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.
- HIV-1 viral load and CD4 cell count in untreated children with vertically acquired asymptomatic or mild disease. Paediatric European Network for Treatment of AIDS (PENTA). Aids. 1998;12(4):F1-8. Read abstract
- Parents’ attitudes to their HIV-infected children being enrolled into a placebo-controlled trial: the PENTA 1 trial. Paediatric European Network for Treatment of AIDS. HIV Med. 1999;1(1):25-31. Read article
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.
- A randomized double-blind trial of the addition of lamivudine or matching placebo to current nucleoside analogue reverse transcriptase inhibitor therapy in HIV-infected children: the PENTA-4 trial. AIDS.1998;12(14):F151-F160. Read abstract
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.
- Drug resistance in a trial of nucleoside analogue and protease inhibitor therapy in children (PENTA 5). 5th International Congress on Drug Therapy in HIV Infection, Glasgow 22-26 October 2000. Poster 308.
- A randomised trial evaluating three NRTI regimens with and without Nelfinavir in HIV-infected children: 48 week follow-up from the PENTA 5 trial. Oral presentation at 5th International Congress on Drug Therapy in HIV Infection, Glasgow 22-26 October 2000 also published in AIDS 2000, Vol 14, supp4 p.58 (abstractPL6.8)
- Immune repopulation after HAART in previously untreated HIV-1 infected children. Lancet.2000; 355: 1331-2. Read abstract
- Reconstitution of the T-cell Pool in Treated, HIV-infected Children.7th Conference on Retroviruses and Opportunistic Infections, San Francisco, January 30- February 2, 2000. Abstract 322.
- T cell repopulation in HIV infected children on highly active anti-retroviral therapy (HAART). Clin Exp Immunol.2001;125(3):447-454. Read article
- Evolution of drug resistance in antiretroviral therapy-naïve children in PENTA 5. Fifth International Workshop on HIV Drug Resistance and Treatment Strategies, 2001, Scottsdale, USA (abstract 109), Antiviral Therapy 2001, Vol 6 (supplement 1) : 82
- The Impact of HIV-1 Subtypes on Virological Response and Emergence of Resistance in the PENTA 5 Trial. Conference on Retroviruses and Opportunistic Infections February 24-28, 2002 – Seattle. Poster 813-
- TREC Response to Antiretroviral Therapy in HIV-infected Children in the PENTA 5 Trial. 9th Conference on Retroviruses and Opportunistic Infections February 24-28, 2002 – Seattle. Poster 807-W.
- Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial. Lancet. 2002;359(9308):733-740. Read abstract
- Increased thymic output after initiation of antiretroviral therapy in human immunodeficiency virus type 1-infected children in the Paediatric European Network for Treatment of AIDS (PENTA) 5 Trial. J Infect Dis. 2002;186(3):312-320. Read article
- Impact of human immunodeficiency virus type 1 subtypes on virologic response and emergence of drug resistance among children in the Paediatric European Network for Treatment of AIDS (PENTA) 5 trial. J Infect Dis 2002; 186: 617-25. Read article
- Evolution of antiretroviral phenotypic and genotypic drug resistance in antiretroviral-naive HIV-1-infected children treated with abacavir/lamivudine, zidovudine/lamivudine or abacavir/zidovudine, with or without nelfinavir (the PENTA 5 trial). Antivir Ther. 2002;7(4):293-303 Read article
- 96 week follow-up of the PENTA 5 trial; comparing ZDV+3TC, ZDV+ABC and 3TC+ABC with or without NFV in ART naive children. XIV World AIDS Conference, Barcelona, Spain, 7-12 July 2002. Poster TuPpB2051
- Biphasic decay of cell-associated HIV-1 DNA in HIV-1 infected children on antiretroviral therapy. AIDS. 2002;16(14):1961-1963
- Adherence to HAART in children: results from a questionnaire study of children in PENTA 5 trial. XIV World AIDS Conference, Barcelona, Spain, 7-12 July 2002. Poster TuPpB2050
- Zidovudine (ZDV) appears to prevent selection of K65R and L74V, mutations normally selected by Abacavir (ABC) mono- or combination therapies not containing ZDV. 2002 International Meeting of the Institute of Human Virology, September 9-13, 2002, Baltimore
- Adherence to prescribed antiretroviral therapy in human immunodeficiency virus-infected children in the PENTA 5 trial. Pediatr Infect Dis J. 2003;22(1):56-62. Read abstract
- Relationship between Cell-Associated HIV-1 DNA and Thymic Output in HIV-1 infected Children Initiating Antiretroviral Therapy in the PENTA 5 Trial. 10th Conference on Retroviruses and Opportunistic Infections February 10th – 14th, 2003 – Boston. Poster P-17. Read poster
- Three year follow-up of the PENTA 5 trial. 10th Conference on Retroviruses and Opportunistic Infections February 10th – 14th, 2003 – Boston. Poster G1-12. Read poster
- Effect of concurrent zidovudine use on the resistance pathway selected by abacavir-containing regimens. HIV Med. 2004;5(6):394-399. Read article
- Maintaining the nelfinavir trough concentration above 0.8 mg/L improves virologic response in HIV-1-infected children. J Pediatr. 2004;145(3):403-405. Read article
- Relationship between changes in thymic emigrants and cell-associated HIV-1 DNA in HIV-1 infected children initiating antiretroviral therapy. Antivir Ther. 2005;10(1):63-71. Read abstract
- 3TC+ABC maintains virological superiority over ZDV+3TC and ZDV+ABC beyond 5 years in children: the PENTA 5 trial. AIDS.2007;21(8):947-955. Read abstract
- Age and CD4 Count at Initiation of Antiretroviral Therapy in HIV-InfectedChildren: Effects on Long-term T-Cell Reconstitution. J Infect Dis. 2011;205(4):548-556. Read article
- Neurocognitive and Quality of Life Outcomes in Children after Planned Treatment Interruptions: the randomized PENTA 11 trial. Read poster
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.
- Nelfinavir doses should be increased in infants less than 3 months. XIII International AIDS Conference, Durban, South Africa, 9-14 July 2000. Abstract Mo PEB 2213
- Evaluation of Toxicity, Tolerability and Antiviral Activity of Early d4T+ddI+Nelfinavir (NFV) Therapy in HIV-1 Vertically Infected Infants : 24 Week Preliminary Results from the PENTA 7 Study. 8th Conference on Retroviruses and Opportunistic Infections, Chicago 4-8 February 2001 Poster 678.
- Pharmacokinetics (PK) of Nelfinavir (NFV) and its Active Metabolite (M8) in Very Young Infants Infected with Human Immunodeficiency Virus (HIV). Pediatric Academic Societies 2001 Annual Meeting, April 28 – May 1 2001, Baltimore MD. Abstract 2609.
- Difficulties in achieving suppression of viral replication in vertically HIV-1 infected infants early treated with d4T+ddI+NFV : The PENTA 7 Study. 9th Conference on Retroviruses and Opportunistic Infections February 24-28, 2002 – Seattle. Poster 809 – W. Read poster
- Pharmacokinetics of Nelfinavir and its Active Metabolite, hydroxy-tert-butylamide, in Infants Perinatally Infected with HIV-1. Pediatr Inf Dis J 2003; 22(1):48-55.
- Impact of NFV and its active metabolite M8 trough levels on virologic response from primary HIV-1 vertically infected children treated with d4T, ddI and NFV in the PENTA 7 study. 2nd IAS Conference on HIV Pathogenesis and Treatment, 13-16 July Paris. Poster 1095. Read poster
- 72-week follow-up of HAART started in infants aged less than 3 months: CD4, viral load and drug resistance outcomes in the PENTA 7 study. AIDS 2004;18 (2):237-245.
- Three year outcomes in children treated with HAART before 3 months of age in the PENTA 7 trial. XV International AIDS Conference, 11-16 July 2004, Bangkok. Abstract B11956. Read abstract
- Highly active antiretroviral therapy started in infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug resistance outcome. Aids. 2004;18(2):237-245. Read abstract
- Lower scores of Nelfinavir metabolite M8 were associated with virological failure vertically infected children in the PENTA 7study. 3rd IAS Conference on HIV Pathogenesis and Treatment, 24-27 July 2005, Rio de Janerio. Abstract MoPe9.2C15. Read abstract
- Does Early Treatment Provide Long Term Benefit in HIV-1 Infected Infants? Five Year Outcomes in Children Treated Before 3 Months of Age in the PENTA 7 Trial. 14th Conference on Retroviruses and Opportunistic Infections, 25th-28th February 2007, Los Angeles. Poster 722 Abstract R -151. Read poster
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.
- A randomised trial of resistance testing versus no resistance testing in children with virological failure: the PERA (PENTA 8) trial. 3rd IAS Conference on HIV Pathogenesis and Treatment, 24-27 July 2005, Rio de Janerio. Oral and poster presentation WeOa010. Read poster
- A randomised controlled trial of genotypic HIV drug resistance testing in HIV-1 infected children: the PERA (PENTA 8). Antivir Ther. 2006;11(7):857-867. Read abstract
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).
- Choice of first-line ART regimen in PENPACT 1: a randomized trial of combination antiretroviral regimens and treatment switching strategies in antiretroviral naive children >30 days and <18 years of age. XV International AIDS Conference, 11-16 July 2004, Bangkok. Poster TuPeB4442.
- PENTA and IMPAACT: A phase II/III randomised, open-label trial of combination antiretroviral regimens and treatment-switching strategies in HIV-1-infected antiretroviral naïve children. XVIII International AIDS Conference, 22nd July 2010, Vienna Austria. Read abstract
- 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. 2011;11(4):273-283. Read article
- HIV-1 resistance after randomized virologic switch at 1,000 or 30,000 c/ml in children. CROI 2014, 3-6 March 2014, Boston. Poster 898.
- Using CD4 Percentage and Age to Optimize Pediatric Antiretroviral Therapy Initiation. Pediatrics, 2014;134(4):e1104-16. Read article
- HIV-1 Drug Resistance and Second-line Treatment in Children Randomized to Switch at Low versus Higher RNA Thresholds. JAIDS 2015;70(1):42-53. Read article
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.
- Pharmacokinetic and virological evaluations after stopping NNRTIs in children: a substudy of the PENTA 11 (TICCH) trial. XVI International AIDS Conference, Toronto, 13-18 August 2006. Poster MOPE0206. Read poster
- Plasma drug concentrations and virologic evaluations after stopping non-nucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1 infected children. Clin Infect Dis 2008. 15;46(10):1601-8. Read article
- Treatment interruption in children with chronic HIV-infection: the results of the paediatric European network for treatment of AIDS (PENTA) 11 trial. Journal of the International AIDS Society 2008, 11(Suppl 1):O21 (10 November 2008.
- Adherence to ART and acceptability of planned treatment interruptions (PTI) in the PENTA 11 trial. 1st International Workshop on HIV Pediatrics, 17 – 18 July 2009, Cape Town, South Africa. (Poster P_90). 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town 19-22 July 2009. Read poster
- Response to Planned Treatment Interruptions in HIV-infection varies across Childhood. UNAIDS HIV This Week 78, 15 Feb 2010. Read
- Immunologic and viral dynamics among HIV-infected children after planned treatment interruption: a substudy of the Paediatric European Network for Treatment of AIDS (PENTA) 11 trial. 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, 16-19 February 2010. Read poster
- Long Term consequences of planned treatment interruptions in HIV infected children: Results from the TICCH (Treatment Interruption in Children with Chronic HIV-Infection)/PENTA 11 trial. 3rd HIV Paediatric Workshop Rome 15-16 July 2011. Read poster
- Neurocognitive and Quality of Life Outcomes in Children after Planned Treatment Interruptions: the randomized PENTA 11 trial. 19th Conference on Retroviruses and Opportunistic Infections, San Francisco, 5-8 March 2012. Read poster
- Adherence to antiretroviral therapy and acceptability of planned treatment interruptions in HIV-infected children. AIDS Behav. 2013;17(1):193-202. Read article
- The Immunological and Virological Consequences of Planned Treatment Interruptions in Children with HIV Infection. PLoS One. 2013;8(10):e76582. Read article
- Long-term consequences of planned treatment interruption in HIV-1-infected children. CROI 2015, Seattle, USA, Feb 23 -26 2015. Poster presentation abstract 919. Read poster
- Response to Planned Treatment Interruptions in HIV-infection varies across Childhood in the PENTA 11 Trial. AIDS. 2010;24(2):231-241. Read abstract
- Neurocognition and quality of life after reinitiating antiretroviral therapy in children randomized to planned treatment interruption. AIDS. 2016;30(7):1075-81. Read abstract
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.
- Pharmacokinetics (PK) of once daily versus twice daily Lamivudine and Abacavir in HIV-1 infected children: PENTA 13. 11th Conference of Retroviruses and Opportunistic Infections, San Francisco, 8-11 February 2004. Poster 934. Read poster
- Pharmacokinetics of once- versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13). Antivir Ther. 2005;10(2):239-246. Read article
- Adherence and acceptability of once daily lamivudine and abacavir in HIV-1 infected children. 3rd IAS Conference on HIV Pathogenesis and Treatment, 24-27 July 2005, Rio de Janerio. Poster MoPe9.2C03.
- Adherence and acceptability of once daily Lamivudine and abacavir in human immunodeficiency virus type-1 infected children. Pediatr Infect Dis J. 2006;25(6):533-537. Read abstract
- A Model-based approach to dose selection in early pediatric development. Clinical Pharmacology and Therapeutics, 2010, 87(3):294-302. Read abstract
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.
- PENTA 14 trial summary (pdf).
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).
- PENTA 15: Once-daily abacavir and lamivudine as part of combination antiretroviral therapy to 48 weeks in HIV-1 infected children aged 3 to 36 months. 1st International Workshop on HIV Pediatrics, 17 – 18 July 2009, Cape Town, South Africa. Read poster
- PENTA 15: plasma pharmacokinetic study of once versus twice daily abacavir and lamivudine as part of combination antiretroviral therapy in HIV-1 infected children aged 3 to <36 months. CROI 2009. February 8-11, 2009. Palais des Congres de Montreal, Canada , Poster S-154. Read poster
- Pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3-<36 months. Antivir Ther. 2010;15(3):297-305. Read article
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).
- Pharmacokinetics of 100/25 mg lopinavir/ritonavir tablets in children when dosed twice daily according to FDA weightbands. 6th Netherlands Conference on HIV Pathogenesis, Prevention and Treatment. November 27, 2012.
- Pharmacokinetics of 100/25 mg lopinavir/ritonavir tablets in children when dosed twice daily according to FDA weight bands. 4th International Workshop on HIV pediatrics 2012. July 20-21, 2012. L’Enfant Plaza Hotel, Washington DC, USA. 4th International Workshop on HIV pediatrics. July 20-21, 2012. L’Enfant Plaza Hotel, Washington DC, USA. Read poster
- Pharmacokinetics of paediatric lopinavir/ritonavir tablets in children when administered twice daily according to FDA weight bands. 31st Annual Meeting of the ESPID- May 28 – June 1, 2013, Milan: Poster discussion Abstract A-534-0018-00429.
- Pharmacokinetics of Pediatric Lopinavir/Ritonavir Tablets in Children When Administered Twice Daily According to FDA weight bands. Pediatr Infect Dis J. 2014;33(3):301-305. Read abstract
- Once vs. twice-daily lopinavir/ritonavir in HIV-1-infected children. AIDS 2015. 29(18):2447-2457. Read article
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.
- Poster KONCERT 4th workshop on HIV pediatrics (pdf).
- Poster KONCERT CROI 2014 (pdf).
- Poster KONCERT ESPID 2014 (pdf).
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.