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PENTA 1
PENTA 3
PENTA 4
PENTA 5
PENTA 7
PERA (PENTA 8)
PenPact 1 (PENTA 9)
PENTA 11
PENTA 13
PENTA 14
PENTA 15
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Currently Recruiting
PENTA 15: This study will assess the pharmacokinetics, feasibility and acceptability of dosing ABC or ABC in combination with 3TC once daily in children aged 3 months to <36 months. It is a cross-over, open-label pharmacokinetic multi-centre study.
Eligible children are those who have been taking ABC
bid with or without 3TC bid for at least 12 weeks as part of an antiretroviral
regimen and:
Stable or rising CD4% and
HIV-1 RNA viral load < 20,000 copies/ml (if the viral load has not
been <400 copies/ml on the last two measurements, it must be decreasing).
Children should be expected to still be gaining benefit from the current
regimen.
PENTA 15 Trial summary
PENTA
15 Full protocol
In Follow Up
PENPACT 1: 266 children have been enrolled in this randomised trial with a factorial design (2x2) to compare
- starting therapy with a 2 NRTIs and a Protease Inhibitor OR 2 NRTIs and a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)
- changing to a new regimen when HIV viral load reaches 1 000 or 30 000 copies/ml
PENPACT 1 is a collaboration between the PENTA network
and the Pediatric AIDS Clinical Trials Group (PACTG) in the USA. The primary
endpoint will be HIV viral load at 4 years after randomisation. The substudy
will look prospectively at the development of lipodystrophy and metabolic
abnormalities in children enrolled in PENTA studies.
PENPACT 1 Trial summary
PENPACT
1 Full protocol
PENTA 11: a randomised
Phase II trial to determine whether children are disadvantaged clinically,
immunologically or virologically by Planned Treatment Interruptions.
This pilot study is for 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).
A PK substudy will look at the best way of stopping NNRTIs. Initial results
were presented at the 2006 XVI World AIDS conference in Toronto .(.pdf
file)
PENTA 11 Trial summary
PENTA
11 Full protocol
PENTA 7: 20 children have been enrolled in an open study to evaluate the toxicity, tolerability and antiviral activity of early d4T+ddI+Nelfinavir (NFV) therapy in HIV infected infants less than 3 months of age. Following the results of PK studies performed on the first infants enrolled, the dose of NFV for very young infants was increased to 150mg/kg/day. 1 child died of non-HIV causes at week 60. 72 week results were published in AIDS.
Data at 3 years has shown:
- Only 5 out of 19 children had an HIV viral load of less than 50 copies/ml
- The triple combination was well tolerated by all infants and associated with good clinical and immunological outcomes however it may not be potent enough to suppress viral load.
Resistance and adherence studies are also underway to better understand
the virological failures.
All PENTA 7 publications
Previous Trials
PENTA 1: between
1992 and 1995 192 children were enrolled in a randomised trial to evaluate
the benefit of starting ZDV while still asymptomatic or mildly symptomatic.
Summary from main paper
PENTA 3 was originally designed as a randomised trial to evaluate the toxicity and tolerability of ZDV+ddC compared with ZDV as initial therapy in symptomatic HIV infected children. 33 children were randomised, however after the release of results from the Delta trial in adults showing a benefit in starting with combination therapy, all children on ZDV monotherapy switched to ZDV+ddC. A further 37 children were enrolled into an open study with all children receiving ZDV+ddC. The drugs were well tolerated and no untoward toxicity was found.
PENTA 4: 162 HIV-1 infected children on stable therapy with ZDV, ZDV+ddI or ddC or ddI alone were randomised to receive lamivudine (3TC) 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 treatment changes in HIV-1 RNA viral load were greater in children taking regimens which included ZDV.
A resistance substudy showed that development of mutation at codon 184 appeared to be slower than seen in similar adult trials suggesting a lower virus turnover, despite the generally high loads seen at baseline (mean 4.9log10 copies/ml).
PENTA 5: 128 children were enrolled in a randomised trial to evaluate the antiviral effect of combinations of NRTIs (3TC+Abacavir, 3TC+ZDV, Abacavir+ZDV) and the tolerability of adding NFV.
3 year follow-up data were presented at CROI 2003. Data showed that improved efficacy (in terms of HIV-1 RNA suppression and growth changes) and lower rates of switching with detectable HIV-1 RNA in the 3TC+ABC group were sustained from 48 to 160 weeks. Clinical evidence of lipodystrophy was reported in only 2 (2%) children. There were a number of PENTA 5 substudies:
-
Resistance testing was performed on baseline samples of previously untreated children enrolled in the PENTA 5 trial. Children who did not achieve viral load suppression or had viral load rebound had subsequent resistance tests. Results were analysed by HIV subtype: 59% of the children in PENTA 5 were non-B subtype. Failure rates for resistance testing may be higher with non-B subtype viruses, but the presence of PI polymorphisms at baseline had no effect on response to ART. (pdf.file)
-
Baseline phenotypic and genotypic resistance tests were performed on 113 children. A further 79 children had resistance tests in samples after baseline if they were classified as non-responders or rebounders. Tests showed:
- Development of resistance to any trial drug was greatest in the ZDV+3TC arm
- Although the most sustained response was seen in the 3TC+ABC arm, phenotypic resistance and mutations to 3TC and ABC were more likely to evolve if the rebound/non-response occurred with 3TC+ABC than with ZDV+ABC
- one third of children did not have genotypic or phenotypic resistance
at RNA rebound
(Reference)
-
Work on TRECs showed that although baseline TREC levels correlate positively with baseline CD4% and inversely with age, the increase in TREC following ART initiation correlate inversely with baseline CD4%, positively with changes in CD4% thoughout ART but are independent of the age of the child. This suggests that thymically derived cells play a significant role in peripheral CD4 cell repopulation throughout childhood and this occurs more actively in those with lower CD4 before initiation of ART. (.pdf file)
-
A pharmacokinetic substudy of 32 children taking NFV showed that a nelfinavir trough concentration above 0.8 mg/L was correlated to viral suppression (.pdf file)
-
At given protocol visits carers were asked to complete a questionnaire about the child's adherence to trial medication. An initial analysis of the data showed:
- The most difficult drug to take was Nelfinavir.
- The difficult of taking NFV seemed to decrease over time (possibly because children changed from NFV powder to tablets).
- There was a trend of poorer adherence in:
- ZDV+3TC arm as compared with the other 2 arms
- Part A (asymptomatic children) compared with Part B (symptomatic children)
- Children who missed one or more doses in the previous 7
days were 2.5 times less likely to achieve undetectable viral
load at 24 weeks
(Reference)
Lancet paper with week 48 results
Further PENTA 5 publications
PERA (PENTA 8): a randomised trial to evaluate the usefulness of resistance testing in the clinical management of children with HIV infection. Children randomised in the resistance testing arm have access to repeat resistance testing in the case of subsequent failure. 171 children were enrolled and followed to 96 weeks.
Results of this first paediatric trial of resistance testing were published in Antiviral Therapy.
In summary:
- A substantial effect on NRTI prescribing patterns was observed.
- However there was no clear evidence of a virological or immunological benefit.
- Resistance testing without expert interpretation is likely to provide at most marginal gains in virological outcomes.
- Better ways to interpret resistance tests and strategise their use
are needed.
PENTA 13 : 24 HIV infected children aged 2-13 were enrolled in a one arm, open label cross-over study to compare the plasma pharmacokinetics of twice daily versus once daily 3TC and Abacavir. The AUC0-24 and Cmax of abacavir given 16mg/kg po q24h and of lamivudine given 8 mg/kg po q24h were not inferior to q12h dosing. Virological data did not indicate a marked difference in antiviral activity between q12h and q24h regimens. Results were published in Antiviral therapy. (.pdf file)
PENTA 14:
This was a randomised 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. Unfortunately
the trial was stopped due to poor recruitment. A prospective cohort of
children receiving TDM is being planned as it is still important to get
better data on drug levels in the paediatric population. 
PENTA 14 Trial summary
PS For the curious: PENTA 2, 6 and 10 never got off the drawing board!
