Publications

Authors: The PENPACT-1 (PENTA 9 / PACTG 390) Study Team.

Published in: Lancet Infectious Diseases. April: 2011, 273-283

Background Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children.

Methods In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385.

Findings Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30,000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30,000 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups.

Interpretation Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low.

Authors: Mok JQ, Giaquinto C, De Rossi A, Grosch-Wörner I, Ades AE, Peckham CS.

Published in: The Lancet

Authors: Gibb DM, Darbyshire JH, Debré M, Giaquinto C, Aboulker JP, Martinez M, Tudor-Williams G.

Published in: The Lancet

Authors: HIV Paediatric Prognostic Markers Collaborative Study

Published in: AIDS 2010, 24, 1213–1217

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

Published in: Antivir Ther. 2010;15(3):297-305.

Background Once-daily dosing of abacavir and lamivudine has been approved for adults, but paediatric data are insufficient. We conducted a pharmacokinetic study of once-daily and twice-daily abacavir and lamivudine in children aged 3-<36 months.

Methods Children with stable HIV type-1 (HIV-1) RNA levels after 12 weeks treatment with twice-daily abacavir (8 mg/kg) with or without lamivudine (4 mg/kg) underwent plasma pharmacokinetic sampling. Children then switched to once-daily abacavir (16 mg/kg) with or without lamivudine (8 mg/kg), and sampling was repeated 4 weeks later. The area under the plasma concentration-time curve over 24 h (AUC(0-24)) and the maximum concentration (C(max)) were compared using geometric mean ratios (GMRs); 90% confidence intervals (CIs) within the range of 0.80-1.25 were considered bioequivalent.

Results A total of 18 children (4, 6 and 8 in the 3-<12, 12-<24 and 24-<36 month age ranges, respectively) provided pharmacokinetic data for abacavir (17 for lamivudine). The GMR of AUC(0-24), once-daily versus twice-daily, was 1.07 (90% CI 0.92-1.23) for abacavir and 0.91 (90% CI 0.79-1.06) for lamivudine. C(max) almost doubled on once-daily versus twice-daily dosing: abacavir and lamivudine GMRs were 2.04 (90% CI 1.73-2.42) and 1.78 (90% CI 1.52-2.09), respectively. At baseline, 12, 24 and 48 weeks, 89%, 94%, 100% and 89% of children had HIV-1 RNA<400 copies/ml, respectively.

Conclusions Bioequivalence was demonstrated on AUC(0-24) between twice-daily and once-daily abacavir; very similar AUC(0-24) values were seen for twice-daily and once-daily lamivudine. Given that viral load suppression rates were maintained, these data suggest that once-daily abacavir and lamivudine might be an option for children aged 3-<36 mont

Authors: Cella M, Gorter de Vries F, Burger D, Danhof M, Della Pasqua O.

Published in: Clinical Pharmacology and Therapeutics, 2010, 87(3):294-302.

Authors: Sefe D, Klein N, Mosconi I, Ricci E, Castro, H (nee Green), Jacobsen M, Bernardi S, Pillay D, Gibb DM, and De Rossi A, on behalf of the PENTA Steering Committee

Published in: 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, 16-19 February 2010, Poster

PENTA and IMPAACT: A phase II/III randomised, open-label trial of combination antiretroviral regimens and treatment-switching strategies in HIV-1-infected antiretroviral naïve children

Published in: XVIII International AIDS Conference, 22nd July 2010, Vienna Austria.

Authors: Lodwick R, Costagliola D, Reiss P, et al. Pursuing Later Treatment Options II (PLATO II) Project Team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE).

Published in: Archives of Internal Medicine. 2010; 170(5):410-419

Background: Life expectancy in people with HIV is now estimated to approach that in the general population in some successfully treated subgroups. However, to attain these life expectancies, viral suppression must be maintained for decades.

Methods: We studied the rate of triple class virologic failure (TCVF) in patients within the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) who started antiretroviral therapy (ART) with an NNRTI- or PI/r-containing regimen from 1998 onwards. We also focussed on TCVF in patients who started a PI/r-containing regimen after virologically failing a first-line NNRTI-containing regimen.

Results: Of 45937 patients followed for a median (IQR) 3.0 (1.5-5.0) years, 980 (2.1%) developed TCVF. By 5 and 9 years after starting ART, an estimated 3.4% (95% CI:3.1%-3.6%) and 8.6% (95% CI:7.5%-9.8%) of patients had developed TCVF. The incidence of TCVF rose during the first 3-4 years on ART, but plateaued thereafter. There was no significant difference in the risk of TCVF according to whether the initial regimen was NNRTI- or PI/r-based (p=0.11). By 5 years after starting a PI/r as second-line, 46% of patients had developed TCVF.

Conclusions: The rate of virologic failure of the three original drug classes is low, but not negligible, and does not appear to diminish over time from starting ART. If this trend continues, many patients are likely to need newer drugs to maintain viral suppression. The rate of TCVF from start of a PI/r after NNRTI failure provides a comparator for studies of response to secondline regimens in resource-limited settings.

Authors: Paediatric European Network for Treatment of AIDS.

Published in: AIDS. 2010;24(2):231-241.

Objective To evaluate clinical, immunological and virological consequences of CD4-guided antiretroviral therapy (ART) planned treatment interruptions (PTIs) compared with continuous therapy in children with chronic HIV infection in the Paediatric European Network for Treatment of AIDS 11 trial.

Design This was a multicentre, 72-week, open, randomized, phase II trial.Methods:One hundred and nine children with HIV-RNA below 50 copies/ml and CD4% of at least 30% (2–6 years) or at least 25% and CD4 cell count of at least 500 cells/μl (7–15 years) were randomized to continuous therapy (53) or PTI (56). In PTI, ART was restarted if confirmed CD4% was less than 20% or more than 48 weeks had been spent off ART. The primary outcome was Centers for Disease Control and Prevention (CDC) stage C event, death or CD4% less than 15% (and CD4 cell count less than 200 cells/μl for children aged 7–15 years).

Results At baseline, median (interquartile range) age was 9 (6–12) years, CD4% 37% (33–41), CD4 cell count 966 (793–1258) cells/μl, nadir CD4% before combination ART 18% (10–27), time on ART 6 (3–6) years and 26% were CDC stage C. After median (range) 130 (33–180) weeks of follow-up, 4 versus 48% of time was spent off ART in continuous therapy and PTI, respectively. No child died or had a new CDC stage C event; one (2%) continuous therapy versus four (7%) PTI children had a primary outcome based on CD4%/cell count (P = 0.2). Lower nadir CD4% predicted faster CD4% decline after stopping ART. Younger age and higher nadir CD4% predicted being off ART for at least 48 weeks and better CD4% recovery following PTI.

Conclusion In this first paediatric trial of PTI, there were no serious clinical outcomes. Younger children had better CD4% recovery after PTIs. Immunology substudies and long-term follow-up in Paediatric European Network for Treatment of AIDS 11 trial are ongoing. Further research into the role of treatment interruption in children is required, particularly, as guidelines now recommend early ART for all infected infants.

Authors: Jacqz-Aigrain, Farrelly L, Compagnucci A, Harrison L, Zhao W, Hamadache D, Welch S, Wintergerst U, Firtion G, Burger D

Published in: CROI 2009. February 8-11, 2009. Palais des Congres de Montreal, Canada , Poster S-154.

Authors: Zhao W, Farrelly L, Compagnucci A, Harrison L, Jacqz-Aigrain E, Hamadache D, Welch S, Wintergerst U, Burger D on behalf of the PENTA Trial Steering Committee .

Published in: 1st International Workshop on HIV Pediatrics, 17 – 18 July 2009, Cape Town, South Africa

Authors: Harrison L, Hamadache D, Bunupuradah T, Mazza A, Ramos Amador JT, Flynn J, Rampon O, Mellado Pena MJ, Floret D, Marczynska M, Puga A, Farrelly L, Riault Y, Lallemant M, Compagnucci A on behalf of the PENTA Trial Steering Committee.

Published in: 1st International Workshop on HIV Pediatrics, 17 – 18 July 2009, Cape Town, South Africa. (Poster P_90). 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town 19-22 July 2009

Authors: Goetghebuer T, Haelterman E, Le Chenadec J, et al. for the European infant collaboration group.

Published in: AIDS 2009;23:597-604

Objective: In the absence of treatment, rapid progression to AIDS occurs in approximately 20% of HIV-1-infected infants over the first year of life. The prognosis of these children has considerably improved with highly active antiretroviral therapy. As data from well resourced countries are lacking, the objective of this collaborative study was to evaluate the impact of early treatment in vertically infected infants.

Design: Children born to HIV-infected mothers between 1 September 1996 and 31 December 2004, who were diagnosed with HIV and free of AIDS before 3 months, were eligible. Demographics and pregnancy data, details of antiretroviral therapy, and clinical outcome were collected from 11 European countries.Methods:The risk of AIDS or death, by whether or not an infant started treatment before 3 months of age, was estimated by Kaplan–Meier survival analysis and Cox proportional hazards models.

Results: Among 210 children, 21 developed AIDS and three died. Baseline characteristics of the 124 infants treated before 3 months were similar to those of the 86 infants treated later. The risk of developing AIDS/death at 1 year was 1.6 and 11.7% in the two groups, respectively (P < 0.001). Deferring treatment was associated with increased risk of progression [crude hazard ratio 5.0; 95% confidence interval (CI) 2.0–12.6; P = 0.001] that persisted after adjusting for cohort in multivariate models (adjusted hazard ratio 3.0; 95% CI 1.2–7.9; P = 0.021).

Conclusion: In HIV-1 vertically infected infants, starting antiretroviral therapy before the age of 3 months is associated with a significant reduction in progression to AIDS and death.

Authors: Goetghebuer T, Haelterman E, Le Chenadec J, Dollfus C, Gibb D, Judd A, Green H, Galli L, Ramos JT, Giaquinto C, Warszawski J, Levy J; for the European Infant Collaboration group.

Published in:  AIDS 2009 Feb

Authors: Gibb DM, Compagnucci A, Green H, Lallemant M, et al.

Published in: Journal of the International AIDS Society 2008, 11(Suppl 1):O21 (10 November 2008)

Authors: Cressey TR, Green H, Khoo S, Treluyer J-M, Compagnucci A, Saidi Y, Lallement M, Gibb DM, Burger D.

Published in: Clin Infect Dis 2008. 15;46(10):1601-8 

Background The optimum strategy for stopping treatment with drugs that have different half-lives in a combination regimen to minimize the risk of selecting drug-resistant viruses remains unknown. We evaluated drug concentrations in plasma, human immunodeficiency virus (HIV) load, and development of drug resistance after a planned treatment interruption of a nonnucleoside reverse-transcriptase inhibitor (NNRTI)-containing regimen in HIV type 1-infected children.

Methods Children with viral loads <50 copies/mL and CD4 cell percentages > or =30% (for children aged 2-6 years) or CD4 cell percentages > or =25% and CD4 cell counts > or =500 cells/microL (for children aged 7-15 years) were randomized to either a planned treatment interruption or to continuous therapy. In the planned treatment interruption arm, either (1) treatment with nevirapine or efavirenz was stopped, and treatment with the remaining drugs was continued for 7-14 days, or (2) nevirapine or efavirenz were replaced by a protease inhibitor, and all drugs were stopped after 7-14 days. Sampling for determination of plasma drug concentrations, measurement of viral load, and drug resistance testing was scheduled at day 0, day 7 (drug concentrations only), day 14, and day 28 after interruption of treatment with an NNRTI.

Results Treatment with an NNRTI was interrupted for 35 children (20 were receiving nevirapine, and 15 were receiving efavirenz). Median time from NNRTI cessation to stopping all drugs was 9 days (range, 6-15 days) for nevirapine and 14 days (range, 6-18 days) for efavirenz. At 7 days, 1 (5%) of 19 and 4 (50%) of 8 children had detectable nevirapine and efavirenz concentrations, respectively; efavirenz remained detectable in 3 (25%) of 12 children at 14 days. At 14 days, viral load was > or =50 copies/mL in 6 of 16 children interrupting treatment with nevirapine (range, 52-7000 copies/mL) and in 2 of 12 children interrupting treatment with efavirenz (range, 120-1600 copies/mL). No new NNRTI mutations were observed.

Conclusions In children with virological suppression who experienced interruption of treatment with an NNRTI, staggered or replacement stopping strategies for a median of 9 days for nevirapine and 14 days for efavirenz were not associated with the selection of NNRTI resistance mutations.

Authors: Dunn DT, Woodburn P, Duong T, Phillips AN, Gibb D, Porter K on behalf of HIV Paediatric Prognostic Markers Collaborative Study (HPPMCS) and the CASCADE Collaboration.

Published in: J Infect Dis 2008, 197:398-404

Authors: Jacobsen MC, Thiebaut R, Fisher C, Sefe D, Clapson M, Klein NJ, Baxendale HE.

Published in: 5th Conference on Retroviruses and Opportunistic Infections, Boston, 2- 8 February 2008, Poster A-152 /453

Authors: Cross Continents Collaboration for Kids (3Cs4kids) Analysis and Writing Committee

Published in: AIDS. 2008 Jan 2;22(1):97-105.

Authors: Goetghebuer T for the European Infant Collaborative Study.

Published in: 4th Dominique Dormont International Conference, 13-15 December, 2007

Published in: American Academy of Pediatrics, 2007; 119: 838-845

Authors: Green H and Gibb DM.

Published in: Curr Opin HIV AIDS 2007; 2:62-68.

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: 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: 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

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

Authors: Babiker AG and Gibb DM.

Published in: Current Opinion in HIV and AIDS 2006; 1(6):488-494

Authors: HIV Paediatric Prognostic Markers Collaborative Study.

Published in: AIDS 2006; 20:1289-1294

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.

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

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.

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.

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

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: HIV Paediatric Prognostic Markers Collaborative Study Group.

Published in: Lancet 2005; 366: 1868-74 .

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.

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: 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.

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: 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

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: 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: 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.

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: HIV Paediatric Prognostic Markers Collaborative Study Group.

Published in: Lancet 2003; 362:1605-11.

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: 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