Penta HIV Trials | PENTA 7

Authors: Compagnucci A, Saïdi Y, Harper L, Blanche S, Gabiano C, de José Gomez I, Notheis G, Gibb DM, Giaquinto C and Faye A for the PENTA 7 committees

Published in: 14th Conference on Retroviruses and Opportunistic Infections, 25th-28th February 2007, Los Angeles. Poster 722 Abstract R -151 

Authors: Compagnucci A, Saïdi Y, Gibb DM, Rampon O, Ramos Amador JT, Feiterna Sperling C, Reliquet V, Giaquinto C, Navarro ML, Girard S, Harper L, Burger D, Treluyer JM, Aboulker JP, Jacqz-Aigrain E and Faye A on behalf of the PENTA 7 Study group.

Published in: 3rd IAS Conference on HIV Pathogenesis and Treatment, 24-27 July 2005, Rio de Janerio. Abstract MoPe9.2C15

Authors: Compagnucci A, Saïdi Y, Harper L, Navarro ML, Girard S, Walker AS, Debré M, Gibb DM, Rampon O, Lachassine E, Schmitz T, Giaquinto C, Aboulker JP, Fay

Published in: XV International AIDS Conference, 11-16 July 2004, Bangkok. Abstract B11956.

Authors: Aboulker JP, Babiker A, Chaix ML, et al; Paediatric European Network for Treatment of AIDS.

Published in: AIDS. 2004.23;18(2):237-45

Authors: Writing Committee (alphabetical): Aboulker J-P, Babiker A, Chaix ML, Compagnucci A, Darbyshire JH, Debré M, Faye A, Giaquinto C, Gibb DM, Harper L, Saidi Y, Walker AS

Published in: AIDS 2004;18 (2):237-245

Objective To assess the feasibility and impact of highly active antiretroviral therapy (HAART) started in vertically HIV-1-infected infants less than 3 months of age.

Design A multicentre, phase I/II, non-randomized, open-label study (PENTA 7).

Methods Adverse events, plasma HIV-1 RNA, CD4 cell counts, CD4 cell percentage (CD4%) and clinical progression were recorded at baseline and prospectively to 72 weeks in order to assess the toxicity, tolerability and efficacy of a combination of stavudine, didanosine and nelfinavir. Selection of genotypic resistance was also investigated.

Results Twenty infants, of whom only three had Centers for Disease Control and Prevention stage B, initiated HAART at median age 2.5 months (range, 0.9-4.7) with median HIV-1 RNA concentration 5.5 log10 copies/ml (range, 3.2-6.8) and CD4% 33% (range, 11-66). Median follow-up was 96 weeks (range, 60-144). At week 72, 11 infants were still taking the original treatment. Few adverse events were reported related to treatment, all minor and causing treatment interruption in only three infants. No AIDS-defining events occurred; one child died of non-HIV-related causes (prematurity). All but two had CD4% > 25% at 72 weeks; however, 14 infants had virological failure and six acquired resistance mutations.

Conclusions Early treatment with stavudine, didanosine and nelfinavir was well tolerated and associated with good clinical and immunological outcomes at week 72. However, a high rate of virological failure with emergence of genotypic resistance is of great concern. More palatable drug combinations for infants and closer drug monitoring are required.

Authors: Compagnucci A, Saidi Y, Faye A, et al.

Published in: 2nd IAS Conference on HIV Pathogenesis and Treatment, 13-16 July Paris. Poster 1095

Authors: Litalien C, Faye A, Compagnucci A, Giaquinto C, Harper L, Gibb DM, Jacqz-Aigrain E for PENTA.

Published in: Pediatr Inf Dis J 2003; 22(1):48-55

Background In children younger than 2 years of age vertically infected with HIV-1, the recommended pediatric dosing regimen for nelfinavir (20 to 30 mg/kg three times a day) provides insufficient drug exposure. This study was conducted to determine the steady state pharmacokinetics of nelfinavir and its active metabolite, M8, in this population.

Methods Fourteen infants (2.3 to 8.5 months) underwent 18 intensive pharmacokinetic studies of nelfinavir and M8 at steady state. Nelfinavir and M8 concentrations were measured by high performance liquid chromatography coupled with mass spectrometry, and individual pharmacokinetic values were determined.

Results A mean nelfinavir daily dose of 135.7 ± 18.8 mg/kg (twice or three times a day) resulted in median Cmin, Cmax, area under the plasma concentration-time curve (AUC0–24 h) and CL/ F for nelfinavir of 0.627 mg/l, 2.39 mg/l, 30.6 mg*h/l and 4.2 liters/h/kg, respectively. When normalized for a daily dose of nelfinavir of 150 mg/kg/day, 16.7% of Cmax and 27.8% of AUC0–24 h values were below the tenth percentile for adult values.

Conclusions During the first year of life, nelfinavir requirement is much higher than in older children and adults to obtain similar drug exposure. The mechanisms underlying such differences may involve higher first past metabolism and/or drug interactions or might be related to feeding conditions.

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: 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: 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.