Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents and young adults (BREATHER): Extended follow-up results of a randomised, open-label, non-inferiority trial

BACKGROUND: Weekends off antiretroviral therapy (ART) may help engage HIV-1-infected young people facing lifelong treatment. BREATHER showed short cycle therapy (SCT; 5 days on, 2 days off ART) was non-inferior to continuous therapy (CT) over 48 weeks. Planned follow-up was extended to 144 weeks, maintaining original randomisation. METHODS: BREATHER was an open-label, non-inferiority trial. Participants aged 8-24yrs with virological suppression on efavirenz-based first-line ART were randomised 1:1, stratified by age and African/non-African sites, to remain on CT or change to SCT. The Kaplan-Meier method was used to estimate the proportion of participants with viral rebound (confirmed VL≥50 copies/mL) under intent-to-treat at 48 weeks (primary outcome), and in extended follow-up at 96, 144, and 192 weeks. SCT participants returned to CT following viral rebound, 3 VL blips or discontinuation of efavirenz. FINDINGS: Of 199 participants (99 SCT, 100 CT), 97 per arm consented to extended follow-up. Median follow-up was 185.3 weeks (IQR 160.9-216.1). 69 (70%) SCT participants remained on SCT at last follow-up. 105 (53%) were male, baseline median age 14 years (IQR 12-18), median CD4 count 735 cells/μL (IQR 576-968). 16 SCT and 16 CT participants had confirmed VL≥50 copies/mL by the end of extended follow-up (HR 1.00, 95% CI 0.50-2.00). Estimated difference in percentage with viral rebound (SCT minus CT) by week 144 was 1.9% (90% CI -6.6-10.4; p = 0.72) and was similar in a per-protocol analysis. There were no significant differences between arms in proportions of participants with grade 3/4 adverse events (18 SCT vs 16 CT participants; p = 0.71) or ART-related adverse events (10 vs 12; p = 0.82). 20 versus 8 serious adverse events (SAEs) were reported in 16 SCT versus 4 CT participants, respectively (p = 0.005 comparing proportions between groups; incidence rate ratio 2.49, 95%CI 0.71-8.66, p = 0.15). 75% of SAEs (15 SCT, 6 CT) were hospitalisations for a wide range of conditions. 3 SCT and 6 CT participants switched to second-line ART following viral failure (p = 0.50). CONCLUSIONS: Sustainable non-inferiority of virological suppression in young people was shown for SCT versus CT over median 3.6 years. Standard-dose efavirenz-based SCT is a viable option for virologically suppressed HIV-1 infected young people on first-line ART with 3-monthly VL monitoring. TRIAL REGISTRATION: EudraCT 2009-012947-40 ISRCTN 97755073 ClinicalTrials.gov NCT01641016

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

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 ( 6517 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/\u3bcl and HIV RNA of 1.7 log 10 copies/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

Etude experimentale de l'ecoulement d'air en convection naturelle autour des cartes electroniques

SIGLECNRS RP 252 (322) / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Long-term clinical, virological and immunological outcomes following planned treatment interruption in HIV-infected children

OBJECTIVES: Planned treatment interruption (PTI) of antiretroviral therapy (ART) in adults is associated with adverse outcomes. The PENTA 11 trial randomized HIV-infected children to continuous ART (CT) vs. CD4-driven PTIs. We report 5\ua0years' follow-up after the end of main trial. METHODS: Post-trial, all children resumed ART. Clinical, immunological, virological and treatment data were collected annually. A sub-study investigated more detailed immunophenotype. CT and PTI arms were compared using intention-to-treat. Laboratory parameters were compared using linear regression, adjusting for baseline values; mixed models were used to include all data over time. RESULTS: In all, 101 children (51 CT, 50 PTI) contributed a median of 7.6\ua0years, including 5.1\ua0years of post-trial follow-up. Post-trial, there were no deaths, one pulmonary tuberculosis and no other CDC stage B/C events. At 5 years post-trial, 90% of children in the CT vs. 82% in the PTI arm had HIV RNA\ua0<\ua050\ua0copies/mL (P\ua0=\ua00.26). A persistent increase in CD8 cells was observed in the PTI arm. The sub-study (54 children) suggested that both na\uefve and memory populations contributed to higher CD8 cells following PTI. Mean CD4/CD8 ratios at 5\ua0years post-trial were 1.22 and 1.08 in CT and PTI arms, respectively [difference (CT - PTI) = -0.15; 95% CI: -0.34-0.05), P\ua0=\ua00.14]. The sub-study also suggested that during the trial and at early timepoints after the end of the trial, reduction in CD4 in the PTI arm was mainly from loss of CD4 memory cells. CONCLUSIONS: Children tolerated PTI with few long-term clinical, virological or immunological consequences

Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority, phase 2/3 trial

Background For HIV-1-infected young people facing lifelong antiretroviral therapy (ART), short cycle therapy with long-acting drugs offers potential for drug-free weekends, less toxicity, and better quality-of-life. We aimed to compare short cycle therapy (5 days on, 2 days off ART) versus continuous therapy (continuous ART). Methods In this open-label, non-inferiority trial (BREATHER), eligible participants were aged 8–24 years, were stable on first-line efavirenz with two nucleoside reverse transcriptase inhibitors, and had HIV-1 RNA viral load less than 50 copies per mL for 12 months or longer. Patients were randomly assigned (1:1) to remain on continuous therapy or change to short cycle therapy according to a computer-generated randomisation list, with permuted blocks of varying size, stratified by age and African versus non-African sites; the list was prepared by the trial statistician and randomisation was done via a web service accessed by site clinician or one of the three coordinating trials units. The primary outcome was the proportion of participants with confirmed viral load 50 copies per mL or higher at any time up to the 48 week assessment, estimated with the Kaplan-Meier method. The trial was powered to exclude a non-inferiority margin of 12%. Analyses were intention to treat. The trial was registered with EudraCT, number 2009-012947-40, ISRCTN, number 97755073, and CTA, number 27505/0005/001-0001. Findings Between April 1, 2011, and June 28, 2013, 199 participants from 11 countries worldwide were randomly assigned, 99 to the short cycle therapy and 100 to continuous therapy, and were followed up until the last patient reached 48 weeks. 105 (53%) were men, median age was 14 years (IQR 12–18), and median CD4 cell count was 735 cells per μL (IQR 576–968). Six (6%) patients assigned to the short cycle therapy versus seven (7%) assigned to continuous therapy had confirmed viral load 50 copies per mL or higher (difference −1·2%, 90% CI −7·3 to 4·9, non-inferiority shown). 13 grade 3 or 4 events occurred in the short cycle therapy group and 14 in the continuous therapy group (p=0·89). Two ART-related adverse events (one gynaecomastia and one spontaneous abortion) occurred in the short cycle therapy group compared with 14 (p=0·02) in the continuous therapy group (five lipodystrophy, two gynaecomastia, one suicidal ideation, one dizziness, one headache and syncope, one spontaneous abortion, one neutropenia, and two raised transaminases). Interpretation Non-inferiority of maintaining virological suppression in children, adolescents, and young adults was shown for short cycle therapy versus continous therapy at 48 weeks, with similar resistance and a better safety profile. This short cycle therapy strategy is a viable option for adherent HIV-infected young people who are stable on efavirenz-based ART

Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents and young adults (BREATHER): Extended follow-up results of a randomised, open-label, non-inferiority trial.

BACKGROUND Weekends off antiretroviral therapy (ART) may help engage HIV-1-infected young people facing lifelong treatment. BREATHER showed short cycle therapy (SCT; 5 days on, 2 days off ART) was non-inferior to continuous therapy (CT) over 48 weeks. Planned follow-up was extended to 144 weeks, maintaining original randomisation. METHODS BREATHER was an open-label, non-inferiority trial. Participants aged 8-24yrs with virological suppression on efavirenz-based first-line ART were randomised 1:1, stratified by age and African/non-African sites, to remain on CT or change to SCT. The Kaplan-Meier method was used to estimate the proportion of participants with viral rebound (confirmed VL≥50 copies/mL) under intent-to-treat at 48 weeks (primary outcome), and in extended follow-up at 96, 144, and 192 weeks. SCT participants returned to CT following viral rebound, 3 VL blips or discontinuation of efavirenz. FINDINGS Of 199 participants (99 SCT, 100 CT), 97 per arm consented to extended follow-up. Median follow-up was 185.3 weeks (IQR 160.9-216.1). 69 (70%) SCT participants remained on SCT at last follow-up. 105 (53%) were male, baseline median age 14 years (IQR 12-18), median CD4 count 735 cells/μL (IQR 576-968). 16 SCT and 16 CT participants had confirmed VL≥50 copies/mL by the end of extended follow-up (HR 1.00, 95% CI 0.50-2.00). Estimated difference in percentage with viral rebound (SCT minus CT) by week 144 was 1.9% (90% CI -6.6-10.4; p = 0.72) and was similar in a per-protocol analysis. There were no significant differences between arms in proportions of participants with grade 3/4 adverse events (18 SCT vs 16 CT participants; p = 0.71) or ART-related adverse events (10 vs 12; p = 0.82). 20 versus 8 serious adverse events (SAEs) were reported in 16 SCT versus 4 CT participants, respectively (p = 0.005 comparing proportions between groups; incidence rate ratio 2.49, 95%CI 0.71-8.66, p = 0.15). 75% of SAEs (15 SCT, 6 CT) were hospitalisations for a wide range of conditions. 3 SCT and 6 CT participants switched to second-line ART following viral failure (p = 0.50). CONCLUSIONS Sustainable non-inferiority of virological suppression in young people was shown for SCT versus CT over median 3.6 years. Standard-dose efavirenz-based SCT is a viable option for virologically suppressed HIV-1 infected young people on first-line ART with 3-monthly VL monitoring. TRIAL REGISTRATION EudraCT 2009-012947-40 ISRCTN 97755073 ClinicalTrials.gov NCT01641016

The immunological and virological consequences of planned treatment interruptions in children with HIV infection

Contains fulltext : 126098.pdf (publisher's version ) (Open Access)OBJECTIVES: 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 naive 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 naive 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