The randomized controlled PENTA 1 trial (1992-1999), coordinated by Penta, was set up to compare starting asymptomatic vertically infected HIV-positive children on Zidovudine monotherapy immediately or only after the onset of symptoms.
After follow up of up to 6.3 years (median 4.6 years), there was no evidence of a benefit to starting Zidovudine monotherapy early, in asymptomatic children.
The study also found after three months of age, these children often have slow disease progression in the absence of therapy. The trial was funded by the European Commission BIOMED 2 programme, the Medical Research Council, UK, Agence Nationale de Recherches sur le Sida, France, and Instituto Superiore di Sanita, Italy, with Glaxo-Wellcome providing study medicine and placebo.
Penta coordinated PENTA 3 was originally designed as a randomised trial to evaluate the toxicity and tolerability of Zidovudine/Zalcitabine in combination compared with Zidovudine alone as initial therapy in symptomatic HIV infected children.
Once a similar trial in adults showed a benefit in starting with combination therapy, all children on Zidovudine alone were switched to Zidovudine/Zalcitabine combination therapy and a further 37 children were enrolled into an open study of Zidovudine and Zalcitabine in combination. The drugs were well tolerated and no untoward toxicity was found.
In the Penta coordinated PENTA 4 trial, HIV-infected children on stable therapy with nucleoside reverse transcriptase inhibitors (NRTIs) were randomised to receive lamivudine syrup or tablets or matching placebo in addition. In this population of children with relatively advanced HIV disease, the addition of lamivudine to current NTRI therapy was safe and well-tolerated. There was evidence that changes in viral load were greater in children taking Zidovudine plus lamivudine compared with other NRTIs plus lamudivine.
Penta coordinated the randomized phase II PENTA 5 trial (1997-2000) comparing the toxicity, tolerability and activity of three different 2-drug Nucleoside Reverse Transcriptase Inhibitor (NRTI) combinations in symptom-free HIV-positive children who had not previously been treated in combination with Nelfinavir or a placebo, at the same time assessing the tolerability and toxicity of Nelfinavir or placebo with these three 2-drug NRTI combinations.
Children with symptoms at the time of enrollment received open label Nelfinavir. Regimens containing abacavir were found to be more effective than zidovudine/lamivudine and could be combined safely with protease inhibitors and non-nucleoside reverse transcriptase inhibitors.
Many sub-studies were conducted assessing thymic outbput after therapy initiation, the impact on virus subtypes on virologic response and drug resistance, adherence to prescribed therapy and development of phenotypic and genotypic drug resistance. The trial was supported by the Medical Research Council, UK.
PENTA 7 was an open study coordinated by Penta to evaluate the toxicity, tolerability and efficacy of a combination of stavudine, didanosine and nelfinavir in vertically-infected HIV-postive infants less than 3 months old. While therapy was well tolerated and associated with good clinical and immunological outcomes after 72 weeks of follow-up, a high rate of virological failure with emergence of genotypic resistance was of great concern and more palatable drug combinations for infants and closer drug monitoring are required.
Penta coordinated the randomized controlled PENTA 8 trial to evaluate the usefulness of resistance testing in the clinical management of children with HIV infection. Children were randomised to have resistance testing or not at baseline and over at least 96 weeks of follow-up. The study found a substantial difference in prescribing of nucleoside reverse transcriptase inhibitors (NRTIs) between the arms, but no long-term virological or immunological benefit to resistance testing was found. At best, resistance testing without expert interpretation was concluded to provide marginal gains in virological outcomes, with better strategies and interpretation methods for these tests necessary.
PENPACT 1 (2002-2006) was an open label randomized phase II/III factorial trial run in collaboration between Penta and PATCG/IMPAACT (Padiatric AIDS Clinical Trials Group/International Maternal Pediatric Adolescent AIDS Clinical Trials Group) that studied which first line antiretroviral treatment (ART) children should start with, and when children should switch to second line ART.
Previously untreated HIV-infected children in Europe and North and South America were randomized to receive two nucleoside reverse transcriptase inhibitors (NRTIs) with either a protease inhibitor or a non-NRTI as first line ART, and to switch to second line ART at either 1000 copies/mL viral load or 30,000 copies/mL viral load.
Good long-term treatment outcomes were seen for both first line therapies, and later switching among children taking protease inhibitors may be reasonable. The study was funded by PENTA, Agence Nationale de Recherche sur le Sida et les hepatites virales, France, and PACTG/IMPAACT.
PENTA 9 Trial summary (pdf).
PENTA 11 was an open, multicentre randomised phase II trial coordinated by Penta to determine whether HIV-positive children are disadvantaged clinically, immunologically or virologically by CD4-driven planned treatment interruptions.
This pilot study enrolled chronically infected children aged 2 – 15 years of age with suppressed HIV viral load and CD4% ≥30% (ages 2-6) or CD4% ≥25% and CD4 ≥500 cells/mm3 (ages 7 and over). After two years of follow-up post-trial, no adverse clinical, immunological or virological consequences of planned treatment interuptions were observed. The study was supported by Penta, Great Ormond Street Children’s Charity, and the European Union’s 7th Framework Programme.
Penta coordinated the PENTA 13 open label crossover study to compare the plasma pharmacokinetics of twice daily versus once daily lamivudine and abacavir among HIV-infected children aged 2-13. Once daily AOC0-24 and Cmax were not inferior to twice daily, and no marked difference in antiviral activity was noted.
Data from PENTA 13, PENTA 15 and the MRC/DFID ARROW trial are being included in a submission to the Federal Drug Administration and European Medicines Agency for licensing of once daily dosing of lamivudine and abacavir.
The Penta-coordinated PENTA 14 open randomised parallel group trial of differing levels of Therapeutic Drug Monitoring (TDM) compared with no TDM in children with HIV infection starting or switching to a new antiretroviral regimen was unfortunately stopped due to poor recruitment.
A prospective cohort of children receiving TDM is being planned as this may be an important strategy for improving virological suppression and adherence while reducing toxicity.
The PENTA 15 trial, coordinated by Penta, assessed the pharmacokinetics, feasibility and acceptability of abacavir or abacavir plus lamivudine once daily in children with HIV infection aged 3 months to <36 months. Results provide support for the option of once daily regimens of abacavir and lamivudine for children. The study was supported by PENTA and GlaxoSmithKline.
Data from PENTA 13, PENTA 15 and the MRC/DFID ARROW trial are being included in a submission to the FDA and EMA for licensing of once daily dosing of lamivudine and abacavir.
PENTA 15 Trial summary (pdf).
The Penta coordinated KONCERT (PENTA 18) study evaluated whether once daily dosing of Kaletra (Aluvia) is non-inferior to twice daily dosing in terms of virological suppression.
The study also assessed the pharmacokinetics of paediatric Kaletra tablets dosed by body weight. Eligible children received Kaletra tablets as part of antiretroviral therapy and were virologically suppressed for at least 6 months prior to entry.
Recruitment was completed in 2012 and all participants were followed for at least 48 weeks. Results indicated that Federal Drug Administration weight band-based dosing recommendations provide adequate exposure to Kaletra when using paediatric tablets.
PENTA 18 Trial summary (pdf).
EuroCoord, Enhancing clinical and epidemiological HIV research in Europe through cohort collaboration (2011-2016), was a Network of Excellence established by several of the biggest HIV cohorts and collaborations within Europe – CASCADE, COHERE, EuroSIDA, and PENTA and funded by the European Commission’s 7th Framework Programme. The EPPICC cohort collaboration began as part of EuroCoord.
The REALITY (Reduction of EArly mortality in HIV-infected adults and children starting antiretroviral therapy) study is a randomized controlled trial run by the Medical Research Council Clinical Trials Unit in several sub-Saharan African countries.
The study investigates the effectiveness of 1) increasing potency of antiviral therapy, 2) augmented prophylaxis against opportunistic infections and 3) macronutrient intervention for reducing early mortality among children, adolescents and adults over a 12 week period.
This study is funded by Penta.
Go to REALITY publications
The overall aim of the BREATHER trial was to evaluate the role of Short-Cycle Therapy (SCT) in the management of HIV-infected young people who responded well to antiretroviral therapy (ART) and to determine whether young people with chronic HIV infection undergoing Short-Cycle Therapy of five days on ART and two days off maintain the same level of viral load suppression as those on continuous therapy, over 48 weeks.
Approximately 100 patients were enrolled in each study arm, followed initially for 48 weeks. Additional long term follow up was be conducted subsequently for two years.
View Project Publications here.
This Project was funded by Penta.