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.
An initial pilot phase in selected centres took place in order to evaluate detailed viral load profiles. The IDMC reviewed the pilot study data and raised no safety concerns. Participants from Argentina, Belgium, Denmark, Germany, Ireland, Spain, Thailand, Uganda, UK, the Ukraine and the USA are taking part in this trial which is now fully recruited. All 199 participants will be followed until the end of May 2014.
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.
Eligible children are taking Kaletra tablets as part of ART and have an undetectable viral load for at least 6 months prior to entry. Recruitment is now complete and all participants will be followed until July 2013.
A Poster on the pharmacokinetics of the paediatric Kaletra tablets when
given twice daily was presented at the 4th International Workshop on
HIV Pediatrics 2012 in Washington DC : data on lopinavir pharmacokinetic
parameters were not significantly different between the FDA weight bands.
Mean AUC and trough concentrations were higher than historical pediatric
data of LPV/r solution and soft-gel capsules, and similar to adult data
reported for tablets. Weight band based dosing recommendations provide
adequate exposure when using the half strength tablets.
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:
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.PENTA 11 Full protocol
Oral presentation of results of randomised study
Poster: results of randomised study
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.
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).
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:
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:
Resistance and adherence studies are also underway to better understand
the virological failures.
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.
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.
The following are copies of letters to families who took part informing them of the trial results:
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)
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.
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.
PS For the curious: PENTA 2, 6 and 10 never got off the drawing board!
12 July, 2013