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    PENTA 1
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    PENTA 5
    PENTA 7
    PERA (PENTA 8)
    PenPact 1 (PENTA 9)
    PENTA 11
    PENTA 13
    PENTA 14
    PENTA 15
    BREATHER (PENTA 16)
    KONCERT (PENTA 18)

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Forthcoming Trials

There are no trials currently recruiting, however 2 new PENTA trials have been granted ethical approval in the the UK and are currently being submitted for ethical and regulatory review internationally. Clinicians interested in enrolling children in either trial should contact a Trials Unit.

BREATHER (PENTA 16) aims to evaluate whether young people with chronic HIV infection undergoing Short Cycle Therapy (SCT) of five days on and two days off can maintain the same level of viral load suppression as those on continuous therapy.

There will be an initial pilot phase in selected centres in order to evaluate detailed viral load profiles.

Acceptability, quality of life and adherence to randomised strategy will be evaluated through the main trial and through the Qualitative Substudy co-ordinated by the London School of Hygiene and Tropical Medicine.

KONCERT (PENTA 18) will evaluate whether once daily dosing of Kaletra is non-inferior to twice daily in terms of virological suppression.

The study will also assesss the pharmacokinetics of paediatric Kaletra tablets dosed on body weight.

To be eligible to participate children should be taking Kaletra tablets as part of ART and have an undetectable viral load for at least 6 months prior to entry.

In Follow Up

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)

Results of a PK substudy after the first PTI have been published: "Plasma drug concentrations and virologic evaluations after stopping treatment with non-nucleoside reverse-transcriptase inhibitors in HIV-1 infected children. Clin Infect Dis. 2008 May 15;46(10):1601-8 (Reference)

Di Gibb presented the results of the randomised study at the Ninth International Congress on Drug Therapy in HIV Infection in Glasgow, UK:

Gibb DM, Compagnucci A, Green H, Lallemant M, Saidi Y, Ngo-Giang-Huong N, Taylor C, Mofenson L, Monpoux F, Tomé MIG, Marczyñska M, Nadal D, Wintergerst U, Kanjavanit S, Lyall H, Giaquinto C, Moye J. 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).

Children will continue to be followed to look at long-term effects of PTIs.

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

PENTA 7: 20 children were 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

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.
  

PERA publication

PENPACT 1: Was a randomised trial with a factorial design (2x2) which compared

• 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

The PENPACT 1 trial suggests children infected with HIV requiring treatment have a choice of antiretroviral combinations to start with, and the timing of switching to 2nd line treatment does not affect long-term viral load.

PENPACT 1 was a long-term trial run in collaboration between PENTA and PATCG/IMPAACT that studied which 1st line antiretroviral treatment (ART) children should start with, and when children should switch to 2nd line ART.

In total, 263 children were randomised, 131 to start with protease inhibitor (PI) based ART and 132 to start with non-nucleoside reverse transcriptase (NNRTI) based ART. Children were also randomised to either switch to 2nd line ART if their viral load increased to 1,000 copies/ml on 1st line treatment (134 children), or to wait until the viral load increased to 30,000 copies/ml before switching (129 children).

Overall, these children had excellent response to treatment over a median of 5 years, and nearly three-quarters were still on 1st line ART at the end of the study. Children in the 30,000 group switched to 2nd line ART about a year later than those in the 1,000 group, resulting in fewer treatment switches in the high viral switch group (23 vs 37 children).

The main result, measured at 4 years after starting treatment, was that there was no difference in viral response when comparing starting with PI or NNRTI based ART, OR when comparing switching at 1,000 or 30,000 copies/ml.

In addition, staying on 1st line treatment for an additional year did not result in any difference in PI or NNRTI resistance which was similar in the early and late switching groups. However, there was evidence that children on NNRTI based ART were more likely to develop resistance to the NRTI drugs (nucleoside reverse transcriptase inhibitors) if they were in the 30,000 compared to the 1,000 viral load switch group. This was not the case for PI based ART.

Children gained CD4 cells throughout the study and very few had disease progression (no difference between groups). There were also no differences in the number of children experiencing side-effects on PI or NNRTI drugs.

In summary, children in this trial taking ART for the first time had excellent results. If children have not been exposed to an NNRTI to reduce mother-to-child transmission of HIV infection, then either PI or NNRTI are equally good choices for 1st line treatment. Although routine viral load testing may help identify children at risk of developing NRTI resistance, it is unlikely to affect NNRTI resistance because this occurs as soon as viral load becomes detectable.

For HIV infected children worldwide, the PENPACT 1 trial sends a powerful message to start and continue those requiring treatment on ART.

The PENPACT 1 substudy will look prospectively at the development of lipodystrophy and metabolic abnormalities in children enrolled in PENTA studies.

Oral presentation of results at the XVIII International AIDS Conference in Vienna, July 2010
PENPACT 1 Trial summary
PENPACT 1 Full protocol

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)

The adherence and acceptability of once daily lamivudine and abacavir in PENTA 13 was published in PIDJ (Reference)

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

PENTA 15: This study assessed the pharmacokinetics, feasibility and acceptability of dosing ABC or ABC in combination with 3TC once daily in children with HIV infection aged 3 months to <36 months.

The Area under the curve (AUC0-24) for once daily dosing of both ABC and 3TC was bioequivalent to twice daily. As expected, Cmax was approximately two times higher, on once compared to twice daily therapy. There was no evidence of loss of efficacy or increased toxicity on once daily therapy.
PK data from PENTA 15 which demonstrated bioequivalence of once and twice daily dosing are
consistent with those from PENTA 13. However, the tendency for lower plasma concentrations
of 3TC observed in younger children in PENTA 13 was not seen in PENTA 15. These results
provide support for the option of once daily regimens of ABC and 3TC for children.

Follow-up to week 48 will be presented at IAS 2009.
PENTA 15 Trial summary
PENTA 15 presentation at CROI 2009

PS For the curious: PENTA 2, 6 and 10 never got off the drawing board!

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