Keywords: Mycobacterium tuberculosis, NO stress, truncated hemoglobins, structure-function relationships, drug design
PENTA-LABNET(PL) is a coordination action aimed at improving the range of products and clinical use of antiretrovirals(ARVs) in HIV-infected children in resource-rich and resource-limited countries. This will be achieved through building capacity of laboratories to undertake co-ordinated studies on pharmacokinetics, pharmacodynamics and pharmacogenetics of new formulations and dosing and studies of viral and immune responses to novel regimens and strategies for using ARVs in children. PL forms a logical, necessary and cost-effective addition to the clinical-trial-focused research activities of the longstanding PENTA network, building on its existing operational infrastructures and expertise. To respond to emerging needs identified by EU as priority areas, the aim of PL is the development of a “drug centred” research platform, which will provide a complimentary range of activities focused on supporting the rational selection of optimal dosage and delivery forms of ARVs, and providing the lab basis for evaluating new ARVs strategies in children. The definition, organisation and management of integrated pharmacological and viro/immunological studies to better characterise the concentration-exposure-effect relationship will be a central activity of PL. In support of these studies, standardised data collection systems will be established enabling linkage of clinical and laboratory data. In addition a central biobank will be set up to provide rapid identification of samples to be used for research. The laboratory and paediatric expertise generated in PL will support rapid assessment of new and existing individual and combined ARVs. The WHO will be a key partner of PL to define research priorities in ARV drug development and (also through PENTA’s extensive international links) to rapidly disseminate results to a range of stakeholders (e.g. EMEA and industries) and support the rapid translation of research findings into guidelines and practice for children in all settings.
PENTA-LABNET represents a coordination action aimed at improving the range of products and clinical use of antiretroviral treatment (ART) regimens in HIV-infected children in resource-rich and resource-limited countries. This will be achieved through building capacity of laboratories to undertake co-ordinated studies on pharmacokinetics, pharmacodynamics and pharmacogenetics of new drug formulations and dosing regimens and undertaking studies of virological and immunological responses to novel strategies for using antiretroviral regimens in HIV – infected children.
PENTA-LABNET forms a logical, necessary and cost-effective addition to the clinical research activities of the longstanding PENTA/ECS network (see text box), building on its existing operational infrastructures (including systems for long term follow-up of children moving from PENTA trials to national cohorts, carefully documented specimen collections, etc) and world-class expertise of individuals. So far, PENTA activities have mainly been focused on co-ordinating clinical trials in children to identify strategies for optimal use of antiretroviral therapy and on training and dissemination activities to improve management of HIV-infected children.
Although some studies have been done to identify appropriate dosing and combinations of drugs, PENTA has not conducted detailed investigations of more complex aspects of therapy, such as the integrated roles of virologic, immunologic, genomic and pharmacokinetic factors in response to therapy in children.
To respond to emerging needs identified by EU and WHO as priority areas, the objective of PENTA-LABNET is the development of a “drug centred” research strategy, which will provide a complementary range of activities focused on supporting the rational selection of optimal dosage and delivery forms of ARV agents, and new ARV drug regimen strategies for paediatric populations. The coordinating activities of PENTA-LABNET will enable implementation of this strategy.
The Paediatric European Network for Treatment of AIDS (PENTA, www.pentatrials.org) was established in 1991 as a collaboration between paediatric HIV centres in Europe. The principal aim was to undertake clinical trials to address questions about antiretroviral therapy (ART) in HIV infected children where answers cannot be extrapolated from trials in adults. By Jan 2007, more than 80 clinical centres in 16 countries and nearly 1200 children have been enrolled in 11 major CTs Within the 6th FP, the coordination of the European Collaborative Study (ECS), one of the largest cohorts of children born to HIV positive mothers, has been integrated with PENTA, thus forming a single centralised European network for research on paediatric HIV. All PENTA activities are coordinated through PENTA Foundation.
The PENTA network will add a new set of coordinating activities to its research focus, specifically aimed towards the better use of existing ARV drugs and development of new ARV agents for HIV infected children. PENTA will establish a network of research laboratories (PENTA-LABNET) to carry out pharmacological, immunological and virological studies to evaluate ARV drug doses and combinations to be used in HIV infected children.
The PENTA network provides an additional ideal setting for a rapid dissemination of the information among centres caring for HIV infected children. To avoid overlapping and duplications, PENTA-LABNET activities will be directly integrated with the existing clinical research activities coordinated by the PENTA Foundation (through the 6th FP funded CA PENTA/ECS).
The mission of PENTA-LABNET network will be to serve as the platform for a number of coordinating activities to ensure that the studies undertaken are coordinated and together facilitate the development and early use of novel and improved paediatric ARV drugs for treating HIV infected children.
PENTA-LABNET proposes to set up and link a pan-European network of Pharmacology, Virology and Immunology laboratories working on paediatric ARV treatment that will use common standards in pharmacokinetic (PK), pharmacogenetic, virology and immunology to undertake priority research studies.
The following specific objectives are expected to be achieved within the duration of the project:
OBJECTIVE 1. To design, initiate and undertake coordinated priority pharmacological, virological and immunological studies to:
A. Evaluate existing and proposed drug dosing recommendations for paediatric HIV treatment, including for new drugs and investigation of the IQ (inhibitory quotient) concept in paediatrics.
B. Evaluate predictors of drug exposure and implications for viral suppression and immunological responses. This includes studies on markers linked to variability in PK (e.g., compliance patterns, pharmacogenetics, demographic factors, co-morbidities, malnutrition, etc).
C. Explore methodological approaches to better characterise the concentration-exposure-effect relationship, including biomarkers of response. This includes evaluation of drug distribution and development of resistance in hidden cellular and anatomical reservoirs, T cell dynamics and differences in first phase antiviral response between classes.
D. Define phenotypic implications of complex viral genetic patterns emerging during long term therapy, and correlate with adherence to therapy.
OBJECTIVE 2. To establish and maintain coordinated datasets to be linked with pharmacological, virological and immunological information.
OBJECTIVE 3. To design, implement and maintain a central plasma bio-bank.
OBJECTIVE 4. To establish, disseminate and exchange best practices in HIV paediatric treatment.
- To optimise the use of antiretrovirals in HIV infected children providing more and new information on pharmacokinetic and pharmacodynamic issues
- To improve the understanding of the mechanism of action of antiretroviral drugs
- To set up an effective PENTA plasma and cell bio-bank enabling to store samples from PENTA studies and to link clinical with biological data.
- The paediatric expertise generated in PENTA LABNET on the fields of clinical pharmacology, virology and immunology will be used to support the rapid assessment of promising new ARV treatment agents and products and to ensure the existing ARV agents are better used for treating children.
Registration of new antiretroviral drugs in children.
Fondazione Penta - for the Treatment and Care of Children with HIV - ONLUS
Via Giustiniani 3, Padova, 35128, Italy
|Official Address||Other Information|
Medical Research Council
Institut National de la Sante et de la Recherche Medicale 101 Rue de Tolbiac, Paris, 75654, France
|Radboud Universiteit Nijmegen
Stichting Katholieke Universiteit Geert Grooteplein-Noord 9, Nijmegen, 6525EZ, Netherlands
The University of Liverpool
|University College London Gower Street, London, WC1E 6BT, United Kingdom||Email: email@example.com|
Oscar Della Pasqua
Universiteit Leiden Rapenburg 70, Leiden, 2311EZ, Netherlands
Evelyne Jacqz- Aigrain
|Assistence Publique - Hopitaux de Paris 3 Avenue Victoria, Paris, 75004, France||Email: firstname.lastname@example.org|
Anita De Rossi
Universita Degli Studi di Padova Via VIII Febbraio 2, Padova, 35122, Italy
|Fondazione IRCCS Policlinico San Matteo Viale Golgi 19, Pavia, 27100, Italy||Email: regazzim@.smatteo.pv.it|
Institut de Recherche pour le Developpement 213, rue La Fayette, Paris, 75480, France
|The School of Pharmacy, University of London Brunswick Square 29-39, London, WC1N 1AX, United Kingdom||Email: email@example.com|
World Health Organization Via Appia 20, Geneve, 1211, Switzerland