2007
Published in: American Academy of Pediatrics, 2007; 119: 838-845
2007
Authors: Green H and Gibb DM.
Published in: Curr Opin HIV AIDS 2007; 2:62-68.
2007
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
2007
Authors: Gibb DM, Green H, Saidi Y, et al; on behalf of PENTA 5.
Published in: AIDS.2007;21(8):947-955
Objective To describe the long-term efficacy over 5 years of regimens including combinations of abacavir, lamivudine and/or zidovudine in previously untreated children in the PENTA 5 trial.
Design PENTA 5 was a 48-week randomised controlled trial comparing three dual nucleoside reverse transcriptase inhibitor (NRTI) combinations as part of first triple antiretroviral therapy (ART).
Methods 128 ART-naïve children were randomised to zidovudine\lamivudine (n = 36), zidovudine\abacavir (45) or lamivudine\abacavir (47). Asymptomatic children (n = 55) were also randomised to nelfinavir or placebo; all other children received open-label nelfinavir. Analyses are intent-to-treat and adjusted for minor baseline imbalances and receipt of nelfinavir/placebo.
Results Median follow-up was 5.8 years. By 5 years, 17 (47%), 28 (64%) and 18 (39%) children had changed their randomised NRTIs in the zidovudine\lamivudine, zidovudine\abacavir and lamivudine\abacavir groups respectively, but 18%, 50% and 50% of these changes were either early single drug substitutions for toxicity or switches with viral suppression (HIV-1 RNA < 400 copies/ml; e.g. to simplify regimen delivery). At 5 years, 55%/32% zidovudine\lamivudine, 50%/25% zidovudine\abacavir and 79%/63% lamivudine\abacavir had HIV-1 RNA < 400/< 50 copies/ml respectively (p = 0.03/p = 0.003). Mean increase in height-for-age 0.42, 0.68, 1.05 (p = 0.02); weight-for-age 0.03, 0.13, 0.75 (p = 0.02). Reverse transcriptase resistance mutations emerging on therapy differed between the groups: zidovudine\lamivudine (M41L, D67N, K70R, M184V, L210W, T215Y); zidovudine\abacavir (M41L, D67N, K70R, L210W, T215F/Y, K219Q); lamivudine\abacavir (K65R, L74V, Y115F, M184V).
Conclusions Five year data demonstrate that lamivudine\abacavir is more effective in terms of HIV-1 RNA suppression and growth changes, with lower rates of switching with detectable HIV-1 RNA than zidovudine\lamivudine or zidovudine\abacavir, and should be preferred as first-line NRTI backbone.
2007
Authors: Dunn D, Woodburn P, Duong T, Phillips A, Gibb DM and Porter K on behalf of HPPMCS and CASCADE.
Published in: 14th Conference on Retroviruses and Opportunistic Infections, 25th-28th February 2007, Los Angeles. Poster 700
2006
Authors: Lallemant M, Burger D, Lyall H, Buck L, Compagnucci A, Ramos Amador J.T, Mellado Pena M, Fregonese F, Campbell S, Rampon O, Castelli-Gattinara G, Cressey, Khoo S, Tréluyer J.-M, Green H, Saidi Y, Nadal D, Giaquinto C, Gibb D.M on behalf of the PENTA 11 study group.
Published in: XVI International AIDS Conference, Toronto, 13-18 August 2006. Poster MOPE0206
2006
Authors: Babiker AG and Gibb DM.
Published in: Current Opinion in HIV and AIDS 2006; 1(6):488-494
2006
Authors: HIV Paediatric Prognostic Markers Collaborative Study.
Published in: AIDS 2006; 20:1289-1294
2006
Authors: LeProvost M, Green H, Flynn J, et al; on behalf of the PENTA 13 study group.
Published in: Pediatr Infect Dis J. 2006;25(6):533-7
Background Data on adherence to and acceptability of once daily lamivudine and abacavir are few.
Methods Twenty-four U.K. human immunodeficiency virus type-1 infected children 2-13 years of age participated in the Pediatric European Network for the Treatment of AIDS (PENTA) 13 single arm, open label pharmacokinetic study of twice (every 12 hours) versus once (every 24 hours) daily lamivudine and abacavir. Caregivers were asked to complete an adherence questionnaire at screening, week 0 (switch once daily to twice daily) and weeks 4, 12 and 24. Acceptability was also assessed at screening and week 24.
Results Fifteen children were taking lamivudine and abacavir as part of their regimens, 8 lamivudine only and 1 abacavir only. After switching to lamivudine/abacavir every 24 hours, 7 (29%) received once daily regimens for all drugs. Twenty-three (96%) caregivers thought that switching to once daily lamivudine/abacavir would make things a lot/a little easier for their child: 17 (71%) thought it was actually easier after switching. Six mothers with children taking a mixture of twice/once daily drugs changed their mind, whereas all mothers of children on once daily regimens agreed that it was a lot easier. Nonadherence (missing doses in the last 3 days) was reported for 8 of 118 (7%) completed questionnaires; missed doses were reported for every drug in the regimen with reasons such as “not at home,” “forgot” or “routine different from normal.” However, viral loads in all these children remained <100 copies/mL.
Conclusion Adherence to once daily abacavir/lamivudine was good with no evidence of an association between nonadherence and virologic rebound. Acceptability of once daily drugs was best when the whole regimen was dosed once daily.
2006
Authors: Aboulker J-P, Babiker A, Bacheler L, et al. On behalf of the PENTA 8 study group
Published in: Antivir Ther. 2006;11(7):857-867
Objective To evaluate the longer-term utility of genotypic resistance testing in HIV-1-infected children with virological failure.
Methods Children aged 3 months-18 years switching antiretroviral therapy (ART) with HIV-1 RNA > 2,000 copies/ml were randomized between genotypic testing (Virtual Phenotype) and no testing at baseline and subsequent virological failures. Children were followed to at least 96 weeks.
Results One hundred and seventy eligible children, from 24 clinical centres in six countries, were randomized to resistance testing(n = 87) or no testing (n = 83) between June 2000-July 2003. At baseline, mean HIV-1 RNA and CD4+ T-cell percentage were 4.7 log10 copies/ml and 20%, respectively. Children had taken ART for a mean of 5 years; 24% had received all three classes, 53% nucleoside reverse transcriptase inhibitors (NRTIs)+protease inhibitors (PIs), 9% NRTIs+non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 14% NRTIs only. There was no difference between the arms in the drug classes or the individual PIs/NNRTIs prescribed. However, 49% in the resistance test arm (RT) versus 19% in the no-test arm (NT) continued at least one NRTI from their failing regimen; 56% versus 19% were prescribed didanosine+stavudine as their NRTI backbone. Adjusting for baseline HIV-1 RNA, mean reductions in HIV-1 RNA at 48 weeks were 1.51 log10 copies/ml in the RT arm and 1.23 in the NT arm (P = 0.3); the difference between the arms was smaller at week 96 (RT: 1.50, NT: 1.47; P = 0.9).
Conclusion In this first paediatric trial of resistance testing, we observed a substantial difference in NRTI-prescribing behaviour across arms. However statistically significant evidence of a long-term virological or immunological benefit was not observed.
2005
Authors: Urschel S, Ramos J, Mellado M, Giaquinto C, Verweel G, Schuster T, Niehues T, Belohradsky B, Wintergerst U; the European PCP-withdrawal Study Group.
Published in: AIDS. 2005 Dec 2;19(18):2103-2108.
2005
Authors: Giaquinto C, Green H, De Rossi A, et al. On behalf of the PENTA 8 study group.
Published in: 3rd IAS Conference on HIV Pathogenesis and Treatment, 24-27 July 2005, Rio de Janerio. Oral and poster presentation WeOa0106
Abstract The development of resistance to antiretroviral drugs is considered to be an important cause of treatment failure in HIV infection. Many randomised trials and studies have been conducted to assess the clinical utility of resistance testing in adults, with mixed conclusions. However, current clinical guidelines recommend the routine use of resistance testing as part of patient management.
2005
Authors: LeProvost M, Green H, Flynn J, et al: on behalf of the PENTA 13 study group.
Published in: 3rd IAS Conference on HIV Pathogenesis and Treatment, 24-27 July 2005, Rio de Janerio. Poster MoPe9.2C03
2005
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
2005
Authors: HIV Paediatric Prognostic Markers Collaborative Study Group.
Published in: Lancet 2005; 366: 1868-74 .
2005
Authors: Bergshoeff A, Burger D, Verweij C, et al; on behalf of the PENTA 13 study group
Published in: Antivir Ther. 2005; 10:239-246
Background There are few data on plasma and intracellular pharmacokinetics (PK) of once-daily (q24h) nucleoside analogues in HIV-infected children.
Methods Children aged 2-13 years receiving combination treatment containing lamivudine (3TC) (4 mg/kg) and/or abacavir (ABC) (8 mg/kg) twice daily (q12h) were included in this single-arm, open-label, crossover study. Intensive plasma PK sampling was performed at steady state, after which children switched to q24h dosing and PK sampling was repeated 4 weeks later. Daily area under the curve (AUC0-24) and peak level (Cmax) of q24h and q12h regimens were compared by geometric mean ratios (GMRs) with 90% confidence intervals (CIs). Children were followed for 24 weeks to evaluate safety and virological response.
Results 24 children were enrolled, of whom 20 [median age (range) 5.6 (2.1-12.8) years] had evaluable PK data for 3TC (n=19) and/or ABC (n=14). GMRs of 3TC and ABC AUC0-24 and Cmax q24h versus q12h significantly exceeded 1.0. GMRs were not significantly different between children aged 2-6 versus 6-13 years old (P>0.08). Of note, 3TC Cmax values for both q12h and q24h were significantly lower in children aged 2-6 versus 6-13 years old. No child discontinued due to adverse events. At baseline, 16 out of 20 children had a viral load <100 copies/ml compared with 17 out of 19 at week 24.
Conclusions AUC0-24 and Cmax of both 3TC and ABC q24h were not inferior to q12h dosing in children. Insufficient results were obtained concerning intracellular levels of the active triphosphate moieties of both agents. Virological data did not indicate a marked difference in antiviral activity between q12h and q24h regimens.
2005
Authors: De Rossi A, Walker AS, De Forni D, Klein N, Dibb DM. Paediatric European Network for Treatment of AIDS (PENTA)
Published in: Antivir Ther. 2005;10(1):63-71
Objectives and Methods To investigate the relationship between cell-associated HIV-1 dynamics and recent thymic T-cell emigrants, HIV-1 DNA and T-cell receptor rearrangement excision circles (TREC, a marker of recent thymic emigrants) were measured in peripheral blood mononuclear cells in 181 samples from 33 HIV-1-infected children followed for 96 weeks after antiretroviral therapy(ART) initiation.
Results At baseline, HIV-1 DNA was higher in children with higher TREC (P=0.02) and was not related to age, CD4 or HIV-1 RNA in multivariate analyses (P>0.3). Overall, TREC increased and HIV-1 DNA decreased significantly after ART initiation, with faster HIV-1DNA declines in children with higher baseline TREC (P=0.009). The greatest decreases in HIV-1 DNA occurred in children with the smallest increases in TREC levels during ART (P=0.002). However, this inverse relationship between changes in HIV-1 DNA and TREC tended to vary according to the phase of HIV-1 RNA decline (P=0.13); for the same increase in TREC, HIV-1 DNA decline was much smaller during persistent or transient viraemia compared with stable HIV-1 RNA suppression.
Conclusions Overall, these findings indicate that TREC levels predict HIV-1 DNA response to ART and suggest that immune repopulation by thymic emigrants adversely affects HIV-1 DNA decline in the absence of persistent viral suppression, possibly by providing a cellular source for viral infection and replication.
2004
Authors: Gibb DM, Melvin A, Compagnucci A, McKinney R, Tudor-Williams G, Walker AS, Harper L, Hodge J, Powell C, Green H, Saïdi Y, Ortiz AA, Toye M, Girard S, Mofenson L, Giaquinto C, Hughes M on behalf of the PENPACT 1 Trial.
Published in: XV International AIDS Conference, 11-16 July 2004, Bangkok. Poster TuPeB4442.
2004
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.
2004
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
2004
Authors: Sharland M, Blanche S, Castelli G, Ramos J, Gibb DM for the PENTA Steering Committee.
Published in: HIV Med 2004; 5, (Suppl. 2), 61-86
2004
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.
2004
Authors: Burger DM, Bergshoeff A, de Groot R, et al; on behalf of the PENTA 5 study group.
Published in: J Paediatr 2004;145(3):403-405
Abstract Differences in virologic response were compared in 32 HIV-infected children with a nelfinavir trough concentration either below (n=7) or above (n=25) 0.8 mg/L. Virologic response at week 48 was observed in 29% of children with subtherapeutic nelfinavir troughs versus 80% in children with therapeutic nelfinavir troughs (P=.02)
2004
Authors: Lanier ER, Givens N, Stone C, et al.
Published in: HIV Med. 2004;5(6):394-399
Objectives Abacavir (ABC) selects for four mutations (K65R, L74V, Y115F and M184V) in HIV‐1 reverse transcriptase (RT), both in vitro and during monotherapy in vivo. The aim of this analysis was to compare the selection of these and other nucleoside reverse transcriptase inhibitor (NRTI)‐associated mutations by ABC‐containing therapies in the presence and absence of concurrent lamivudine (3TC) and/or zidovudine (ZDV) and to assess the effect of these mutations on phenotypic susceptibility to the NRTIs.
Design This study was a retrospective analysis of the patterns of NRTI‐associated mutations selected following virological failure in six multicentre trials conducted during the development of ABC.
Methods Virological failure was defined as confirmed vRNA above 400 HIV‐1 RNA copies/mL. RT genotype and phenotype were determined using standard methods.
Results K65R was selected infrequently by ABC‐containing regimens in the absence of ZDV (13 of 127 patients), while L74V/I was selected more frequently (51 of 127 patients). Selection of both K65R and L74V/I was significantly reduced by co‐administration of ZDV with ABC (one of 86 and two of 86 patients, respectively). Y115F was uncommon in the absence (seven of 127 patients) or presence (four of 86 patients) of ZDV. M184V was the most frequently selected mutation by ABC alone (24 of 70 patients) and by ABC plus 3TC (48 of 70 patients). Thymidine analogue mutations were associated with ZDV use. The K65R mutation conferred the broadest phenotypic cross‐resistance of the mutations studied.
Conclusions The resistance pathway selected upon virological failure of ABC‐containing regimens is significantly altered by concurrent ZDV use, but not by concurrent 3TC use. These data may have important implications for the efficacy of subsequent lines of NRTI therapies.
2004
Authors: Bergshoeff A, Burger D, Verweij C, Farrelly L, Flynn J, LeProvost M, Walker AS, Novelli V, Lyall H, Gibb DM.
Published in: 11th Conference of Retroviruses and Opportunistic Infections, San Francisco, 8-11 February 2004. Poster 934.
2003
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
2003
Authors: HIV Paediatric Prognostic Markers Collaborative Study Group.
Published in: Lancet 2003; 362:1605-11.
2003
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.
2003
Authors: Gibb DM, Giaquinto C, Walker AS, Harper L, Compagnucci A, Saidi Y, Moulinier C, Aboulker JP, Babiker AG, Debré M, Darbyshire JH on behalf of the PENTA 5 Executive Committee
Published: 10th Conference on Retroviruses and Opportunistic Infections February 10th – 14th, 2003 – Boston. Poster G1-12
2003
Authors: De Rossi A, Walker AS, De Forni D, Gibb DM on behalf of PENTA.
Published in: 10th Conference on Retroviruses and Opportunistic Infections February 10th – 14th, 2003 – Boston. Poster P-17
2003
Author: Gibb DM, Goodall RL, Giacomet V, McGee L, Compagnucci A, Lyall H. Paediatric European Network for Treatment of AIDS Steering Committee.
Published in: Pediatr Infect Dis J. 2003;22(1):56-62
2002
Authors: Ait-Khaled M, Lanier R, Richards N, Stone C, Griffin P, Gibb DM, Walker AS, Craig C, Loeliger E, Tisdale M
Published in: 2002 International Meeting of the Institute of Human Virology, September 9th-13th, 2002, Baltimore
2002
Authors: Giacomet V, Gibb DM, Goodall R, McGee L, Walker AS, Giaquinto C.
Published in: XIV World AIDS Conference, 7th-12th July 2002, Barcelona, Spain. Poster TuPpB2050
2002
Authors: Gibb DM, Walker AS, Giaquinto C, Harper L, Compagnucci A, Saidi Y, Aboulker JP, Babiker A, Debré M, Darbyshire JH on behalf of the PENTA 5 Steering Committee.
Published in: XIV World AIDS Conference, July 7th-12th 2002, Barcelona, Spain- Poster TuPpB2051
2002
Authors: Sharland M, Castelli Gattinara G, Tomas Ramos J, Blanche S, Gibb DM for the PENTA Steering Committee.
Published in: HIV Med 2002; 3:215-226
2002
Authors: De Rossi A, Walker AS, De Forni D, Gibb DM; Paediatric European Network for Treatment of AIDS (PENTA).
Published in: AIDS. 2002;16(14):1961-1963
2002
Authors: Pillay D, Walker AS, Gibb DM, De Rossi A, Kaye S, Ait-Khaled M, Muñoz-Fernandez M, Babiker A. for the PENTA Steering Committee.
Published in: J Infect Dis 2002; 186: 617-25
Abstract The association between virologic response and human immunodeficiency virus type 1 (HIV-1) subtype was investigated in 113 HIV-1-infected children randomly assigned to receive zidovudine plus lamivudine, zidovudine plus abacavir, or lamivudine plus abacavir in the Paediatric European Network for Treatment of AIDS (PENTA) 5 trial. Symptomatic children (n=68) also received nelfinavir; asymptomatic children (n=45) were randomly assigned to receive nelfinavir or placebo. HIV-1 subtypes A, B, C, D, F, G, H, A/E, and A/G were found in 15%, 41%, 16%, 9%, 5%, 2%, 1%, 5%, and 7% of the children, respectively. Resistance assay failure rates were higher for non-B subtypesthan for B subtypes (genotype, P=.01; phenotype, P=.02). HIV-1 subtype was not associated with virologic response at 24 and 48 weeks after initiation of treatment. No differences were observed in the frequency of development of resistance mutations L90M (P=1.00) and D30N (P=.61) in B and non-B viruses. In conclusion, no evidence that subtype determined virologic response to therapy was found.
2002
Authors: Gibb DM, Walker AS, Kaye S, et al.
Published in: Antivir Ther. 2002;7(4):293-303
Purpose and Methods To describe the evolution of resistance to zidovudine (ZDV), lamivudine (3TC), abacavir (ABC) and nelfinavir (NFV), 113 previously untreated children in the PENTA 5 trial had resistance assayed at baseline, rebound and/or 24, 48, 72 weeks (VIRCO: phenotyping and genotyping with ‘Virtual Phenotype’ interpretation).
Results At baseline, few reverse transcriptase mutations and no primary protease inhibitor mutations were observed. Time to detectable HIV-1 RNA with reduced phenotypic susceptibility to any drug was shortest in the ZDV+3TC arm (overall logrank P=0.02). Through a median follow-up of 55 weeks, at their last assessment 11 (28%), 16 (40%) and 13 (32%) children with detectable HIV-1RNA and a resistance test available had mutations conferring resistance to none, one, or two or more trial drugs, respectively, according to the virtual phenotype. Reduced phenotypic susceptibility to ABC only occurred in the 3TC+ABC arm and required K65R and/or L74V in addition to M184V. NFV-resistant virus was selected slowly through D30N or L90M pathways, and selection of ZDV-resistant virus was rare.
Conclusions Selection of 3TC-resistant virus was most frequent, followed by NFV and/or ABC; selection of ZDV-resistant virus was rare. Importantly, although in vitro, ABC selects for M184V as the first mutation, ABC did not select for M184V when combined with ZDV without 3TC. The most sustained HIV-1 RNA response was in the 3TC+ABC arm, but mutations conferring reduced susceptibility to 3TC and/or ABC evolved more frequently if virological failure occurred with 3TC+ABC than with ZDV+ABC.
2002
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.
2002
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.
2002
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.
2002
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.
2002
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
2001
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.
2001
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
2001
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.
2001
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
2000
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.
2000
Authors: Sharland M, Gibb DM, Giaquinto C.
Published in: European Journal of Pediatrics 2000; 159:649-656.
2000
Authors: Bernardi S, Thorne C, Newell ML, Giaquinto C,Tovo PA, Rossi P.
Published in: European Journal of Pediatrics 2000; 159(3):170-5