Penta HIV Trials | PENTA 5

Authors: Lewis J, Walker AS, Castro H, et al.

Published in: J Infect Dis. 2011;205(4):548-556

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.

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.

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)

Authors: Lanier ER, Givens N, Stone C, et al.

Published in: HIV Med. 2004;5(6):394-399

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.

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

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

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

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

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

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

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

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.

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.

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: 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: 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: 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.