BREATHER (PENTA 16) Short-Cycle Therapy (SCT) (5 Days on/2 Days Off) in Young People With Chronic HIV-infection (BREATHER)

The overall aim of the BREATHER trial is to evaluate the role of Short-Cycle Therapy (SCT) in the management of HIV-infected young people who have responded well to antiretroviral therapy (ART) and to determine whether young people with chronic HIV infection undergoing Short-Cycle Therapy of five days on ART and two days off maintain the same level of viral load suppression as those on continuous therapy, over 48 weeks.

To assess the advantages and disadvantages of the strategy, the incidence of toxicities, immunological control, resistance mutations, acceptability, quality of life and adherence to the randomised strategy will also be compared.

Importantly, because of insufficient data on short-term viral load rebound after stopping ART in this population, the trial will incorporate an initial pilot phase in selected centres, to assess the safety of the SCT strategy by evaluating detailed HIV-1 RNA profiles of participants on the SCT strategy.

Study Overview

• Status: Unknown
• Conditions: HIV
• Intervention / Treatment: Drug: efavirenz

• Study Type: Interventional
• Enrollment (Anticipated): 160
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Villejuif, France
    • INSERM
• Germany
  • Frankfurt am Main
    • Frankfurt, Frankfurt am Main, Germany, 60596
      • Universitatsklinikum Frankfurt
• Ireland
  • Dublin, Ireland
    • Our Lady's Children's Hospital
• Thailand
  • Bangkok, Thailand
    • HIV-NAT Thai Red Cross AIDS Research Centre
  • Chiang Mai
    • Changklan, Muang, Chiang Mai, Thailand, 50100
      • Program for HIV Prevention and Treatment (PHPT)/IRD 174
• Uganda
  • Kampala, Uganda
    • Joint Clinical Research Centre
• Ukraine
  • Vidpochynku 11
    • Kiev, Vidpochynku 11, Ukraine, 03115
      • Kiev City AIDS Center
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Heartlands Hospital
  • Bristol, United Kingdom
    • University Hospital Bristol
  • Leeds, United Kingdom
    • Leeds General Infirmary
  • Leicester, United Kingdom
    • Leicester Royal Infirmary
  • London, United Kingdom
    • Mortimer Market Centre
  • London, United Kingdom
    • Evelina Children's Hospital
  • London, United Kingdom
    • Great Ormond Street Hospital
  • London, United Kingdom
    • St George's Hospital
  • Nottingham, United Kingdom
    • Nottingham University Hospital
  • Oxford, United Kingdom
    • John Radcliffe Hospital
• United States
  • Tennessee
    • Memphis, Tennessee, United States
      • St Jude Children's Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-1 infected young people aged 8 to 24 years inclusive (Young people recruited between the ages of 16-21 must either be in regular physical contact with their clinician or be able to transfer to an adult physician at the same site for follow-up or to an affiliated adult site).
• Parents/carers and/or young people, where applicable, willing to provide informed consent.
• On a stable first-line ART treatment containing at least 2 NRTIs/NtRTIs and EFV for at least 12 months and willing to continue the regimen throughout the study period. Young people on regimens containing nevirapine (NVP) or a boosted protease inhibitor with undetectable viral load for over one year who wish to enrol should switch to EFV. Once they are stable on the EFV containing regimen for more than 12 weeks they may be enrolled (must have 2 subsequent HIV-1 RNA measurements <50 c/ml over a minimum period of 12 weeks). Previous dual therapy and/or substitution of NRTIs is allowed providing any changes were not for disease progression, immunological or virological failure (where virological failure is defined as two successive HIV-1 RNA results>1000 c/ml) subsequent to virological control having been achieved on ART.
• Viral suppression (HIV-1 RNA <50 c/ml) for at least the prior 12 months (at least the last 3 measurements, including screening): young people who have experienced a single viral load >50 but <1000 copies/ml (preceded and followed by VL<50 c/ml) in the last 12 months can be enrolled.
• CD4 cell count ≥350 106/L at screening visit.
• Centre must routinely use an assay which detects HIV RNA-1 viral load ≥50 c/ml.

Exclusion Criteria:

• Pregnancy or risk of pregnancy in females of child bearing potential.
• Acute illness (young people may be enrolled after illness).
• Receiving concomitant therapy for an acute illness (young people may be enrolled after finishing therapy).
• A creatinine, AST or ALT of grade 3 or above at screening.
• On a regimen including nevirapine or a boosted PI (young people may switch to an EFV based regimen).
• Previous ART monotherapy (except for the prevention of mother-to-child transmission)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Continuous Therapy; Continue with current antiretroviral therapy regime as per standard care	Drug: efavirenz; May be taken as 600mg tablet, 200mg tablet or as part of a combination pill; Other Names: Trade name: Sustiva
Experimental: Short Cycle Therapy; Take current antiretroviral therapy 5 days a week (2 days off) as instructed by clinician	Drug: efavirenz; May be taken as 600mg tablet, 200mg tablet or as part of a combination pill; Other Names: Trade name: Sustiva

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIV-1 RNA ≥50 copies/ml (confirmed on a separate sample within 1 week) at any of week 4, 12, 24, 36 or 48.	This outcome measure only considers HIV-1 RNA measurements at these time points due to the difference in viral load monitoring in the pilot phase and the main trial. However if a young person enrolled in the pilot phase has HIV-1 RNA ≥50 copies/ml at weeks 1, 2 or 3 (reproducible on the same sample) or at week 8 (confirmed on the same sample within 1 week), they will be considered as reaching the primary outcome at week 4 and 12 respectively	48 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
HIV-1 RNA <50 c/ml at 24 and 48 weeks	24 and 48 weeks
Number of HIV mutations present at week 4, 12, 24, 36 or 48 conferring resistance to drugs taken at randomisation or during the tria	Weeks 4, 12, 24, 36, 48
Change in CD4 (absolute and percentage) from randomisation to 24 and 48 weeks	24 and 48 weeks
Change in ART (defined as any change from the ART regimen at randomisation)	48 weeks
Grade 3 or 4 clinical and laboratory adverse events	48 weeks
ART treatment modifying adverse events (all grades)	48 weeks
New CDC stage B or C diagnosis or death	48 weeks
Changes in fasting glucose, cholesterol, triglycerides, LDL, HDL and VLDL levels through 48 weeks	48 weeks
Adherence, acceptability, and quality of life over 48 weeks as assessed by patient completed questionnaires	48 weeks

Collaborators and Investigators

• Sponsor: PENTA Foundation
• Collaborators: Medical Research Council; ANRS, Emerging Infectious Diseases
• Investigators: Principal Investigator: Karina M Butler, MRCPI, Medical Research Council

Publications and helpful links

General Publications

• Turkova A, Moore CL, Butler K, Compagnucci A, Saidi Y, Musiime V, Nanduudu A, Kaudha E, Cressey TR, Chalermpantmetagul S, Scott K, Harper L, Montero S, Riault Y, Bunupuradah T, Volokha A, Flynn PM, Bologna R, Ramos Amador JT, Welch SB, Nastouli E, Klein N, Giaquinto C, Ford D, Babiker A, Gibb DM; BREATHER (PENTA 16) trial Group. 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. PLoS One. 2018 Apr 23;13(4):e0196239. doi: 10.1371/journal.pone.0196239. eCollection 2018.
• Bernays S, Paparini S, Seeley J, Namukwaya Kihika S, Gibb D, Rhodes T. Qualitative study of the BREATHER trial (Short Cycle antiretroviral therapy): is it acceptable to young people living with HIV? BMJ Open. 2017 Feb 17;7(2):e012934. doi: 10.1136/bmjopen-2016-012934.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): June 1, 2014
• Study Completion (Anticipated): June 1, 2016

Study Registration Dates

• First Submitted: July 12, 2012
• First Submitted That Met QC Criteria: July 12, 2012
• First Posted (Estimate): July 16, 2012

Study Record Updates

• Last Update Posted (Estimate): March 2, 2015
• Last Update Submitted That Met QC Criteria: February 27, 2015
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: HIV; young people; short cycle therapy
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Efavirenz
• Other Study ID Numbers: BREATHER (PENTA 16); 2009-012947-40 (EudraCT Number)