Publications

19

Apr, 2010

Discordance between CD4 cell count and CD4 cell percentage: implications for when to start antiretroviral therapy in HIV-1 infected children. concise Communication.

 

Authors: HIV Paediatric Prognostic Markers Collaborative Study

Published in: AIDS 2010, 24, 1213–1217

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19

Apr, 2010

Pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3-<36 months.

 

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

 

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19

Apr, 2010

A Model-based approach to dose selection in early pediatric development

 

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.

Abstract The establishment of a rationale for determining dosing regimens in pediatric patients remains a challenge in drug development. In this investigation, we explored several methodologies to support bridging studies and evaluated the best descriptor of developmental changes that can be used as a covariate for dose adjustment in children. The proposed approach is illustrated for the antiviral drug abacavir. Using data from six pharmacokinetic studies in adults and one study in children, a model-based analysis was applied in order to characterize differences in parameter distributions and their implications for systemic exposure to abacavir. Simulations were subsequently performed to define the appropriate dosing regimen in children. Although body weight was identified as a covariate for clearance and volume, dosing recommendations calculated on the basis of mg/kg cannot be linearly applied across all weight ranges. Our analysis shows the consequences of empirical dose adjustment and the importance of priors from historical data to support dose selection in children.

18

Apr, 2010

Immunologic and viral dynamics among HIV-infected children after planned treatment interruption: a substudy of the Paediatric European Network for Treatment of AIDS (PENTA) 11 trial.

 

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

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18

Apr, 2010

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

 

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.

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4

Mar, 2010

Triple-class virologic failure in HIV-infected patients undergoing antiretroviral therapy for up to 10 years

 

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.

 

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19

Jan, 2010

Response to Planned Treatment Interruptions in HIV-infection varies across Childhood in the PENTA 11 Trial

 

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.

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