Penta HIV Trials | PENTA 11

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.

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

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.

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.

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.

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 %).

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

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

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

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

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: 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: 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:  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