Support for UK clinical centres enrolling in PENTA trials

Lead Research Organisation: Medical Research Council
Department Name: UNLISTED

Abstract

Combinations of anti-HIV drugs (antiretroviral therapy or ART) can slow the growth of the HIV virus in the body, and now children with HIV can often live into adulthood. However, there are problems with taking these drugs long-term; in terms of both side effects and being able to take them regularly as required. We need to understand how best to use the ART drugs we have, by looking at whether it is possible to stop taking them at certain times, as well as ensuring that we are giving children the correct doses. However we also need to explore new ways of treating those children who do not respond as well to these drugs - for example, by encouraging the body to fight HIV itself, rather than using drugs to kill the virus.

Randomised clinical trials where neither the family nor the doctor choose the treatment are the best way of evaluating treatment strategies. The current proposal is for 3 clinical trials in children:

i. Some ongoing trials are exploring whether it is safe for adults to stop therapy for a while if they have very low amount of virus in the blood (HIV viral load) and good CD4 counts (which indicate how well the body can fight infections). It is important to assess this strategy in children as well, because their immune system is still developing and may be better at repairing itself. Otherwise they will have to take drugs for life from a young age.
ii. In adults an experimental medicine called IL-2, given as an injection, can increase the CD4 count. However, IL-2 may work much better in children, again because their immune system is still developing and responds better to help. We also need to understand whether children can tolerate the injections and side effects.
iii. One reason for medicines working less well in children than in adults is that it is difficult to get the doses right at different ages, weights and heights, and with individual children?s metabolisms. Directly measuring the level of drug in the blood and then altering the dose to get the best blood levels might be better at lowering the HIV viral load and might also reduce side effects.

Results from all these trials will be promoted at national and international conferences, the PENTA website (www.pentatrials.org), treatment guidelines, and newsletters to ensure that families and doctors have access to them.

Technical Summary

PENTA is a European collaboration, conducting clinical trials addressing questions relevant to the care and treatment of HIV-infected children, where results cannot be extrapolated from trials in adults. Trials are funded from several sources, mainly the EU and governmental bodies with some support from the pharmaceutical industry. The MRC Clinical Trials Unit, with INSERM SC10 in Paris, co-ordinates the trials on behalf of PENTA. Core MRC support for PENTA consists of 0.5 Band 5 data manager, and the pivotal involvement of CTU scientists in the Steering Committee as well as the operational and statistical aspects of the trials.

This Research Grant would support UK enrolment into 3 new PENTA trials in children with chronic HIV infection.

PENTA 11 is a randomised open parallel group trial to evaluate the safety of planned treatment interruptions, as a strategy for reducing life-time exposure to therapy whilst avoiding increased risk of disease progression. 100 children who have responded well to therapy will be randomised to continue their current treatment or interrupt treatment until their CD4% falls below a threshold, and followed for 72 weeks. An estimated 25-30 children will be enrolled in the UK.

PENTA 10, a collaboration with the USA PACTG, is a randomised open-label parallel group trial to evaluate the safety and efficacy of adding subcutaneous Interleukin-2 (IL-2) to effective antiretroviral therapy, as an immune-based strategy for improving host control of HIV. 40 children who have not responded well immunologically to therapy will be randomised to immediate cycles of IL-2 or IL-2 deferred for 48 weeks, and followed for 96 weeks. This trial will include intensive immunological and virological assessments. An estimated 4-6 children will be enrolled in the UK.

PENTA 14 is a randomised open parallel group trial to evaluate the use of therapeutic drug monitoring (TDM), as a strategy to improve virological suppression and adherence and reduce toxicity, by avoiding under- and over-dosing. 166 children starting a new antiretroviral regimen will be randomised to full TDM (a 5-point pharmacokinetic curve), single sample TDM or no TDM, and followed for 96 weeks. It is estimated that 20-40 children will be enrolled in the UK.

Funding is requested to support the research activity in clinical sites in the UK: ie doctor and nurse time in completing CRFs; blood sampling, separation, storage and transport; hospital admissions and laboratory work not contributing to individual patient management (non-reclaimable from NHS service support).

Publications

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Cressey TR (2008) Plasma drug concentrations and virologic evaluations after stopping treatment with nonnucleoside reverse-transcriptase inhibitors in HIV type 1-infected children. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Cross Continents Collaboration For Kids (3Cs4kids) Analysis And Writing Committee (2008) Markers for predicting mortality in untreated HIV-infected children in resource-limited settings: a meta-analysis. in AIDS (London, England)

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Donegan K (2013) Lopinavir dosing in HIV-infected children in the United Kingdom and Ireland. in The Pediatric infectious disease journal

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Paediatric European Network For Treatment Of AIDS (2010) Response to planned treatment interruptions in HIV infection varies across childhood. in AIDS (London, England)

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Paediatric European Network For Treatment Of AIDS (PENTA) (2010) Pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3-<36 months. in Antiviral therapy

 
Description PENTA Guidelines for the use of antiretroviral therapy
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact PENTA guidelines for the use of antiretroviral therapy are regularly updated (latest version 2009) and are used in developed countries worldwide.
 
Description Tr@inforPed HIV Training Course
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Tr@inforPed HIV has been a highly successful training course run by experts from the PENTA network since 2005. The course is designed for all healthcare professionals caring for children living with HIV, including training doctors, nurses, counsellors and psychologists. In 2008 the course became part of the Oxford Paediatric Infectious Diseases Diploma.
 
Title PENTA trials database 
Description Data collected for the ongoing trials 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2008 
Provided To Others? Yes  
Impact Data used in meta-analyses and in modelling 
 
Description EuroCoord 
Organisation European Commission
Country European Union (EU) 
Sector Public 
PI Contribution scientific lead in writing project proposal; major partner. running paediatric PENTA trials and coordinating EPPICC (European Pregnancy and Paediatric HIV Cohort Collaboration).
Collaborator Contribution scientific coordinator 2011-2012 (Work Package 3). data harmonisation
Impact The PENPACT-1 (PENTA 9 / PACTG 390) Study Team. First-line antiretroviral therapy initiation with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor combination and switch at higher versus low viral load in HIV-infected children: an open randomised controlled phase 2/3 trial. Lancet Infectious Diseases. April: 2011, 273-283.
Start Year 2011
 
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 Radboud University Nijmegen Medical Centre, the Netherlands 
Organisation Radboud University Nijmegen Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution The research team at the MRC co-ordinates the ARROW, CHAPAS-1,2,3 and PENTA trials and provides scientific input and analysis of EDCTP funded VITA 1 and 2 trials.
Collaborator Contribution Long standing nesting of key pharmacokinetic studies within larger trial programmes. Contributed to several PhD studentships (all Dutch), PK data resulted in licensing of new appropriate antiretroviral formulations for children in resource limited settings.
Impact Radbound University has been involved in the analysis and writing up of the pharmacokinetics data from ARROW, PENTA 18 and the CHAPAS trials which has resulted in presentations at international conferences, peer review publications, FDA and EMA approval of drugs and Clinton Foundation and UNITAID dissemination in Africa.
Start Year 2007
 
Description University of Zambia 
Organisation University of Zambia
Country Zambia 
Sector Academic/University 
PI Contribution Contribution to CHAP, CHAPAS 1 & 3 trials
Collaborator Contribution enrolled patients into CHAP, CHAPAS 1 & 3 trials Project lead of EDCTP project Contribution to all aspects of reserach including outputs and implementation (CHAP Trial of cotimroxazole prophylaxis)
Impact Trial results and substudies and implementation and impact of CHAP & CHAPAS 1 and 3 trials, including economic analyses CHAPAS 3 trial just completed and papers ongoing
Start Year 2006
 
Description University of Zimbabwe 
Organisation University of Zimbabwe
Country Zimbabwe 
Sector Academic/University 
PI Contribution DART, ARROW, REALITY Trials funding and coordination by MRC CTU LAblite Project on enabling rollout of antiretroviral therapy.
Collaborator Contribution Clinical sites for DART, ARROW, REALITY, PENTA 20(ODYSSEY) Trials Staff are partners in all aspects of reserach from design through to enrolling patients and writing results papers
Impact DART and ARROW trials and substudy outcomes and implementation impact; ARROW young lives study and economic substudies REALITY trial ongoing LAblite Project outputs
Start Year 2006
 
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 PENPACT 1 - PENTA 9 
Description A randomised study of combination antiretroviral regimens and treatment-switching strategies in antiretroviral naive children > 30 days and < 18 years of age 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Development Status Closed
Clinical Trial? Yes
UKCRN/ISCTN Identifier ISRCTN73318385
Impact WHO guidelines have been updated to include use of an NNRTI in children > 3 years of age and in children less than 3 years as an alternative to Kaletra based on trial data which supports continuing treatment with an NNRTI as there is little difference in the resistance acquired on Pi or NNRTI. 
URL http://www.pentatrials.org
 
Title PENTA 11 - TICCH 
Description 5 year follow-up is continuing of children enrolled in PENTA 11 - a randomised study to evaluate CD4 driven planned treatment interruptions in children with HIV infection. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Development Status Under active development_distribution
Clinical Trial? Yes
Impact PENTA 11 and the CHER trial have provided randomised data for the possibility of planned treatment interruptions in HIV treatment. 
URL http://pentatrials.org
 
Title PENTA 15 
Description Data from PENTA 13 and PENTA 15 are being submitted to the FDA and EMA to support once daily dosing of abacavir and lamivudine in children with HIV infection. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Market authorisation
Development Status Closed
Clinical Trial? Yes
UKCRN/ISCTN Identifier ISRCTN38147516
Impact Data from PENTA 15 (and PENTA 13) are being submitted to regulatory bodies to support a marketing authorisation of once daily dosing. 
URL http://www.pentatrials.org
 
Title PENTA 18 - Once daily Kaletra 100/25ml 
Description Currently being analysed Kaletra 100/25ml paediatric tablets once daily in the KONCERT (PENTA 18) in process of submission to FDA 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2009
Development Status Closed
Clinical Trial? Yes
UKCRN/ISCTN Identifier ISRCTN02452400
Impact If lopinavir is shown to be non-inferior when taken once daily rather than twice daily in terms of virological suppression, we expect this will become the standard of care for this drug. 
URL http://www.pentatrials.org
 
Description Talk to HIV infected young people 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact 40 young people with HIV infection attended a session on involvement in clinical trials

This led to further discussion with the CHIVA youth group about consumer involvement in trials
Year(s) Of Engagement Activity 2009,2010
 
Description Website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact PENTA trials website is regularly updated with information about the PENTA trials and activities

Queries are received from healthcare workers and from students about trials and HIV in general
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010