Publications

Authors: De Rossi A, Walker AS, Klein N, De Forni D, King D, Gibb DM.

Published in: J Infect Dis 2002; 186:312-20

Abstract To investigate the thymic contribution to immune reconstitution during antiretroviral therapy (ART), T cell receptor gene rearrangement excision circles (TRECs) were measured in peripheral blood mononuclear cells (PBMC) and CD4 cells from 33 human immunodeficiencyvirus (HIV) type 1-infected children monitored for 96 weeks after ART initiation. Baseline TREC levels were associated positively with baseline CD4 cell percentage and inversely with age and HIV-1 RNA load. During therapy, TREC level changes in PBMC and CD4 cells were fairly comparable. TREC level changes were inversely related to baseline CD4 cell percentage and positively associated with CD4 cell percentage increases, the main source being naive CD4 cells. TREC changes were independent of age and baseline HIV-1 RNA load; however, HIV-1 suppression was independently associated with smaller TREC changes. Thymic output appears to be the main source of CD4 cell repopulation in children receiving ART. Recovery of thymic function is independent of age and influenced by the status of peripheral CD4 cell depletion and HIV-1 suppression.

Authors: Paediatric European Network for Treatment of AIDS (PENTA)

Published in: Lancet.2002;359(9308):733-740

Introduction Treatment options for children with HIV-1 are limited. We aimed to compare activity and safety of three dual-nucleoside analogue reverse-transcriptase inhibitor (NRTI) regimens with or without a protease inhibitor in previously untreated children with HIV-1.

Methods In our multicentre trial, we randomly assigned 36 children to zidovudine and lamivudine, 45 to zidovudine and abacavir, and 47 to lamivudine and abacavir. Children who were symptomfree (n=55) were also randomly assigned to receive nelfinavir or placebo. Children with more advanced disease received open-label nelfinavir (73). Primary endpoints were change in plasma HIV-1 RNA at 24 and 48 weeks for the NRTI comparison and occurrence of serious adverse events for both randomised comparisons. Analyses were by intention to treat.

Findings Children had a median CD4 percentage of 22% (IQR 15–29) and a mean HIV-1 RNA concentration of 5·0 log copies/mL (SD 0·8). One child was lost to follow-up and one died of sepsis. At 48 weeks, in the zidovudine/lamivudine, zidovudine/abacavir, and lamivudine/abacavir groups, mean HIV-1 RNA had decreased by 1·71, 2·19, and 2·63 log copies/mL, respectively (estimated in absence of nelfinavir) (p=0·02 after adjustment for baseline factors). One child had a hypersensitivity reaction to abacavir; and three with possible reactions stopped abacavir. There were 24 serious adverse events—six in the symptom-free children (all on nelfinavir), but none were attributed to nelfinavir.

Interpretation Regimens containing abacavir were more effective than zidovudine/lamivudine. Such regimens could be combined with protease inhibitors and non-nucleoside reverse transcriptase inhibitors for safe and effective treatment of previously untreated children with HIV-1.

Authors: Compagnucci A, Saidi Y, Chaix ML, et al.

Published in: 9th Conference on Retroviruses and Opportunistic Infections February 24-28, 2002 – Seattle. Poster 809 – W.

Authors: De Rossi A, Klein N, Walker AS, De Forni D, Babiker A, King D, Gibb DM for the PENTA Group.

Published in: 9th Conference on Retroviruses and Opportunistic Infections, February 24th-28th , 2002 – Seattle. Poster 807-W.

Authors: Pillay D, Gibb DM, Walker AS, De Rossi A, Kaye S, Ait-Khaled M, Muñoz-Fernandez M, Babiker A for the PENTA Group.

Published in: 9th Conference on Retroviruses and Opportunistic Infections, February 24th-28th, 2002 – Seattle. Poster 813-W

Authors: Litalien C, Faye A, Compagnucci A, Jacqz-Aigrain E.

Published in: Pediatric Academic Societies 2001 Annual Meeting, April 28th – May 1st 2001, Baltimore MD. Abstract 2609.

Authors: Loveday. C., Walker. A.S., Gibb. D.M., on behalf of the PENTA virology Group

Published in:  Fifth International Workshop on HIV Drug Resistance and Treatment Strategies, 2001, Scottsdale, USA. Abstract  109

Authors: King D J.S., Gotch F M., Larsson-Sciard E.

Published in: Clin Exp Immunol.2001;125(3):447-454

Abstract In this pilot study, we address the nature of the re-population of the T-cell compartment in HIV-1+ (Human Immunodeficiency Virus 1), vertically infected children placed on successful regimens of HAART (highly active anti-retroviral therapy) incorporating 2 NRTI and a protease inhibitor. The clonality of the T-cell compartment and the abundance of RTEs (Recent Thymic Emigrants) were determined 2 weeks before and 20 weeks after initiation of HAART in a subgroup of children taking part in the PENTA (Paediatric European Network for the Treatment of AIDS) 5 trial. Analysis of the clonality of the circulating T-cell compartment was assessed using CDR3 spectratyping and analysed using the Kolmogorov-Smirnov two sample test. This revealed that a high degree of T-cell clonal restriction still exists 5 months into therapy, despite the appearance of previously undetectable T-cell clones within the periphery. We detected no increase in RTE abundance in this 5 month period, as determined by PCR detection of TRECs (T-Cell Receptor Excision Circles). We conclude that the observed re-population of T cells within the periphery of treated children is heavily reliant upon the maintenance/expansion of pre-existing cells during the 5 month period immediately following the initiation of therapy.

Authors: Faye A , Compagnucci A., Saidi Y; for the PENTA 7 Executive Committee

Published in: 8th Conference on Retroviruses and Opportunistic Infections, February 4th-8th, 2001, Chicago. Poster 678

Authors: Litalien C. Giaquinto C. Faye A. Mechinaud F. Grosch I. Compagnucci A. Jacqz-Aigrain E.

Published in: XIII International AIDS Conference July 9th-14th 2000, Durban, South Africa. Abstract Mo PEB 2213

PENTA 7 is a phase I/II multi-centre trial to evaluate the efficacy, safety and pharmacokinetics of nelfinavir, used in combination with didanosine and stavudine in HIV-infected infants of less than three months of age.

Vertically infected infants with very high viral load appear to be more at risk for rapid disease progression and so early treatment is recommended. There has been limited paediatric pharmacokinetic research for nelfinavir, but recent data suggests that older children (age range 3 months to 13 years) need doses (mg/kg) 2 to 4 times higher than adult doses to achieve similar plasma concentrations.

In this study the initial dose of nelfinavir was 40mg/kg TID (120mg/kg), but three months after its initiation, this was increased to 75mg/kg BID (150mg/kg) after the original dose failed to achieve therapeutic levels. Also BID dosing was implemented in line with adult studies showing comparable efficacy and better adherence with this schedule in comparison with TID. In addition didanosine and stavudine were given BID at doses of 100 mg/m2 and 1mg/kg respectively.

From September 1999 to February 2000, 9 pharmacokinetic studies were performed at steady state at least 2 weeks after initiation of the therapy on patients (N=8) aged between 1.5 and 7.2 months.

Important inter-patient variability was observed for Cmin and no correlation was found between this PK parameter and either the dose or the patient’s age. Only 2 patients (aged 5.7 and 2.6 months) were considered to have the equivalent of the desired adult minimum therapeutic Cmin value (Cmin ->1000ng/ml). And among the 5 patients aged less than 4 months, only infants receiving a daily dose range of 130 to 150 mg/kg/d achieved the adult target value for AUC. Indicating that infants less than 3 or 4 months need higher doses compared to adults and older children to achieve therapeutic concentrations.

Authors: Sharland M, Gibb DM, Giaquinto C.

Published in: European Journal of Pediatrics 2000; 159:649-656.

Authors: Bernardi S, Thorne C, Newell ML, Giaquinto C,Tovo PA, Rossi P.

Published in: European Journal of Pediatrics 2000; 159(3):170-5

Authors: King D, Gibb DM, Gotch F, Larsson-Sciard E.

Published in: 7th Conference on Retroviruses and Opportunistic Infections, January 30th- February 2nd, 2000, Abstract 322., San Francisco. Abstract 322

Authors: Gibb DM, Newberry A, Klein N, de Rossi A, Grosch-Wörner I, Babiker A

Published in: Lancet.2000; 355: 1331-2

Abstract In 25 vertically HIV-infected children receiving highly-active antiretroviral therapy, a 3-log10 reduction in plasma HIV RNA load was maintained for 1 year and was associated with a doubling of the CD4-cell percentage. Most (75%) new CD4 cells carried the CD45RA marker of naive cells and there was only a small rise in memory cells (CD45RO). This pattern of immune restoration differs from adults, and may be due to the presence of a functioning thymus in children.

Authors: Gibb. D. M. for the PENTA 5 Executive and the PENTA Steering Committee.

Published in: 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)

Authors: Kaye S. on behalf of the PENTA Virology Committee.

Published in: 5th International Congress on Drug Therapy in HIV Infection, October 22nd-26th 2000, Glasgow. P_308.

Authors: Paediatric European Network for Treatment of AIDS (PENTA)

Published in: HIV Med. 1999;1(1):25-31

Objective The study aimed to explore the experience of parents/care-givers to their child’s participation in a European randomized trial of immediate (zidovudine) with deferred (placebo) antiretroviral treatment in asymptomatic children with vertically acquired HIV infection (PENTA 1 trial).

Design One hundred and thirty-three questionnaires were distributed to parents/care-givers (68% of children in the trial) through their paediatrician prior to unblinding the individual child’s therapy (zidovudine/placebo) and 84 (63% response rate) were returned.

Methods & Results Thirty-six (43%) parents described moderate (n = 30) or great (n = 6) interference with everyday life. This was more frequent among parents of children whose HIV disease progressed (P = 0.03, Fisher’s exact test) but was unrelated to ethnicity, country of origin, treatment allocated or adverse events. Invited comments suggested that concern about forgetting doses and the taste/volume of the trial medication contributed to interference with everyday life. Seventy-six (90%) parents considered information received during the trial adequate. The eight expressing dissatisfaction were recruited in the same country and five of them were among the eight (10%) who stated that they would not want to enroll their child in another trial.

Conclusions There is a need for adequate ongoing feedback about trial progress to participating families. With increasing use of complex antiretroviral regimens, innovative ways of helping families with adherence issues require development and evaluation

Authors:  Kaye S, Loveday C, Gibb DM., Newberry A.

Published in: 4th International Congress, November 8ht-12th 1998, Glasgow.  P_305

Authors: Aboulker JP, Babiker A, Carrière I, et al.

Published in: AIDS.1998;12(14):F151-F160

Objective To evaluate the toxicity, tolerability and effect on laboratory markers of adding lamivudine (3TC) to nucleoside analogue reverse transcriptase inhibitors (NRTI) in children with HIV-1 infection.

Methods HIV-1-infected children on stable NRTI therapy were randomized to receive 3TC syrup or tablets (4 mg/kg twice daily) or matching placebo in addition to existing therapy. Endpoints were serious adverse events, and changes in CD4 cell count and plasma HIV-1 RNA. Analyses were on an intention-to-treat basis.

Results A total of 162 (81 on 3TC, 81 on placebo) children [median age, 6.5 years; interquartile range (IQR), 4.1-10.1 years] were included. At randomization, 52 were receiving zidovudine (ZDV), 39 didanosine (ddl), 54 ZDV-ddl and 17 ZDV-zalcitabine (ddC); 32 (20%) had AIDS; median CD4 cell count was 328 x 10(6)/I (IQR, 127-696 x 10(6)/l), and median HIV-1 RNA was 4.9 log10 copies/ml (IQR, 4.3-5.4 log10 copies/ml). Median follow-up was 40 weeks (IQR, 29-49 weeks) and 76% of follow-up was on blinded therapy for both 3TC and placebo groups. There were 11 serious adverse events in the blinded phase [two clinical (both placebo) and nine laboratory (five 3TC, four placebo)], five (two 3TC, three placebo) resulting in stopping trial drug. At 24 weeks, the CD4 cell count was greater in the 3TC group by a median of 47 x 10(6)/l and HIV-1 RNA was lower by 0.30 log10 copies/ml (P = 0.03 and 0.002, respectively, versus the placebo group). The difference in reduction in HIV-1 RNA up to 24 weeks, as measured by area under the curve minus baseline, between 3TC and placebo groups was 0.38 log10 copies/ml (95% confidence interval, 0.12-0.65) greater in children taking ZDV-containing regimens at baseline, compared with those on ddl monotherapy (P = 0.005), after adjusting for other factors at baseline. Thirteen children developed new AIDS events (six on 3TC, four on placebo) of whom three died (all placebo).

Conclusions The addition of 3TC to current NRTI therapy in children was safe and well-tolerated. There was evidence that treatment changes in HIV-1 RNA viral load were greater in children taking regimens that included ZDV.

Authors: Paediatric European Network for Treatment of AIDS (PENTA)

Published in: AIDS. 1998;12(4):F1-8

Background Plasma HIV-1 RNA levels are high in vertically infected infants. Information in older children is limited, particularly in those who have not received antiretroviral therapy.

Objectives To describe the relationships between HIV-1 RNA, age and CD4 cell count in untreated vertically infected children.

Design HIV-1 RNA was measured in 70 children [median age, 3.5 years (range, 0.4-11.9 years); median CD4 cell count, 881 x 10(6)/l (interquartile range, 576-1347 x 10(6) cells/l)] enrolled in a randomized placebo-controlled trial comparing immediate with deferred zidovudine in asymptomatic or mildly symptomatic vertically infected children (PENTA-1 trial). Short-term variability was assessed by comparing HIV-1 RNA at -2 and 0 weeks (prior to randomization). The relationship between age and HIV-1 RNA, and CD4 cell countwas analysed using data from all children prior to randomization and sequential samples from 35 remaining on placebo for up to 105 weeks, by fitting mixed linear models.

Results The within-individual SD in viral load was 0.26 log10 copies/ml. The median plasma HIV-1 RNA at enrollment was 4.61 log10 (range, 2.3-6.56 log10 copies/ml), significantly higher in children aged < or = 2 years (median, 5.23 log10 copies/ml) than in those aged > 2 years (4.51 log10 copies/ml; P < 0.0001). Mean HIV-1 RNA fell by 0.38 log10 copies/ml per year up to 2 years of age, by 0.21 log10 copies/ml per year from 2 to 4 years of age, and by 0.03 log10 copies/ml per year from 4 to 6 years of age reaching a nadir of 4.25 log10 copies/ml at 6 years. Mean log10 CD4 cell count declined steadily with age and was not significantly correlated with HIV-1 RNA, although there was some evidence that the rate of log10 CD4 cell decline was negatively correlated with the initial rate of HIV-1 RNA decline. No mutations associated with resistance to zidovudine were observed.

Conclusions Age is a key factor in the interpretation of both viral load and CD4 cell count in vertically infected children.

Authors: Gibb DM, Carrière I, Giaquinto C, Martinez M for PENTA

Published in: VIth European Conference on Clinical Aspects and Treatment of HIV-Infection, 1997, October 1st-15th, Hamburg, Germany

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Published in: XIth International Conference on AIDS, Vancouver, Canada 7 – 12 July, 1996.

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Published in: 2nd International Congress on Drug Therapy in HIV Infection, Glasgow, UK 19-22 November, 1994.

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Published in: Xth International Conference on AIDS, Yokohama, Japan 7 – 12 August,. 1994.

Authors: Paediatric European Network for treatment of AIDS – a network for multicentre trials.

Published in: First European Paediatric Congress, Paris, France 9 – 12 March, 1994.