Paediatric Programme - HIV and other Diseases of Poverty.

Lead Research Organisation: University College London

Abstract

Our studies aim to improve management of children with severe illnesses of poverty (predominantly HIV, Malaria, bacterial infections, TB) worldwide. We have 20 years experience of HIV in children, inintially in Europe, now mainly in Africa. In Europe, prevention of mother-to-child HIV transmission has reduced new infections in babies, but many children are now entering adolescence. Our research is finding out the best medicines with the fewest longterm side-effects, as children have to take treatment for life. In UK, we are starting a new study (AALPHI) to find out how HIV and its treatment affects young people entering adulthood. |Rollout of HIV treatment in Africa is increasing, bringing many questions about how best to do this in countries with few trained staff or health infrastructure. HIV-infected children have many other problems including malnutrition, tuberculosis, bacterial infections, malaria; without treatment, ~50% die before their second birhtday. We are undertaking large studies with colleagues in south/east African countries aimed at providing ways to enable more children to access HIV treatment. |Throughout Africa, death from malaria and other severe infections is unacceptably high, most occurring <24 hours after admission to hospital. Little attention has been paid to resuscitation with fluids. We are working with colleagues in Kenya to find out the best way to resuscitate these very sick children, particularly with malaria.

Technical Summary

The CTU paediatric programme of trials and cohorts of childhood diseases of poverty - HIV, malaria, tuberculosis and sepsis - aims to generate evidence to inform policy and practice in both well-resourced and resource-limited countries worldwide, particularly Africa. |The PENTA (Paediatric European Network for treatment of AIDS, www.pentatrials.org) program (funding EU 1990-2015) undertakes cohorts and trials in ~15 countries in Europe, South America, Asia(Thailand) and Africa (Uganda) addressing questions on HIV-infection in children which cannot be extrapolated or assumed from adult studies. New trials aimed at older children/adolescents focus on strategies to maximise efficacy and adherence to antiretroviral therapy (ART) while minimising longterm toxicity (PENTA 16, 18 & 20 trials). Two trials recently completed: (1)PENTA 11, a trial of CD4-guided treatment interruptions (AIDS 2010) has 5 year follow-up ongoing; (2)PENPACT1: a 5-year trial of what treatment to start and when to switch will be presented at World AIDS 2010. |Individual patient meta-analyses of European cohort data address multiple questions, including informing trial design, facilitating recruitment and longterm follow-up during/after trials, comparisons between adults and children and pharmcovigilance information for the EMEA. The Childrens HIV Paediatric Study (CHIPS, a UK/Irish paediatric HIV cohort, www.chipscohort.org, DOH funding 1990-), contributes to the above and also provides annual feedback to inform national paedaitric HIV services. Recently (2012) a new cohort study of HIV-infected adolescents and HIV-negative controls has started recruitment. It will evaluate long-term health outcomes in these two groups, with a particular focus on neurodevelopment, quality of life and growth. |In Africa, large ongoing trials in Uganda, Zambia, Zimbabwe and South Africa (total ~2,500 children) are addressing multiple management questions including: when to start ART in children; when and whether ART can be stopped after early treatment; how to monitor children on ART; simplification of ART using fixed dose combination baby pills and once-daily dosing; whether cotrimoxaozole prophylaixs can be stopped in children on ART. Several trials have 2 or more randomisations (in factorial design), have multiple substudies (e.g. pharmacokinetics, adherence, co-morbidities tuberculosis, sepsis, malnutirition) and include additional social science and economic components. A new trial addressing ways to reduce early mortality in HIV-infected adults and children is planned. |In collaboration with Wellcome Trust centre, Kilifi, Kenya, FEAST (www.Feast.org, 2009-2011) is a large (3,600) pragmatic trial evaluating fluid resuscitation strategies in sick children in Uganda, Tansania and Kenya, predominantly due to malaria and sepsis. CTU plays a key role in design, analysis and mentoring. A new trial evaluating transfusion, antibiotic and prophylaxis strategies in sick anaemic children coming into hospital is in the planning stages (TRACT trial).

Publications

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Collaborative Initiative For Paediatric HIV Education And Research (CIPHER) Global Cohort Collaboration (2019) Incidence of switching to second-line antiretroviral therapy and associated factors in children with HIV: an international cohort collaboration. in The lancet. HIV

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Collaborative Initiative For Paediatric HIV Education And Research (CIPHER) Global Cohort Collaboration (2018) The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis. in PLoS medicine

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Collins IJ (2017) Clinical Status of Adolescents with Perinatal HIV at Transfer to Adult Care in the UK/Ireland. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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European Pregnancy And Paediatric HIV Cohort Collaboration (EPPICC) And Early-Treated Perinatally HIV-Infected Individuals: Improving Children's Actual Life With Novel Immunotherapeutic Strategies (EPIICAL) Study Groups (2019) Predictors of faster virological suppression in early treated infants with perinatal HIV from Europe and Thailand. in AIDS (London, England)

 
Guideline Title GUIDELINE ON WHEN TO START ANTIRETROVIRAL THERAPY AND ON PRE-EXPOSURE PROPHYLAXIS FOR HIV
Description ARROW influence on WHO Guidelines on When to Start ART (2015)
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact The new WHO guidelines cite the ARROW results, saying "Expanding ART services for children will require strategies to improve retention in care and to support adherence. Careful clinical monitoring remains essential to assess the risk of treatment failure, but lack of laboratory monitoring should not be a barrier to initiating ART." ARROW showed that children on ART had excellent outcomes with clinical monitoring, and that routine laboratory monitoring was not cost-effective in most circumstances. It is important that this is acknowledged in the WHO guidelines, as there is a move towards requiring routine viral load monitoring, which could act as a barrier to access for children in rural areas in low-income countries.
URL http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf?ua=1
 
Guideline Title Guidelines for tPanel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. 2016. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdfhe Use of Antiretroviral Agents in Pediatric HIV Infection
Description HYPNet mortality audit citation in US paed guidelines
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
 
Guideline Title WHO Guideline on Paediatric emergency triage, assessment and treatment: Care of critically ill children
Description Influence on WHO Guideline on Paediatric emergency triage, assessment and treatment: Care of critically ill children
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact The new WHO guidelines recommend that rapid fluid resuscitation is not used for children with 1 or 2 signs of shock, following the results of the FEAST trial. However, they still recommend (more conservative) fluid resuscitation for children with all three signs of shock. FEAST found that rapid fluid resuscitation was associated with excess mortality for children with any definition of shock. The new guidelines are progress, but do not completely accord with the FEAST recommendations.
URL http://apps.who.int/iris/bitstream/10665/204463/1/9789241510219_eng.pdf?ua=1
 
Description CHAPAS 3: Expanding the Availability of Fixed Dose Combination Antiretroviral Formulations for First-line Treatment of HIV-infected Children - the Children with HIV in Africa Pharmacokinetics and Acceptability/Adherence of Simple Antiretroviral Regimens
Amount € 4,617,034 (EUR)
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country European Union (EU)
Start 01/2010 
End 01/2014
 
Description CIPHER Cohort Collaborative Projects ($ 142964; 2014 - 2015)
Amount $46,842 (USD)
Organisation International AIDS Society (IAS) 
Sector Learned Society
Country Switzerland
Start 01/2016 
End 12/2018
 
Description CIPHER Cohort Collaborative Projects II (2017) (C3P2 2017)
Amount £287,000 (GBP)
Organisation International AIDS Society (IAS) 
Sector Learned Society
Country Switzerland
Start 01/2018 
End 12/2018
 
Description MRC Engagement in Science Activities Seed Fund
Amount £3,850 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2018 
End 12/2018
 
Description UCL Global Engagement Funds
Amount £1,788 (GBP)
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 07/2018
 
Description ViiV Healthcare
Amount £7,500,000 (GBP)
Organisation Viiv Healthcare 
Sector Private
Country United Kingdom
Start 01/2016 
End 12/2020
 
Description Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) 
Organisation Harvard University
Department Harvard T.H. Chan School of Public Health
Country United States 
Sector Academic/University 
PI Contribution The Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) of the International AIDS Society (IAS) is aimed at optimizing clinical management and delivery of services to infants, children and adolescents affected by HIV in resource-limited settings through advocacy and research promotion. We have led the oversight and analysis of two key international individual patient data meta-analyses, on duration of first line, and epidemiology of adolescents. We participate in the Steering Committee for the collaboration, review grant applications submitted to the collaboration, and provide high level advice in terms of meeting planning. Participation in CIPHER has also led to us being guest editor for a special issue of the Journal of the International AIDS Society on adolescent transition.
Collaborator Contribution Our partners have provided similar contributions.
Impact Our team presented data from this collaboration at the UNAIDS Paediatric Reference Group meeting on 9 and 10 November 2016. We also presented data at the "Estimating paediatric HIV and the need for ART meeting", World Health Organization, in 2015
Start Year 2014
 
Description Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) 
Organisation University of Cape Town
Country South Africa 
Sector Academic/University 
PI Contribution The Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) of the International AIDS Society (IAS) is aimed at optimizing clinical management and delivery of services to infants, children and adolescents affected by HIV in resource-limited settings through advocacy and research promotion. We have led the oversight and analysis of two key international individual patient data meta-analyses, on duration of first line, and epidemiology of adolescents. We participate in the Steering Committee for the collaboration, review grant applications submitted to the collaboration, and provide high level advice in terms of meeting planning. Participation in CIPHER has also led to us being guest editor for a special issue of the Journal of the International AIDS Society on adolescent transition.
Collaborator Contribution Our partners have provided similar contributions.
Impact Our team presented data from this collaboration at the UNAIDS Paediatric Reference Group meeting on 9 and 10 November 2016. We also presented data at the "Estimating paediatric HIV and the need for ART meeting", World Health Organization, in 2015
Start Year 2014
 
Description Gilead 
Organisation Gilead Sciences, Inc.
Department Gilead
Country United Kingdom 
Sector Private 
PI Contribution Design and conduct of trial protocol
Collaborator Contribution Review of protocol; provision of free drug
Impact Final protocol; fpfv planned Q2 2016; clinical, virology, immunology, pharmacokinetics
Start Year 2015
 
Description Joint Clinical Research Centre, Kampala, Uganda 
Organisation Joint Clinical Research Center, Kampala
Country Uganda 
Sector Academic/University 
PI Contribution Multicentre clinical trial collaboration on DART, ARROW, CHAPAS 3, PENTA 16 (BREATHER) and REALITY Trials and substudies Partner on the Lablite Project and on PENTA 17 (SMILE) and PENTA 20 (ODYSSEY) trials
Collaborator Contribution Clinical trials site and coordination of satelite sites. Laboratory substudies e.g HIV virology and immunology
Impact Trial results and substudies DART, ARROW, CHAPAS 2, CHAPAS 3, BREATHER and REALITY trials including virology, social science and economic substudies DART trial Fim Young lives project from ARROW trial Outputs from the Lablite Project
Start Year 2006
 
Description PENTA Foundation 
Organisation PENTA Foundation
Country France 
Sector Academic/University 
PI Contribution Scientific lead in writing project proposal. scientific leadership, coordination of trials and studies, coordinating role and speakers on PENTA training online and residential courses worldwide. Contribute to European PENTA guidelines.
Collaborator Contribution INSERM, France and PHPT, Thailand clinical trials units work collaboratively with MRC CTU at UCL on coordination of PENTA trials.
Impact completion and publication of PENTA 11, 15 and PENTA 18 trials; completion of main and extended follow-up PENTA 16 trial; finalisation of PENTA 17 protocol; activation and co-ordination of PENTA 20
Start Year 2006
 
Description PERUKI - the Paediatric Emergency Medicine research collaborative for the United Kingdom & Ireland 
Organisation Paediatric Emergency Research in the United Kingdom & Ireland (PERUKI)
Country United Kingdom 
Sector Public 
PI Contribution The CAP-IT trial has been developed in conjunction with the PERUKI network
Collaborator Contribution Development of trial protocol and operational requirements
Impact Feasibility study for the CAP-IT trial; ongoing collaboration in the CAP-IT trial involving clinicians, nurses and pharmacists
Start Year 2014
 
Title BREATHER - PENTA 16 
Description All young people enrolled in this clinical trial evaluating the role of Short Cycle Therapy (5 days on, 2 days off) in the management of HIV infection will be followed until July 2014. Young people continued to be followed on their randomised treatment, where appropriate, in a 2 year extended follow-up period until July 2016. Results were presented at CROI 2017 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2010
Development Status Closed
Clinical Trial? Yes
Impact Results were presented at CROI 2017. A further trial is planned to look at the possibility of a short course therapy in settings where viral loads are measured annually. 
URL http://pentatrials.org
 
Title CAP-IT - amoxicillin 
Description Efficacy, safety and impact on antimicrobial resistance of duration and dose of amoxicillin treatment for young children with Community Acquired Pneumonia (CAP): a randomIsed controlled Trial (CAP-IT). Funded by NIHR HTA. Recruitment started Q1 2017. Collaboration with PERUKI, SGUL, Universities of Bristol, Southampton, Oxford. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier HTA 13/88/11
Impact Feasibility study completed. Pilot study will include validation of saliva swabs against nasopharyngeal swabs for identification of S.pneumoniae and identification of changes in antibiotic resistance. 
 
Title SMILE - PENTA 17 
Description SMILE: Strategy for Maintenance of HIV suppression with once daily integrase inhibitor+darunavir / ritonavir in children (PENTA 17). A two-arm, Phase 2/3 multicentre, open-label, randomised study evaluating safety and antiviral effect of current standard antiretroviral therapy compared to once daily integrase inhibitor administered with darunavir/ritonavir (DRV/r) in HIV-1 infected, virologically suppressed paediatric participants. FPFV enrolled June 2016. Funding from EU, PENTA Foundation, Gilead, Janssen, INSERM, ViiV. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact n/a 
URL http://penta-id.org
 
Description AALPHI cognition 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Talks at European AIDS Treatment Group (EATG) conference on cognition and anxiety/ depression in young people with HIV
Year(s) Of Engagement Activity 2017
URL https://www.ageingwithhiv.com/
 
Description AIDS Impact plenary 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk (plenary) at AIDS Impact Conference, Cape Town 2017
Year(s) Of Engagement Activity 2017
 
Description CHIVA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Twice yearly contribution of lay text on the CHIPS study to the CHIVA Newsletter; yearly presentation of key findings from the CHIPS and AALPHI studies at the CHIVA national conference. Updating on results and ongoing PENTA trials

Improved reporting of patients to CHIPS, and general understanding of the CHIPS data and its importance. Recruitment of patients into PENTA trials
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Graphic novels on growing up with HIV (based on ARROW Young Lives research) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact We produced a series of 3 graphic novels to communicate the findings of the ARROW Young Lives social science sub-study. These novels explore what it is like to grow up with HIV in Uganda. The novels are available in English and Luganda.
The novels were distributed to study participants at a results meeting, and to clinic waiting rooms. They are also available online, and are being translated into different languages for use in other countries.
Year(s) Of Engagement Activity 2015
URL http://www.ctu.mrc.ac.uk/resources/multimedia/arrow_graphic_novels/
 
Description Media Publications 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Results reported from the REALITY trial in Paris for the IAS conference on HIV science where published by the British media.
Year(s) Of Engagement Activity 2017
URL https://www.theguardian.com/global-development/2017/jul/24/cocktail-of-drugs-could-prevent-10000-hiv...
 
Description Series of training videos for managing children on antiretroviral therapy 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact We have produced a set of interactive training videos to teach paediatric HIV care. The videos were filmed mostly in a district hospital in Malawi and follow the management of children with HIV over time. They are designed to force students to make the kinds of clinical decisions they will face in their work. Topics include early infant diagnosis, ART initiation, common opportunistic infections, drug reactions and assessing possible treatment failure.

The videos have frequent stop points with questions which can be used to generate discussion. They are accompanied by detailed notes for teachers and trainers which can easily be adapted to different settings and guidelines. At present the videos are being used in PENTA (Paediatric European Network for the Treatment of AIDS) courses which are held around the world.

The films are available to watch and download for free on our Vimeo Channel, where the notes and scripts can also be downloaded. They vary in length from 3 minutes to 16 in length. At present 12 videos are complete. There will be an additional 8 videos uploaded in coming months.
Year(s) Of Engagement Activity 2014,2015,2016
URL http://www.ctu.mrc.ac.uk/resources/multimedia/arrow_videos_and_teaching_scripts/