Publications

18

Apr, 2002

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

 

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.

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18

Apr, 2002

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

 

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.

18

Feb, 2002

Difficulties in achieving suppression of viral replication in vertically HIV-1 infected infants early treated with d4T+ddI+NFV : The PENTA 7 Study.

 

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.

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18

Feb, 2002

TREC Response to Antiretroviral Therapy in HIV-infected Children in the PENTA 5 Trial

 

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.

18

Feb, 2002

The Impact of HIV-1 Subtypes on Virological Response and Emergence of Resistance in the PENTA 5 Trial

 

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

18

Apr, 2001

Pharmacokinetics (PK) of Nelfinavir (NFV) and its Active Metabolite (M8) in Very Young Infants Infected with Human Immunodeficiency Virus (HIV)

 

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.

18

Apr, 2001

Evolution of drug resistance in antiretroviral therapy-naïve children in PENTA 5

 

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

18

Apr, 2001

T cell repopulation in HIV infected children on highly active anti-retroviral therapy (HAART)

 

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.

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18

Feb, 2001

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

 

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

18

Jul, 2000

Nelfinavir doses should be increased in infants less than 3 months

 

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.