Penta HIV Trials

18

Jul, 2015

“But it’s my story”: exploring the experience and effect of telling children how they have acquired HIV

 

Authors:  Seeley J on behalf of the Bernays S, Paparini S, Namukwaya Kihika S,  Rhodes T and the BREATHER Trial Team.

Published in: 3rd International ASSHH Conference, Stellenbosch, South Africa, 6-9 July 2015.

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19

Apr, 2015

Once vs. twice-daily lopinavir/ritonavir in HIV-1-infected children.

 

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

Published in: AIDS 2015. 29(18):2447-2457

Objective To evaluate whether once daily (q.d.) lopinavir/ritonavir is noninferior to twice daily (b.i.d.) dosing in children.

Design International, multicentre, phase II/III, randomized, open-label, noninferiority trial (KONCERT/PENTA18/ANRS150).

Setting Clinical centres participating in the PENTA, HIV-NAT and PHPT networks.

Participants Children/adolescents with HIV-1 RNA viral load less than 50 copies/ml for at least 24 weeks on lopinavir/ritonavir-containing antiretroviral therapy.

Intervention Children were randomized to continue lopinavir/ritonavir b.i.d. or change to q.d.

Main Outcome Measure Confirmed viral load ≥50 copies/ml by 48 weeks (12% noninferiority margin).

Results One hundred seventy-three children were randomized in the KONCERT trial (86 q.d., 87 b.i.d.); 46% men, median (IQR) age 11 (9-14) years, CD4% 33 (27-38)%. By week 48, 97 and 98% of time was spent on q.d. and b.i.d., respectively (one q.d. child lost at week 4). Twelve q.d. vs. seven b.i.d. children had confirmed viral load ≥50 copies/ml within 48 weeks; estimated difference in percentage with viral load rebound 6% [90% CI (-2, 14)]. Numbers of children with grade 3/4 adverse events (11 vs. 7) or major resistance mutations (3 vs. 2) were similar, q.d. vs. b.i.d. (both P > 0.3). Among 26 children in an intrasubject lopinavir/ritonavir pharmacokinetic substudy, lower daily exposure (AUC0-24 161 h.mg/l vs. 224 h.mg/l) and lower Clast (1.03 mg/l vs. 5.69 mg/l) were observed with q.d. vs. b.i.d. dosing.

Conclusion Noninferiority for viral load suppression on q.d. vs. b.i.d. lopinavir/ritonavir was not demonstrated. Although results, therefore, do not support routine use of q.d. lopinavir/ritonavir, lack of safety concerns or resistance suggest that q.d. dosing remains an option in selected, adherent children, with close viral load monitoring.

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23

Feb, 2015

ART With Weekends Off Is Noninferior to Continuous ART in Young People on EFV+2NRTI

 

Authors: Karina M. Butler on behalf of the BREATHER trial team

Published in: CROI 2015, Seattle, USA, Feb 23 -26 2015.

Abstract For HIV-1 infected young people (YP) facing lifelong ART, short cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity and better adherence, as well as cost savings.

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18

Feb, 2015

Long-term consequences of planned treatment interruption in HIV-1-infected children.

 

Authors: Freguja R, De Rossi A, Paulson H, Klein N, Del Bianco P, Compagnucci A, Saidi Y, Giaquinto C, Harper L, Gibb D, on behalf of the PENTA Steering Committee

Published in: CROI 2015, Seattle, USA, Feb 23 -26 2015. Poster presentation abstract 919

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1

Jan, 2015

HIV-1 Drug Resistance and Second-line Treatment in Children Randomized to Switch at Low versus Higher RNA Thresholds

 

Authors: Harrison L, Melvin A, Fiscus S, et al; PENPACT-1 (PENTA 9PACTG 390) Study Team.

Published in: J Acquir Immune Defic Syndr. 2015;70(1):42-53

Background The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold.

Methods PENPACT-1 had a 2 × 2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, and switch at a 1000 copies/mL versus 30,000 copies/mL threshold. Switch criteria were not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or Center for Disease Control and Prevention stage C event. Resistance tests were performed on samples ≥1000 copies/mL before switch, resuppression, and at 4-years/trial end.

Results Sixty-seven children started PI-based ART and were randomized to switch at 1000 copies/mL (PI-1000), 64 PIs and 30,000 copies/mL (PI-30,000), 67 NNRTIs and 1000 copies/mL (NNRTI-1000), and 65 NNRTI and 30,000 copies/mL (NNRTI-30,000). Ninety-four (36%) children reached the 1000 copies/mL switch criteria during 5-year follow-up. In 30,000 copies/mL threshold arms, median time from 1000 to 30,000 copies/mL switch criteria was 58 (PI) versus 80 (NNRTI) weeks (P = 0.81). In NNRTI-30,000, more nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000 copies/mL (23% NNRTI-1000, 27% NNRTI-30,000). Sixty-two children started abacavir + lamivudine, 166 lamivudine + zidovudine or stavudine, and 35 other NRTIs. The abacavir + lamivudine group acquired fewest NRTI mutations. Of 60 switched to second-line, 79% PI-1000, 63% PI-30,000, 64% NNRTI-1000, and 100% NNRTI-30,000 were <400 copies/mL 24 weeks later.

Conclusions Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet resuppressed on second-line. An abacavir + lamivudine NRTI combination seemed protective against development of NRTI resistance.

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18

Apr, 2014

Using CD4 Percentage and Age to Optimize Pediatric Antiretroviral Therapy Initiation

 

Authors: Yin D., Warshaw M., Miller W., Castro H., Fiscus S., Harper L., Harrison L., Klein N., Lewis J., Melvin A., Tudor-Williams G., McKinney R.

Published in: Pediatrics, 2014;134(4):e1104-16

Background Quantifying pediatric immunologic recovery by highly active antiretroviral therapy (HAART) initiation at different CD4 percentage (CD4%) and age thresholds may inform decisions about timing of treatment initiation.

Methods HIV-1-infected, HAART-naive children in Europe and the Americas were followed from 2002 through 2009 in PENPACT-1. Data from 162 vertically infected children, with at least World Health Organization “mild” immunosuppression and CD4% <10th percentile, were analyzed for improvement to a normal CD4% (≥10th percentile) within 4 years after HAART initiation. Data from 209 vertically infected children, regardless of immune status, were analyzed for CD4% outcomes at 4 years and viral failure within 4 years.

Results Seventy-two percent of baseline immunosuppressed children recovered to normal within 4 years. Compared with “severe” immunosuppression, more children with “mild” immunosuppression (difference 36%, 95% confidence interval [CI]: 22% to 49%) or “advanced” immunosuppression (difference 20.8%, 95% CI: 5.8% to 35.9%) recovered a normal CD4%. For each 5-year increase in baseline age, the proportion of children achieving a normal CD4% declined by 19% (95% CI: 11% to 27%). Combining baseline CD4% and age effects resulted in >90% recovery when initiating HAART with “mild” immunosuppression at any age or “advanced” immunosuppression at age <3 years. Baseline CD4% effects became greater with increasing age (P = .02). At 4 years, most immunologic benefits were still significant but diminished. Viral failure was highest in infancy (56%) and adolescence (63%).

Conclusions Initiating HAART at higher CD4% and younger ages maximizes potential for immunologic recovery. Guidelines should weigh immunologic benefits against long-term risks.

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10

Apr, 2014

Pharmacokinetics of Pediatric Lopinavir/Ritonavir Tablets in Children When Administered Twice Daily According to FDA weight bands.

 

Authors: Bastiaans DE, Forcat S, Lyall H, et al.

Published in: Pediatr Infect Dis J. 2014;33(3):301-305

Background Lopinavir/ritonavir (LPV/r) pediatric tablets (100/25 mg) are approved by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) as part of combination antiretroviral therapy. Dosing is based on body weight bands or body surface area under FDA approval and only body surface area by the EMA. This can lead to a different recommended dose. In addition, weight band–based dosing has not been formally studied in the target population. We evaluated the pharmacokinetics (PK) of LPV/r in children, administered twice daily according to the FDA weight bands, using pediatric tablets.

Methods Fifty-three HIV-infected children were included in the PK substudy of the Paediatric European Network for the Treatment of AIDS 18 trial (KONCERT). In this study, children were randomized to receive LPV/r twice or once daily, according to FDA weight bands. A PK assessment was performed in 17, 16 and 20 children in the 15–25 kg, ≥25–35 kg and >35 kg weight band, respectively, while children took the tablets twice daily. Rich sampling was performed, and PK parameters were calculated by noncompartmental analysis. Given the high percentage of Asian children, it was also tested whether there was a difference in PK parameters between Asian and non-Asian children.

Results For the total group, LPV geometric mean AUC0–12, Cmax and C12 were 106.9 h × mg/L, 12.0 mg/L and 4.9 mg/L, respectively. There were no significant differences in LPV PK parameters between the weight bands. In addition, weight was not found to be associated with variability in Cmax, C12 or AUC0–12 for the LPV PK parameters.

Conclusions FDA weight band–based dosing recommendations provide adequate exposure to LPV when using LPV/r pediatric tablets.

18

Mar, 2014

HIV-1 resistance after randomized virologic switch at 1,000 or 30,000 c/ml in children.

 

Authors: Harrison L, Gibb DM, Fiscus S, Saïdi Y, Nastouli E, Harper L, Compagnucci A, Babiker A, Melvin A, Tudor-Williams G and the PENPACT 1 (PENTA 9/PACTG 390) Study Team.

Published in: CROI 2014, 3-6 March 2014, Boston. Poster 898.

23

Oct, 2013

The Immunological and Virological Consequences of Planned Treatment Interruptions in Children with HIV Infection.

 

Authors: Klein N, Sefe D, Mosconi I, et al; on Behalf of the Paediatric European Network for Treatment of AIDS (PENTA) 11 Trial Team

Published in: PLoS One. 2013;8(10):e76582.

Objective To evaluate the immunological and viral consequences of planned treatment interruptions (PTI) in children with HIV.

Design This was an immunological and virological sub-study of the Paediatric European Network for Treatment of AIDS (PENTA) 11 trial, which compared CD4-guided PTI of antiretroviral therapy (ART) with continuous therapy (CT) in children.

Methods HIV-1 RNA and lymphocyte subsets, including CD4 and CD8 cells, were quantified on fresh samples collected during the study; CD45RA, CD45RO and CD31 subpopulations were evaluated in some centres. For 36 (18 PTI, 18 CT) children, immunophenotyping was performed and cell-associated HIV-1 DNA analysed on stored samples to 48 weeks.

Results In the PTI group, CD4 cell count fell rapidly in the first 12 weeks off ART, with decreases in both naïve and memory cells. However, the proportion of CD4 cells expressing CD45RA and CD45RO remained constant in both groups. The increase in CD8 cells in the first 12 weeks off ART in the PTI group was predominantly due to increases in RO-expressing cells. PTI was associated with a rapid and sustained increase in CD4 cells expressing Ki67 and HLA-DR, and increased levels of HIV-1 DNA.

Conclusions PTI in children is associated with rapid changes in CD4 and CD8 cells, likely due to increased cell turnover and immune activation. However, children off treatment may be able to maintain stable levels of naïve CD4 cells, at least in proportion to the memory cell pool, which may in part explain the observed excellent CD4 cell recovery with re-introduction of ART.
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19

May, 2013

Pharmacokinetics of paediatric lopinavir/ritonavir tablets in children when administered twice daily according to FDA weight bands.

 

Authors: D Bastiaans, S Forcat, H Lyall, T Cressey, S Chalermpantmetagul, Y Saïdi, C Koenigs,  D Nayagam, A Compagnucci, S Montero, L Harper, C Giaquinto, E Colbers, D Burger.

Published in: 31st Annual Meeting of the ESPID- May 28 – June 1, 2013, Milan: Poster discussion Abstract A-534-0018-00429.