build on existing collaborative links between UCT, JHU and VUMC. UCT and VUMC researchers have recently collaborated on the establishment of a multidisciplinary drug hypersensitivity clinical platform in Cape Town that will facilitate a research collaboration in this field.
Outcomes of the Program will include:
The Program will be administered by the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) in the Institute of Infectious Disease and Molecular Medicine (IDM), led by Professor Graeme Meintjes (Principal Investigator, Member of the IDM), together with the UCT members of the Co-ordinating Committee Associate Professor Jonny Peter, Associate Professor Sipho Dlamini, Professor Gary Maartens, Professor Andrew Boulle and Ms Kathryn Wood (CIDRI-Africa). Other members of the Co-ordinating Committee are: Professor Richard Chaisson (JHU), Associate Professor Jonathan Golub (JHU), Professor David Haas (VUMC), and Professor Tim Sterling (VUMC).
Deadline 30th October 2017
Dr Nashied Peton from the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) - Department of Pathology – Division of Medical Microbiology has been awarded a Carnegie Corporation Early-Career Fellowship for a period of 3 years. He held a previous Carnegie fellowship award in the Next Generation of Academics in Africa Programme, as a Postdoctoral Research Fellow from May 2015 to April 2016.
Dr Peton obtained his doctoral degree in 2013 under the supervision of Professor Jonathan Blackburn in the Department of Integrated Biomedical Sciences at the University of Cape Town. After becoming the recipient of a 2015 Carnegie Postdoctoral fellowship, he joined the CIDRI-Africa research group under the supervision of Dr Anna Coussens and Professor Robert J Wilkinson.
Dr Peton’s research focus is on Tuberculosis and HIV-1 (TB-HIV) host-directed therapies. He is investigating the human macrophage response to infection, specifically how HIV perturbs the macrophage response to Mycobacterium tuberculosis (Mtb) and how modulating the host response can enhance pathogen clearance and prevent pathogen induced cell death.
We would like to congratulate Dr Peton on this prestigious award, and wish him well as he takes his research forward and contributes further to new knowledge in the field of Tuberculosis and HIV Infectious Diseases.
Department of Medicine Research Day
The University of Cape Town and Groote Schuur Hospital held their 43rd Annual Department of Medicine Research Day meeting from Wednesday 4th October to Thursday 5th October 2017 in the Nico Malan Conference Centre at Groote Schuur Hospital.
Dr Charlotte Schutz from the Wellcome Centre for Infectious Diseases Research in Africa in the Institute of Infectious Disease and Molecular Medicine and the Department of Medicine delivered an oral presentation titled “Biomarkers associated with high early mortality in hospitalized patients with HIV-associated tuberculosis”. Other presentations on the day included studies conducted in the fields of Neurology, Pulmonology, Nephrology, Dermatology, and Gastroenterology. At the Awards Ceremony event following the oral presentations, Dr Schutz received the prize for the best oral presentation (clinical research).
This study forms part of her PhD thesis and is nested within a larger study on HIV-associated tuberculosis conducted at Khayelitsha Hospital by Professor Graeme Meintjes from CIDRI-Africa, the IDM and Department of Medicine and funded by the Wellcome Trust.
Annual Scientific Meeting of Malawi-Liverpool-Wellcome Research Group
Dr David Barr from the University of Liverpool joined Professor Meintjes research group in November 2015, having received a Wellcome Trust Liverpool-Glasgow Centre for Global Health Research Clinical PhD fellowship, to conduct research in the field of HIV-associated tuberculosis.
Dr Barr attended and presented at the Annual Scientific Meeting of the Malawi-Liverpool-Wellcome research group based in Blantyre, Malawi from 1st to 4th October 2017. The title of his presentation was: “HIV-associated blood-stream disseminated tuberculosis among inpatients: rapid diagnostics and clinical phenotype”. Several UK-based and Malawi-based infectious disease researchers also presented at the meeting.
At the close of the meeting, Dr Barr was honoured as presenter of the best talk, adjudicated by experienced international researchers.
Dr Barr is an infectious diseases registrar in the West of Scotland Deanery and is conducting his clinical research at Khayelitsha Hospital and UCT currently.
Dr Barr’s PhD is supervised by Professor David Lalloo and Dr Gerry Davies at the University of Liverpool and Professor Graeme Meintjes from the Wellcome Centre for Infectious Diseases Research in Africa, at the Institute of Infectious Disease and Molecular Medicine in the Faculty of Health Sciences at University of Cape Town.
Well done David!
Ms Amanda Jackson from CIDRI-Africa and Mr Suresh Maslamoney from CBIO attended this networking meeting held in London from 27-28 September 2017.
The first day of the meeting took place at the Wellcome Genome Campus Conference Centre in Hinxton, Cambridgeshire. The programme began with an overview of the Wellcome Genome Campus, given by Dr Tim Cutts, Head of Scientific Computing, and was followed by a site tour of the Sequencing and Data centres.
In the next session, the meeting participants, who came from centres in Africa, Vietnam and the UK, presented their current IT / Data Management Strategies and shared some of the challenges they faced as well as some of their successes.
We then were given an overview of the data sharing services, international projects and bioinformatics systems of the European Bioinformatics Institute (EBI) who maintain a comprehensive range of freely available molecular data resources. The EBI presenters also reviewed their databases, bioinformatics training and tools for data sharing and analysis.
On Thursday, the first sessions, given by Kieron O’Hara, Associate Professor, University of Southampton and Kenan Direk, a Data Scientist from the Farr Institute of Health Informatics Research, University College London, explored the theory and practice of data security and governance to maximise the value of data and support data sharing. A case study was presented by Kobus Herbst from the Africa Health Research Institute (AHRI), on the evolution of AHRI data management systems.
The group then subdivided into sub-groups of Data Managers and IT specialists to attend parallel sessions on Clinical Trials Data, and Cloud Technology respectively. The former explored some of the different data management solutions available for clinical trials through case studies and was conducted by Mary Rauchenberger, Head of Data Management Systems at the MRC Clinical Trials Unit. Hien Ho Van from OUCRU in Vietnam presented a case study of the MACRO electronic data management system they have developed for use in their clinical studies.
A session on Information Technology Infrastructure Library (ITIL) was aimed at IT Managers to explore how ITIL can add value to IT service management. An overview of the UK Data was given by Louise Corti, from the UK Archive, looking at the systems in place at the Archive to enable them to manage large datasets.
|AORTIC 2017 best Data Analysis||Maia Lesosky|
|Objectives and Aims of the Workshop||Robert Wilkinson|
|Clinical study design: observational studies & randomised controlled trials||Graeme Meintjes|
|Elements of a Research Protocol||Elsa Du Bruyn|
|Funding opportunities for South Africans||Yolande Harley|
|Grant writing: optimising the ‘other bits’ of grants||Yolande Harley|
|Grant writing: Introduction||Robert Wilkinson|
|Graphical presentation of data||Bruno Andrade|
|Statistical considerations in research||Delva Shamley|
|Really Important Statistical Considerations||Maia Lesosky|
|Statistical considerations in research||Maia Lesosky|
|Specific opportunities within NIH U01 program||Robert Wilkinson|
|Why Immunology matters in Africa||Alan Sher|
We warmly congratulate Hlumani Ndlovu from the Department of Integrative Biomedical Sciences on being selected as one of the Mail & Guardian’s 200 Young South Africans for 2017.
Hlumani has a long-standing association with the IDM, having completed his PhD with Frank Brombacher and postdoc with both Frank and Mohlopheni Marakalala, and as a member of our Education Task Team. Hlumani and Mohlopheni have recently published a fascinating review in PLoS Pathogens on signaling C-type lectin receptors in antimycobacterial immunity.
To learn more about Hlumani and his work, go to:
Following new funding from Wellcome, the original Clinical Infectious Diseases Research initiative (CIDRI) has evolved into the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa). This Centre will be directed by Honorary Professor Robert J Wilkinson supported by co-applicants representing departments and divisions across the IDM and the Faculty of Health Sciences. To celebrate this prestigious new Centre, a mini-symposium was held on Wednesday 26th April 2017 in the IDM’s Wolfson Pavilion Lecture Theatre. The Centre was officially opened by the Vice-Chancellor, Dr Max Price, followed by a review by Professor Robert J Wilkinson, explaining the rationale leading to the Strategic Award in 2008 as well as the achievements and awards of postgraduate scholarships and post doctoral fellowships during the period of the Clinical Infectious Diseases Research initiative.
This was followed by presentations from five CIDRI fellows showcasing their research supported by the Initiative and how the support of the Initiative has subsequently enabled them to pursue their research careers to obtain further achievements.
The presenters were:
The Dean of the Faculty of Health Sciences, Professor Bongani Mayosi – also a member of CIDRI-Africa Steering Committee – delivered a presentation detailing the value of the Centre within the Faculty.
Following a break, Dr Marilet Sienaert, the Executive Director of the UCT Research Office gave an overview of Research Centres within UCT. An application to accredit the Wellcome Centre by the University Research Committee is in process.
The Centre supports 3 platforms:
The additional co-applicants who form the Steering Committee for the Centre are:
Professor Robert J Wilkinson and the platform leads presented the Centre’s vision for cross-departmental collaborations and research excellence over the next 5 years.
The event was concluded with a social cocktail reception in the IDM Foyer where further questions were discussed.
Tuberculosis (TB) remains a major global health problem, with 10 million cases and 2 million deaths per year according to the World Health Organization. The only available vaccine is effective in children, but its effect wanes in older children and adults.
People who are already infected with HIV are more susceptible to TB infection, and they often encounter severe complications and experience a much higher mortality rate as a result of their co-infection. The brunt of the co-epidemic of HIV and TB is especially felt in sub-Saharan Africa, a region that also struggles with high rates of poverty and inequality.
While the TB bacteria (Mycobacterium tuberculosis) has been evolving with humans for thousands of years, HIV co-infections create immunological environments within the host that this bacterium has not encountered before and could, therefore, be nudging it to evolve new characteristics.
In one of the first studies to have investigated this possibility, Dr Anastasia Koch from UCT’s Institute of Infectious Disease and Molecular Medicine conducted an evolutionary analysis of M. tuberculosis full genome sequences from HIV uninfected and HIV co-infected individuals. She conducted her research under the supervision of Professor Robert Wilkinson from the Wellcome Centre for Infectious Disease Research in Africa and Associate Professor Darren Martin from Computational Biology, and in collaboration with colleagues from the Institute of Infectious Disease and Molecular Medicine and from the Swiss Tropical and Public Health Institute.
These M. tuberculosis strains were isolated from individuals living in Khayelitsha, a community with among the highest HIV and TB infection rates in the world.
The research team uncovered specific sites within M. tuberculosis genomes where the bacterium may have been forced to evolve in response to HIV co-infections.
Of particular significance was that when these sites were classified according to their function, an unusually large number occurred in parts of the M. tuberculosis genome that provide the genetic information for epitopes. Epitopes are the parts of M. tuberculosis proteins that are recognised by the B and T cells in the human immune system. However, in this study only epitopes that might be recognised by T cells were investigated.
“This is the first time that evolutionary models have been applied to M. tuberculosis whole genome sequence data to detect natural selection that might be influenced by HIV co-infection. An important finding of this work is that natural selection on M. tuberculosis can be detected using these methods, and that HIV may be impacting how M. tuberculosis is presently evolving,” said Koch.
“The influence of HIV on M. tuberculosis epitope evolution could have implications for the design of vaccines to be administered in settings with high rates of HIV-associated TB. However, it is highly desirable that our results are validated on larger datasets in other settings to establish how generalisable our findings are,” she said.
“So it’s extremely important to stress that this requires a lot more work: firstly, to validate our findings in larger cohorts; secondly, to understand exactly how M. tuberculosis is changing during HIV co-infection; and thirdly, to understand how much of an impact this would have on immune recognition of M. tuberculosis.”
Koch hopes that the work will inform thinking around the potential for M. tuberculosis to evolve not just in response to human interventions such as the antibiotics or vaccines that have been used to control this bacterium, but also in response to the largely uncontrollable and ever-changing microbial communities that share humans as their preferred homes.
The research team’s findings appear in the advanced online edition of Molecular Biology and Evolution.
The setting for this study: Khayelitsha, Cape Town. The high rates of HIV and TB in this setting are fuelled by poverty and inequalities in access to healthcare. The picture was taken as part of Eh!woza – a public engagement project that Dr Koch is involved in running.
A study published this week in the journal BMC Medicine by researchers from the University of Cape Town shows that among hospitalised patients with HIV infection, a simple and inexpensive urine test identified more TB diagnoses in the first 24 hours of admission than rapid sputum-based tests.
This urine test (the Determine TB-LAM assay, similar to a pregnancy test) detects components of the cell wall of the TB bacterium in the urine and takes about 20 minutes to undertake without need for special infrastructure.
One of the researchers on the study, Professor Graeme Meintjes said: "The results of this study build on findings of other UCT researchers that this urine test can reduce mortality among HIV-infected patients admitted to hospital by speeding up the diagnosis of TB.
"The findings of these studies challenge the dogma that the first place to look for TB is in the sputum. Among a select group of patients (HIV-infected patients with very weak immune systems admitted to hospital) a combination of tests is required, including urine and sputum tests, to facilitate a quick diagnosis of TB thereby allowing doctors to start patients with TB on appropriate treatment rapidly."
Historically, the laboratory examination of sputum samples has been the method used to diagnose most cases of TB. However, it is well recognised that this approach often fails in patients with HIV infection. In many of these patients, TB spreads from the lungs to the blood and other organs in the body due to poor immunity.
Additionally, there may be few or no TB bacteria found in their sputum, either because they are too weak or ill to produce a good sputum sample or because of less TB cavity formation in their lungs.
The difficulty of diagnosing TB is particularly true for patients with HIV who are sick enough to be admitted to hospital. Notably, in such patients, it is critically important to make a rapid diagnosis of TB so that treatment may be initiated promptly to avoid deaths.
The study was conducted at GF Jooste Hospital prior to it being decommissioned. A total of 427 consecutive patients with HIV infection admitted to the medical wards were screened for TB using sputum, urine and blood tests. In total, one in three (33%) of these patients were diagnosed with active TB disease. Among patients with TB, sputum microscopy and sputum Xpert diagnosed TB within 24 hours of admission in 19% and 27%, respectively, compared to 38% using the urine Determine TB-LAM assay. The urine test was particularly useful for diagnosing TB in the patients with the lowest CD4 counts or weakest immune systems as well as those who were anaemic.
The main reason that the urine test outperformed the sputum test was because of how difficult it was to obtain a sputum specimen from many patients on admission. Whereas almost all patients, even those were very ill, could provide a urine sample.
The study was led by Professor Steve Lawn, who passed away in September 2016, after a long battle with brain cancer. Professor Lawn, originally from the UK, conducted research in Cape Town from 2004 until the time of his death. He made seminal contributions to understanding the interactions between HIV and TB, the role of antiretroviral therapy in preventing TB in HIV-infected people and the important role of new diagnostic tests in improving the diagnosis of TB in HIV-infected people. Professor Lawn published over 100 papers with UCT colleagues on HIV and TB in leading international journals.
Authors: Stephen D. Lawn, Andrew D. Kerkhoff, Rosie Burton, Charlotte Schutz, Andrew Boulle, Monica Vogt, Ankur Gupta-Wright, Mark P. Nicol, Graeme Meintjes
The Clinical Infectious Diseases Research Initiative (CIDRI) clinical research site located at Site B Community Health Centre in Khayelitsha has been activated as one of the trial sites to participate in the pivotal HVTN702 randomised controlled trial assessing the safety and efficacy of the novel HIV vaccine (ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59). It is one of fifteen sites across South Africa participating in this trial. The other site in Cape Town is Emavundleni in Crossroads run by UCT's Desmond Tutu HIV Centre. The Emavundleni site has been recruiting since late 2016.
The trial aims to enroll 5,400 men and women aged 18-35 years. It is planned that each of the 15 sites will enroll 360 HIV-negative participants over a 2-year period. Each participant will be followed for 2-3 years in the study.
The vaccine used in HVTN 702 is based on the vaccine investigated in the RV144 clinical trial in Thailand. The Thai trial delivered landmark results in 2009: the experimental vaccine regimen it tested was found to be 31 percent effective in preventing HIV infection over the 3.5-year follow-up period after vaccination.
In the HVTN 702 study, the vaccination schedule and vaccine components of the RV144 vaccine regimen have been modified in an attempt to increase the magnitude and duration of the protective immune responses elicited. Funders of the trial are the National Institute for Allergy and Infectious Diseases (NIAID), the Bill & Melinda Gates Foundation, and the South African Medical Research Council (MRC).
The principal investigator at the Khayelitsha site is Professor Graeme Meintjes. The trial staff of over 20 members has worked hard over the past 6 months to prepare the site for the trial in terms of training and developing clinical, regulatory laboratory and pharmacy infrastructure and capacity. A Community Advisory Group (CAG) of 12 community members has also been established and has advised the trial team on strategies for messaging and recruitment in the community. Meintjes said: "This is the first time that the community of Khayelitsha has the opportunity to participate in an HIV vaccine trial. This is fitting given the key role that members of this community have played in the fight against the HIV epidemic through activism and disseminating knowledge about the virus to combat its spread. The ongoing burden of new HIV infections among young people in this and many other communities in South Africa means that its vital to develop and evaluate new prevention methods."
The Khayelitsha HVTN702 trial team at Site B Community Health Centre
The findings of the PredART trial were presented at the annual Conference on Retroviruses and Opportunistic Infections (CROI) that took place in Seattle, United States, from 13-16 February 2017. This trial is the first to demonstrate the efficacy and safety of prednisone for preventing the tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in patients at high risk for this condition.
The trial was conducted as a collaboration between investigators from UCT, Imperial College London and the Institute of Tropical Medicine in Belgium. UCT investigators included Graeme Meintjes (Principal Investigator), Robert J. Wilkinson, Gary Maartens, Cari Stek, Liz Blumenthal, Friedrich Thienemann and Charlotte Schutz. The main funder of the trial was the the European and Developing Countries Clinical Trials Partnership (EDCTP), with co-funding received from the South African National Department of Science and Technology and the Wellcome Trust.
TB-IRIS is the most frequent complication of starting antiretroviral therapy in patients with advanced HIV being treated for active TB disease (it affects up to 50% of such patients). It manifests with recurrent or new inflammatory features of TB during the first few weeks of ART resulting in clinical deterioration frequently necessitating hospital admission. Patients complain of recurrence of their TB symptoms, and may develop enlarging lymph glands in their neck, TB abscesses or worsening of their chest X-rays.
The trial was conducted at Site B clinic in Khayelitsha at the Clinical Infectious Diseases Research Initiative (CIDRI) clinical research facility. It was a randomized, double-blind, placebo-controlled trial: 240 patients who were HIV-infected with a CD4 T-cell count of 100 cells/mm3 or lower, who had never received ART previously and were recently diagnosed with TB disease were enrolled. All participants received TB treatment and ART. Participants were randomized in a 1:1 ratio to receive prednisone for 4 weeks or identical placebo for 4 weeks started at the same time as their ART medication, and followed intensively for a further 8 weeks. A moderate dose of prednisone was used: 40mg per day for 2 weeks followed by 20mg per day for 2 weeks. Prednisone is a corticosteroid anti-inflammatory drug that is widely used for the treatment of conditions such as asthma and certain forms of arthritis.
The primary comparison was the proportion of participants who were diagnosed with TB-IRIS. In participants who received prednisone there was a significant (30%) relative reduction in the risk of developing TB-IRIS: 46.7% of patients in the placebo arm developed TB-IRIS compared with 32.5% in the prednisone arm. There was a trend towards fewer hospital admissions in the prednisone-treated participants.
Also important is that prednisone appeared to be safe in these patients with advanced HIV. Adverse events and severe infections were not more common in the prednisone-treated participants. One case of Kaposi’s sarcoma (an HIV-related cancer) occurred: this was in a patient in the placebo arm who stopped taking ART.
Prednisone is a cheap and readily accessible drug in developing world settings. In this trial, it was demonstrated that it reduces the incidence of TB-IRIS by 30% in patients on TB treatment at high risk for TB-IRIS starting ART. It was also safe. These findings provide the first evidence of an effective strategy for reducing the risk of developing TB-IRIS which is a very common early complication of ART in South Africa.
CROI press conference:
Short film about PredART trial made in 2015 by EDCTP:
PredART trial clinical team meeting at Site B clinic in Khayelitsha where the trial was conducted.
Chest X-ray worsening due to TB-IRIS: the first X-ray was taken prior to ART, the second when the patient presented with TB-IRIS.
Current treatment of TB is long, complicated to administer, and can have severe side-effects. To prevent recurrence of the disease after treatment is stopped patients undergoing treatment must take a combination of different antibiotics for at least 6 months– this often leads to improper adherence, which consequently can result in the development of multi-drug-resistant TB (MDR). Treatment for drug-resistant TB can take up to two years, and is yet more complex, expensive, and toxic. The staggering cost of curing MDR-TB poses a significant challenge to governments, health systems, and other payers – and still, many patients are unable to even access treatment. Among those who do receive treatment for MDR TB, only 50% survive.
Thus, shortening of standard treatment is a main priority of current TB research. Previous studies of treatment shortening, usually to 4 months, have all been unsuccessful when compared to standard 6-month treatment. Six-month courses cure 95% of patients and shorter courses only 80-85% of patients. This still means, however, that most patients are cured after 4 months - but we cannot currently know beforehand which patients belong to that group. If it were possible to identify the patients who only require 4-month therapy, we would be able to reduce treatment duration in the vast majority of patients.
This is precisely what the Predict-TB consortium wants to do:
Over the next five years, the consortium, led by Prof. Clifton Barry from the US National Institutes of Health and Prof. Gerhard Walzl from Stellenbosch University in South Africa, is planning to develop a smart set of treatment stopping criteria, and a point-of-care device to measure immunological markers that can contribute to the decision making. The group will perform an ambitious phase 2B clinical trial in South Africa and China, looking at demographic, radiographic, bacteriologic and immunologic parameters, to answer two key questions:
This new method – if successful – could be a true game changer, advancing treatment standards from the current practice of "one size fits all" to precision-guided individualised therapy, which would allow for shortened treatment in a significant proportion of drug sensitive TB patients.
Millions of patients could benefit from a much shorter treatment. This will not only make their lives much easier: Reducing the TB burden will have a beneficial effect on the economic situation in many developing countries, and less drug resistance will benefit public health on a global scale.
The Predict-TB project will receive over 20 million EUR funding from the EDCTP, the Bill & Melinda Gates Foundation through the Foundation for the National Institutes of Health, National Institutes of Health, the National Science Foundation of China (NSFC) and China Ministry of Science and Technology (MOST).