PENTA 11

24

Apr, 2016

Neurocognition and quality of life after reinitiating antiretroviral therapy in children randomized to planned treatment interruption

 

Authors: Ananworanich J, Melvin D, Ramos Amador JT, et al; on behalf of the PENTA 11 study group.

Published in: AIDS. 2016;30(7):1075-81.

Objective Understanding the effects of antiretroviral treatment (ART) interruption on neurocognition and quality of life (QoL) are important for managing unplanned interruptions and planned interruptions in HIV cure research.

Design Children previously randomized to continuous (continuous ART, n = 41) vs. planned treatment interruption (PTI, n = 47) in the Pediatric European Network for Treatment of AIDS (PENTA) 11 study were enrolled. At study end, PTI children resumed ART. At 1 and 2 years following study end, children were assessed by the coding, symbol search and digit span subtests of Wechsler Intelligence Scale for Children (6–16 years old) or Wechsler Adult Intelligence Scale (≥17 years old) and by Pediatrics QoL questionnaires for physical and psychological QoL. Transformed scaled scores for neurocognition and mean standardized scores for QoL were compared between arms by t-test and Mann–Whitney U test, respectively. Scores indicating clinical concern were compared (<7 for neurocognition and <70 for QoL tests).

Results Characteristics were similar between arms with a median age of 12.6 years, CD4+ of 830 cells/μl and HIV RNA of 1.7 log10copies/ml. The median cumulative ART exposure was 9.6 in continuous ART vs. 7.7 years in PTI (P = 0.02). PTI children had a median of 12 months off ART and had resumed ART for 25.2 months at time of first assessment. Neurocognitive scores were similar between arms for all tests. Physical and psychological QoL scores were no different. About 40% had low neurocognitive and QoL scores indicating clinical concern.

Conclusion No differences in information processing speed, sustained attention, short-term memory and QoL functioning were observed between children previously randomized to continuous ART vs. PTI in the PENTA 11 trial.

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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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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18

Feb, 2013

Outcomes after reinitiating antiretroviral therapy in children randomized to planned treatment interruptions in the PENTA 11 Study

 

Authors: Bunupuradah T, Duong T, Compagnucci A, et al; on behalf of the PENTA 11 Extension Study Group

Published in: AIDS. 2013;27(4):579-89

Background Excess risks for death/opportunistic disease in adults randomized to CD4-driven planned treatment interruption (PTI) in the Strategies for Management of Antiretroviral Therapy (SMART) trial remained after antiretroviral therapy (ART) re-initiation. Risks for childrenfollowing PTI were evaluated in long-term follow-up of children in the PENTA 11 trial.

Methods Children with HIV RNA below 50 copies/ml and CD4 at least 30% (2-6 years) or at least 500 cells/μl (7-15 years) were randomized to continuous ART (cART) or PTI in PENTA 11 (ISRCTN 36694210). After the end of the trial, all were recommended to resume ART. Data were collected annually and analysed up to the second year of visit.

Results One hundred and one (51 cART, 50 PTI; median baseline age 9.2 years) children had median overall follow-up 4.6 (range 3.7-5.0) years. During 2-year post-trial period, there were no deaths or new Centers for Disease Control and Prevention (CDC) stage B/C events. Rate of clinical grade of at least two events was similar between PTI and cART [relative risk (RR) 1.03; 95% confidence interval (CI) 0.43, 2.50; P = 0.94]. At 2 years, difference in absolute CD4% between PTI and cART was -1.6% (-4.5%; 1.3%; P = 0.27), and proportions with HIV RNA below 50 copies/ml were 82 versus 86% (P = 0.57), respectively; no differences in growth or fasting lipids were observed. Key predictors of greater CD4% recovery after re-initiating ART were higher CD4% at baseline (P < 0.001) and longer time since ART re-initiation (P < 0.001). During overall follow-up, 4 (8%) PTI versus 5 (10%) CT children switched ART for failure (P = 0.75) and 9 (18%) versus 1 (2%) (P = 0.008) substituted ART for simplification.

Conclusions No adverse clinical, immunological or virological consequences of PTI were observed 2 years after the end of PENTA 11 trial. Although ART interruption is not generally recommended, it may be an acceptable option for children, particularly when there is high risk of unplanned treatment interruptions.

17

Jan, 2013

Adherence to antiretroviral therapy and acceptability of planned treatment interruptions in HIV-infected children

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Authors: Harrison L, Ananworanich J, Hamadache D, et al; on Behalf of the Paediatric European Network for Treatment of AIDS (PENTA) 11 Trial Team

Published in: AIDS Behav. 2013;17(1):193-202.

Abstract There have been no paediatric randomised trials describing the effect of planned treatment interruptions (PTIs) of antiretroviral therapy (ART) on adherence, or evaluating acceptability of such a strategy. In PENTA 11, HIV-infected children were randomised to CD4-guided PTIs (n = 53) or continuous therapy (CT, n = 56). Carers, and children if appropriate, completed questionnaires on adherence to ART and acceptability of PTIs. There was no difference in reported adherence on ART between CT and PTI groups; non-adherence (reporting missed doses over the last 3 days or marking <100 % adherence since the last clinical visit on a visual analogue scale) was 18 % (20/111) and 14 % (12/83) on carer questionnaires in the CT and PTI groups respectively (odds ratios, OR (95 % CI) = 1.04 (0.20, 5.41), χ(2) (1) = 0.003, p = 0.96). Carers in Europe/USA reported non-adherence more often (31/121, 26 %) than in Thailand (1/73, 1 %; OR (95 % CI) = 54.65 (3.68, 810.55), χ(2) (1) = 8.45, p = 0.004). The majority of families indicated they were happy to have further PTIs (carer: 23/36, 64 %; children: 8/13, 62 %), however many reported more clinic visits during PTI were a problem (carer: 15/36, 42 %; children: 6/12, 50 %).

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8

May, 2012

Neurocognitive and Quality of Life Outcomes in Children after Planned Treatment Interruptions: the randomized PENTA 11 trial.

 

Authors: Ramos J., Melvin D, Medin G, Compagnucci A, Bleier J, Boscolo V, Barclay L, Ory S, Giaquinto C, Gibb D. on behalf of the PENTA Steering Committee.

Published in: 19th Conference on Retroviruses and Opportunistic Infections, San Francisco, 5-8 March 2012, Poster

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18

Jul, 2011

Long Term consequences of planned treatment interruptions in HIV infected children: Results from the TICCH (Treatment Interruption in Children with Chronic HIV-Infection )/PENTA 11 trial.

 

Authors: Compagnucci A. on behalf of the PENTA Steering Committee

Published in: 3rd HIV Paediatric Workshop Rome 15-16 July 2011.

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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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19

Feb, 2010

Response to Planned Treatment Interruptions in HIV-infection varies across Childhood

 

Authors: UNAIDS

Published in: UNAIDS HIV This Week 78, 15 Feb 2010

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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.