BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2 days off) in young people with chronic human immunodeficiency virus infection: an open, randomised, parallel-group Phase II/III trial

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 08/53/25 and 11/136/108. The contractual start date was in July 2010. The draft report began editorial review in March 2015 and was accepted for publication in November 2015. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Jamie Inshaw, Anna Turkova, Nigel Klein, Sarah Bernays, Julia Kenny, Eleni Nastouli, Karen Scott, Lynda Harper, Sara Paparini, Rahela Choudhury, Tim Rhodes, Abdel Babiker and Diana Gibb report grants from the PENTA Foundation during the conduct of the study. Jamie Inshaw, Anna Turkova, Nigel Klein, Julia Kenny, Eleni Nastouli, Karen Scott, Lynda Harper, Rahela Choudhury, Abdel Babiker and Diana Gibb report grants from the European Commission (FP7) during the conduct of the study.

Copyright statement

© Queen’s Printer and Controller of HMSO 2016. This work was produced by Butler et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Intermittent therapy

Short-cycle therapy in adults and adolescents

Two Phase II trials of SCT in adults reported before the start of the BREATHER trial. First, a small single-arm pilot study of 5 days on, 2 days off ART in adults in the USA showed that long-term suppression of VL could be achieved. 28 Two of nine patients on protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) had confirmed virological rebound by 48 weeks compared with one of 10 patients on nevirapine (NVP)-containing HAART and none of eight patients receiving efavirenz (EFV)-based regimens. As a result of this pilot, the randomised FOTO (Five On Two Off) trial in 60 adults with a VL of < 50 copies/ml on tenofovir (TDF)/emtricitabine (FTC)/EFV was conducted comparing daily ART with a strategy of 5 days on, 2 days off treatment. The 24-week results showed that all 25 patients in the FOTO arm and 24 of 28 patients (86%) in the daily arm who reached week 24 had a VL of < 50 copies/ml at this time point. 29 Reasons for not reaching 24 weeks were psychological (n = 2), because of the time burden (FOTO arm) (n = 3), pregnancy (n = 1) and loss to follow-up (daily ART arm) (n = 1); of note, all had a VL of < 50 copies/ml at discontinuation. There were six blips (VL 50–500 copies/ml) in the FOTO arm and nine in the daily ART arm to week 24; there were no instances of virological failure (confirmed VL > 400 copies/ml).

Second, in a trial in Uganda,30,31 146 adults who had a suppressed VL of < 50 copies/ml on a three-drug ART regimen were randomised to receive a week on, week off ART regimen (n = 32; this arm of the study was discontinued early), a 5 days on, 2 days off schedule (SCT) (n = 57) or CT (n = 57). The majority of subjects (94%) received an EFV-based regimen. The trial showed that SCT was not inferior to continuous HAART; there were 11 cases of failure in the CT group (including one death) and six in the SCT group (failure defined as VL > 1000 copies/ml, a decrease in CD4 count from randomisation of > 30% or a CD4 count of < 100 cells/mm³ on two consecutive occasions through the 72 weeks of follow-up; or VL > 400 copies/ml or development of an opportunistic infection at 72 weeks). Levels of resistance were no different between the SCT group and the CT group. For patients on HAART containing stavudine, there was a significant decrease in the incidence of lactic acidosis in the SCT arm compared with the CT arm.

The US-based Adolescent Trials Network conducted the only study of SCT in adolescents prior to the BREATHER trial, which had a non-randomised single-arm design to assess VL suppression (< 400 copies/ml, confirmed) on SCT (4 days on HAART, 3 days off) over 48 weeks. 32 Thirty-two participants aged 12–24 years and on a stable PI-based HAART regimen for at least 12 months were enrolled. Twelve of the 32 (38%) participants had confirmed virological rebound by 48 weeks, seven out of 15 (47%) of those infected before 9 years of age and five out of 17 (29%) of those infected after 9 years of age (p = 0.5). However, 75% of children had been exposed to five or more drugs in the past, with a previous history of virological failure. Overall, adherence was good (88% of participants showed > 90% adherence), with no difference between those with and those without VL rebound (p = 0.6).

Antiretroviral agents, viral load rebound and resistance

The plasma half-life of ARV agents in an ART regimen [or intracellular half-life of nucleoside reverse transcriptase inhibitor (NRTIs)] and their genetic barrier to resistance are important factors that may influence VL rebound and the development of resistance during a strategy of stopping therapy for 2 days every week.

An ART regimen containing three drugs, with relatively similar long half-lives and maintained therapeutic concentrations of > 2 days when treatment is stopped, would be an ideal regimen to avoid risk of VL rebound during the interruption and minimise the development of resistance. The regimen with the most favourable pharmacokinetic profile is TDF/FTC/EFV (median intracellular half-life of 150 hours, median intracellular half-life of 39 hours and plasma half-life of between 36 and 100 hours, respectively). 33 Coformulation of TDF/FTC/EFV34 in a single pill makes this a very attractive combination for older adolescents and young adults. However, in the Ugandan trial,31 EFV was given with either stavudine/lamivudine (3TC) or zidovudine (ZDV)/3TC without evidence of inferior virological performance, even though stavudine, 3TC and ZDV have shorter half-lives than TDF and FTC. PI drugs [e.g. lopinavir/ritonavir (Kaletra^®; AbbVie Inc.), the most commonly used PI in children and adolescents] have substantially shorter half-lives and therefore if a regimen containing two NRTIs (with longer half-lives) and a PI (with a shorter half-life) is stopped, ‘functional dual NRTI therapy’ may result, with a risk of VL rebound and the development of resistance.

Data on viral dynamics in the first few days following treatment cessation are scarce. Jacobsen et al. ,24 in a four-arm study of planned treatment interruption ± HIV immunisation, reported viral rebound to > 50 copies/ml following treatment interruption at a median [interquartile range (IQR)] of 15 (8–31) days for those with a prior planned treatment interruption and 21 (13–30) days for those without a prior planned treatment interruption. Harrigan et al. ,35 while assuming a constant rate of viral increase that starts as soon as the patient stops therapy, suggest that many patients stopping therapy (previously suppressed) will have an increase in plasma viral HIV ribonucleic acid (RNA) of about 0.2 log/day and will reach detectable levels (> 50 copies/ml) only within 1–2 weeks of stopping therapy.

A substudy of PENTA 11 evaluated the pharmacokinetics, VL rebound and resistance profiles in 35 children stopping non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. 36 In total, 21 children followed a staggered stop strategy whereby the NNRTI (NVP or EFV) was stopped at randomisation and the remaining two NRTI drugs were stopped 7–14 days later, and 14 children followed a replacement strategy whereby the NNRTI was replaced with a PI and all drugs were stopped 7–14 days later. Results of HIV VL testing in eight children following the staggered stop strategy and seven children following the replacement strategy showed that the majority of children still had undetectable HIV RNA 5–8 days after stopping all drugs (minimum 12 days after stopping the NNRTI). No NNRTI resistance mutations were detected in any of the children in the substudy.

Rationale and objectives

Adherence issues tend to worsen for older children and adolescents after they start taking charge of their own medication (after HIV diagnosis is disclosed); self-consciousness and not wanting to be different from peers predominate. There is the additional burden of secrecy around HIV infection and ART,15 and social and family pressures prevent young people from sharing information of their diagnosis or treatment with friends. 37 The result is often worsening adherence with frequently missed doses, particularly at weekends, which are typically times of socialising. Factors contributing to this include alcohol ingestion19 as well as the absence of school and overnight stays with friends at weekends. Therefore, a regimen in which ARVs need be taken only as part of the daily routine during weekdays could be attractive for older children (> 8 years) as well as teenagers and young people (16–24 years) who continue to be followed at paediatric or affiliated adolescent units.

Data from adult studies evaluating the strategy of 5 days on, 2 days off were promising, with low rates of virological rebound seen. However, no randomised trial had been undertaken in older children and adolescents, a population with potentially more to gain in terms of quality of life, long-term adherence to medication and the potential for better treatment options in adulthood. The effect on overall adherence of allowing 2 days off treatment per week was unknown and it was therefore important to first evaluate the strategy in young people who have a history of good adherence, the argument being that offering this strategy could prevent ad hoc missed doses occurring. In view of the relatively shorter half-life of PIs and because both adult trials referred to above were undertaken with EFV-based regimens, enrolment was limited to children who are on, or who are willing to switch to, a regimen containing EFV.

The BREATHER trial aimed to assess whether or not young people with chronic HIV infection undergoing SCT of 5 days on and 2 days off following complete virological response to first-line ART for at least 12 months maintained the same level of VL suppression as those on CT. Importantly, because of insufficient data on short-term VL rebound after stopping ART in this population, the trial incorporated an initial pilot phase to assess the safety of the SCT strategy.

Risks and benefits

The potential risks of the SCT strategy were as follows:

• The main risk was that the SCT strategy would prove ineffective at maintaining VL suppression, either because VL could not be maintained below detection levels during 2 days off ART or because of non-adherence to the strategy by extending the time off treatment. However, if a raised VL was confirmed on repeat testing (carried out within 1 week) then the participant was placed back on CT.

• An additional risk was that young people who had been fully adherent to ART before enrolment in the study might extend the permitted very short interruptions and that overall adherence would decline. Of note, there was equipoise about whether adherence would be better or worse in the SCT arm than in the CT arm as young people in the continuous arm may also not take their treatment regularly. All young people were given a diary to record when they had taken ART and were asked to comment about difficulties in remembering to take medication. Rebounding VL comes with the risk of development of resistance (particularly to EFV and 3TC, which have low genetic barriers to resistance), which in turn may limit future therapeutic options. Resistance testing was performed on all young people who lost virological suppression in either arm at the point of loss of suppression (≥ 50 copies/ml), as well as on any subsequent samples with a HIV-1 RNA level of ≥ 1000 copies/ml.

The potential benefits of the SCT strategy were:

• improvement in quality of life from having weekends free from taking medication

• improved long-term adherence during the week

• decreased long-term toxicity of ARV drugs (particularly relevant for some NRTI drugs, e.g. ZDV and TDF)

• decreased cost, which is important to any health-care service and in particular for many parts of the world where HIV prevalence is highest.

Young people and carers were fully informed of the possible benefits and known risks by means of a patient information sheet as appropriate and this was reinforced by discussions with the study research teams at the individual sites prior to enrolment.

Pilot study

Because of insufficient data on short-term VL rebound after stopping ART in this population, the trial incorporated an initial pilot phase in selected centres. The aim of the pilot phase was to ensure that the SCT strategy did not result in a high proportion of young people with an increased VL (≥ 50 copies/ml) of ART in the first few weeks.

Those enrolled in the pilot and randomised to SCT were permitted to take only Saturday and Sunday off treatment. They received VL testing on Monday, prior to resumption of ART. Recruitment to the main trial commenced only when all pilot participants had completed 3 weeks on the study and the results were reviewed by the Independent Data Monitoring Committee (IDMC) to ensure that there were no safety concerns. Preset criteria for stopping included a HIV-1 RNA level of ≥ 50 copies/ml (validated by a HIV-1 RNA level of ≥ 50 copies/ml on the same sample) at weeks 1, 2 or 3 following weekend interruption and before restarting ART in more than five participants as this would have given evidence that VL suppression rates on a SCT strategy in general were < 90% [10/15 suppressed = 66%, 95% exact confidence interval (CI) 38% to 88%]. Data from the pilot phase were reviewed by the IDMC who identified no safety concerns and recommended that recruitment continue.

Substudies

Plasma and cells were stored for both arms throughout the trial for the virology, inflammatory biomarkers and immunology substudies. The rationale behind the biomarker substudy was to determine whether or not any markers of inflammatory response were increased among children in the SCT arm compared with the CT arm, even if VL suppression was no different. This has been observed in adult trials such as the SMART trial in which interruptions resulted in an increase in VL. 22

There was also a qualitative substudy that aimed to (1) evaluate the acceptability of SCT and of the trial from the perspectives of young people participating; (2) explore whether or not they perceived that SCT facilitated improved adherence; (3) document how young people experience life with ART; and (4) understand how their experiences in adolescence affect their capacity and willingness to adhere to taking their treatment. As well as producing knowledge to better support optimum adherence among adolescents, the study also aimed to (5) compare the HIV treatment and trial experiences of young people in the UK, Ireland, Uganda and the USA.

Trial entry criteria

The trial enrolled HIV-1-infected young people aged 8–24 years inclusive who had been on a stable first-line ART treatment containing at least two NRTIs/NNRTIs and EFV for at least 12 months and who were willing to continue the regimen throughout the study period. Previous dual therapy and/or substitution of NRTIs was allowed providing any changes were not the result of disease progression or immunological or virological failure (with virological failure defined as two successive HIV-1 RNA results of > 1000 copies/ml) subsequent to virological control having been achieved on ART. They must have had viral suppression (HIV-1 RNA < 50 copies/ml) for at least the previous 12 months (at least the last three measurements, including screening). Young people who had experienced a single VL of > 50 copies/ml but < 1000 copies/ml (preceded and followed by a VL of < 50 copies/ml) in the last 12 months could be enrolled. They must have had a CD4 cell count of ≥ 350 × 10⁶/l at the screening visit.

Exclusion criteria were pregnancy or risk of pregnancy in females of childbearing potential, acute illness, receiving concomitant therapy for an acute illness or a creatinine, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation of grade 3 or above at screening. Participants could not be on a regimen including NVP or a boosted PI (young people could be switched to an EFV-based regimen) or have had previous ART monotherapy (except for the prevention of mother-to-child transmission).

The age group of 8–24 years was chosen as young people between these ages are likely to undertake independent weekend activities and thus SCT could improve their quality of life by giving them more control over when they take their HIV medication, helping them to maintain their privacy regarding HIV infection and treatment taking while socialising at weekends.

Randomisation and treatment strategies

Participants were randomly assigned 1 : 1 to maintain CT or switch to SCT. Randomisation was performed centrally by the Medical Research Council Clinical Trials Unit (MRC CTU) at University College London (UCL) according to a computer-generated randomisation list, using random permuted blocks stratified by age at randomisation (8–12, 13–17 and 18–24 years) and by African compared with non-African country.

The trial sites enrolled patients and assigned participants to interventions by either accessing the trial randomisation server directly or contacting the relevant trial unit who performed the randomisation on their behalf.

Young people randomised to SCT followed a cycle of 5 days on ART (Monday–Friday or Sunday–Thursday) and 2 days off (Saturday and Sunday or Friday and Saturday). Participants randomised to the SCT arm were able to choose which 2 days off ART they preferred and whichever days were chosen were continued throughout the entire time on SCT within the study. Young people randomised to CT continued their current ART regimen and stopped or switched drugs in their ART regimen only for virological, immunological or clinical failure according to local practice. However, if simplification of the ART regimen or substitution of one drug (not EFV) was deemed necessary for clinical reasons, this was allowed after discussion with the appropriate trials unit.

Sample size

This trial planned to enrol a minimum of 160 young people, at least 80 per arm.

Assuming that 90% of young people in the CT arm and in the SCT arm maintained a HIV-1 RNA level of < 50 copies/ml to week 48, 155 young people would have provided at least 80% power to exclude a difference of 12% between the two arms (i.e. to exclude suppression rates of < 78% in the SCT arm) (one-sided alpha = 0.05). 38 A minimum of 160 young people (80 per arm) had to be enrolled to allow for loss to follow-up (in previous PENTA trials loss to follow-up has been < 3%).

The power calculations were based on the assumption that 90% of patients in the CT arm would remain virally suppressed to week 48. Any decrease in this percentage was likely to underpower the study and would lead to an equivocal result, as could other changes to the assumptions.

A sample size of 220 participants would have increased the power of the study by at least 10% for varying levels of suppression. At its meeting in December 2012, the Trial Steering Committee (TSC) recommended that the study should remain open to randomisation until the end of the defined recruitment period, even if the total number of participants enrolled exceeded 160, as this would enhance the power of the study; this was communicated to and agreed by the IDMC. The specified sample size was increased in protocol version 1.7 (dated 24 April 2013) from a recruitment target of 160 to a target of at least 160 but not exceeding 220 participants (see Appendix 1).

The trial was not formally powered to detect differences between CT and SCT, but to exclude substantial virological disadvantages [i.e. HIV-1 RNA suppression rates (< 50 copies/ml) of < 78%] in the SCT arm by following a 5 days on, 2 day off strategy, that is, a non-inferiority trial.

A non-inferiority margin of 12% was chosen to represent a clinically acceptable difference in the rate of virological suppression (HIV-1 RNA < 50 copies/ml) between the two arms and to allow the trial to be adequately powered and feasible to conduct based on estimates of available young people followed in PENTA centres.

Pilot study

The first participants randomised in the study (n = 15 in the SCT arm and n = 17 in the CT arm) were included in the pilot phase and had weekly HIV-1 RNA measurements during the first 3 weeks of the study. Those randomised to the SCT arm and included in the pilot phase stopped taking their ART on Saturdays and Sundays, that is, they followed a cycle of 5 days on ART (Monday–Friday) and 2 days off ART (Saturday–Sunday) during the pilot phase. Recruitment to the CT arm ran concurrently.

Young people in the pilot phase had four additional phlebotomy visits (HIV-1 RNA and blood store only) at weeks 1, 2, 3 and 8. For young people in the SCT arm the blood draws were on the Monday after the first, second and third weekends off ART and before ART recommenced; for young people in the CT arm these blood draws were at any time during the first, second and third weeks.

The IDMC met at the end of the pilot phase to review the interim data (see Appendix 2 for dates of all IDMC meetings).

Management of young people and viral load tests

• Pilot phase. Polymerase chain reaction (PCR) tests for HIV-1 RNA can occasionally yield spurious results suggestive of low-level viraemia. During the pilot phase only, any HIV-1 RNA measurement detected of ≥ 50 copies/ml at weeks 1, 2 or 3 was repeated on the same sample to ensure that the result was valid and reproducible.

• SCT arm. Participants with a HIV-1 RNA measurement of ≥ 50 copies/ml had a confirmatory VL measurement taken on a separate sample within 1 week. No further interruptions to ART were undertaken until the repeat test result was obtained. Participants with a confirmed viral rebound of ≥ 50 copies/ml recommenced CT and should not have undergone further interruptions to their therapy. Participants with an isolated HIV-1 RNA measurement of ≥ 50 copies/ml and a subsequent measurement of < 50 copies/ml could remain on SCT. There could be a maximum of three such occurrences during the lifetime of the study. After the third increase, CT was resumed with no further interruptions.

• CT arm. Participants with a HIV-1 RNA measurement of ≥ 50 copies/ml had a confirmatory VL measurement taken on a separate sample within 1 week. Participants with a confirmed VL of ≥ 50 copies/ml received standard clinical care.

Study duration

Young people were followed until the last randomised participant had completed 48 weeks of follow-up, at which point the main trial was considered complete. Participants who were followed after week 48 were seen every 12 weeks until the main trial was complete. Participants randomised to the SCT arm continued to follow the SCT strategy until the main trial was complete unless the clinician or the family had concerns, which the clinician discussed with the appropriate trials unit.

Following the recommendations of the TSC (December 2013) and the subsequent protocol amendment (version 1.9) and participant consent, ongoing long-term follow-up of the trial for a further 2 years commenced in July 2014 (see Appendix 1). Stable and virologically suppressed young people who were randomised to SCT can opt to continue SCT during the long-term follow-up if they have 12- to 16-week VL monitoring and if agreed by the clinician and family. Management of HIV-1 RNA VL will continue as during the main study period.

Data collection and handling

Sites in the UK and Ireland were managed by the MRC CTU, subsequently the MRC CTU at UCL. Sites in the USA, Germany, Uganda, Thailand (HIV Netherlands Australia Thailand Research Collaboration) and the Ukraine were managed by the MRC CTU at UCL in collaboration with national co-ordinators. Sites in Spain, Belgium, Denmark and Argentina are managed by the French National Institute for Health and Medical Research (INSERM SC10-US19) in collaboration with national co-ordinators. Program for HIV Prevention and Treatment (PHPT) sites in Thailand were managed directly by the PHPT.

Data were recorded on case report forms (CRFs); the completed CRFs were sent to the appropriate trials unit for data entry and a copy kept at the local clinical centre. Data from the CRFs were entered onto databases held at the co-ordinating trials units and exported into Stata 13.1 (StataCorp LP, College Station, TX, USA) for analysis. After completion, adherence and acceptability questionnaires were sent to the appropriate trials unit for data entry.

Data received at each of the trials units were checked for missing or unusual values (range checks) and for consistency within participants over time. If any such problems were identified, a missing data report of the problematic data was sent to the local site by password-protected e-mail for checking and confirmation or correction, as appropriate; any data that were changed were crossed through with a single line and initialled. The amended data were returned to the appropriate trials unit and filed in the notes at the site. The trials units sent reminders to sites under their management for any overdue and missing data.

Interim analysis

The trial was reviewed by the PENTA IDMC. No member of the PENTA Steering Committee or the BREATHER TSC or any clinician (investigator) responsible for the clinical care of trial participants could be a member of the IDMC. The IDMC reviewed all aspects of the trial, including the number of participants recruited.

The IDMC met four times in strict confidence over the course of the trial: 28 October 2011, 5 September 2012, 31 July 2013 and 7 February 2014, with the last meeting being about VL monitoring only. The IDMC was to inform the chairperson of the TSC if, in its view, the results provided either:

1. unequivocal evidence* that was likely to convince a broad range of HIV clinicians, including the study investigators, that one of the two treatment strategies (CT or SCT) was performing poorly for all participants or for a particular category of participants and there was a reasonable expectation that this new evidence would materially influence patient management or

2. good evidence* that CT was superior to SCT in terms of the primary outcome and the non-inferiority of SCT was extremely unlikely to be demonstrated with continued enrolment and/or follow-up.

*The criteria for the strength of evidence could not be defined precisely and were left to the judgement of the IDMC. However, as an example, if in an interim analysis the 99% CI for the hazard ratio for the primary outcome excluded 1, this may be considered as providing good evidence of a difference in risk between the two groups. If the 99.9% CI also excluded 1, this may be regarded as providing unequivocal evidence of a difference between the two groups.

Clinical site monitoring

Trial-related monitoring at trial sites was carried out according to the trial protocol. Trial sites had to agree to provide access to source data/documents. Consent from parents/carers/young people, as appropriate, for direct access to data was also obtained.

In addition to a site initiation (either through a visit or in a teleconference), all clinical centres were monitored at least once during the trial and the following data were validated from source documents:

• eligibility and signed consent

• clinical disease progression to new Centers for Disease Control (CDC) C event or death

• HIV-1 RNA VLs ≥ 50 copies/ml (primary end point only)

• a random sample of CD4 measurements

• a random sample of laboratory results

• a random sample of original records of ARV prescriptions (with batch numbers)

• a random sample of clinical data

• all original records of ARV prescriptions (with batch numbers) for all young people participating in the qualitative substudy.

Patient and public involvement

Polly Clayden, a patient advocate, has been an independent member of the PENTA Steering Committee for many years and was closely involved in the discussions about the protocol during its development. She works at i-Base, a treatment activist group, which is developing a young person Community Advisory Committee with the UK Children’s HIV Association (CHIVA). Members of the study team, particularly in the UK and Ireland, are closely involved with CHIVA, which promotes issues relevant to children infected or affected by HIV, including the needs of adolescents and good practice in transitional care. Collaborator Magda Conway is an independent consultant with extensive experience of working directly with young people with HIV. She has been awarded a grant by the Elton John AIDS (acquired immunodeficiency syndrome) Foundation to strengthen networks of young people living with HIV in the UK and facilitated a group discussion with MRC CTU staff and a CHIVA youth group prior to the finalisation of the study protocol. CHIVA was closely involved in developing a communication and dissemination strategy for the main trial results and created a one-page results information leaflet (see Appendix 3) that was sent out to sites to give to their patients.

Protocol changes

See Appendix 1.

Main study statistical methods

Inflammatory biomarkers substudy

Immunology substudy

Virology substudy

Qualitative substudy

Baseline characteristics

In total, 199 young people were randomised from 11 countries between 1 April 2011 and 28 June 2013 (Table 3). A Consolidated Standards of Reporting Trials diagram for the trial can be found in Figure 1.

FIGURE 1.

Consolidated Standards of Reporting Trials diagram.

Baseline demographic data were well matched between arms, with 105 (53%) male participants, a median (IQR) age of 14.1 (11.9–17.6) years and a median (IQR) weight of 45.2 (33.8–56.0) kg. In total, 35% of all young people randomised were recruited from an African site; 180 (90%) young people were vertically infected; and 41 (21%) were white, 112 (56%) were black and 37 (19%) were Asian (Table 4).

There was a minor imbalance at baseline in CDC events, with 13% of young people in the SCT arm having had a CDC stage C event compared with 21% in the CT arm. The median (IQR) CD4% at randomisation was 34.0% (29.5–38.5%) and the median (IQR) absolute CD4 count was 735.0 cells/mm³ (575.5–967.5 cells/mm³) (Table 5).

Twenty-nine (14.6%) young people had had previous exposure to PIs at randomisation, but none had switched from PIs because of virological failure, and at trial entry all young people were on regimens containing NRTIs and EFV only.

In baseline acceptability questionnaires completed by young people randomised to SCT, 70 out of 80 (87.5%) young people who answered the questionnaires said that they thought that taking weekends off treatment would make things either much easier or a little easier compared with taking ART continuously.

Follow-up

At the end of the trial, the median (IQR) follow-up time was 85.7 (62.0–118.3) weeks. Two young people, both from the CT arm, were lost to follow-up by the end of the trial, one because of leaving the country after the week 24 visit and the other because of transferring to an adult clinic and withdrawing consent after the week 48 visit. Attendance to clinic visits was good, with > 90% of young people still in follow-up attending each visit (Table 6).

Primary end point

Thirteen young people reached the primary end point by the end of the 48-week assessment, six from the SCT arm and seven from the CT arm. In the primary analysis, the estimated probability (90% CI) of reaching the primary end point was 6.1% (2.1% to 10.2%) for individuals in the SCT arm and 7.3% (2.9% to 11.7%) for those in the CT arm. The estimated difference between arms (SCT – CT) was 1.2% in favour of SCT (90% CI –7.3% to 4.9%) and so the upper bound of the 90% CI was less than the non-inferiority margin of 12% (Figure 2).

FIGURE 2.

Adjusted Kaplan–Meier estimates of time to first detected HIV-1 RNA ≥ 50 copies/ml (confirmed) up to the week 48 assessment.

Therefore, at the end of the 48-week assessment, the results are consistent with the non-inferiority of SCT compared with CT.

When not adjusting for stratification factors, the estimated probability (90% CI) of reaching the primary end point was 6.1% (3.2% to 11.7%) in the SCT arm and 7.3% (4.0% to 13.1%) in the CT arm. The estimated difference between arms (SCT – CT) was 1.1% in favour of SCT (90% CI –6.8% to 4.6%) and so the upper bound of the CI was less than the non-inferiority margin of 12% (Figure 3). Therefore, non-inferiority was demonstrated in this analysis as well as in the primary analysis.

FIGURE 3.

Kaplan–Meier graph of time to first detected HIV-1 RNA ≥ 50 copies/ml (confirmed) up to the 48-week assessment.

The crude proportion (90% CI) of young people experiencing virological failure was 0.061 (0.027 to 0.116) in the SCT arm and 0.070 (0.033 to 0.127) in the CT arm. Therefore, the estimated difference in crude proportion (90% CI) between arms (SCT – CT) was –0.009 (–0.067 to 0.048) (Table 7).

Secondary end points

Virology

The primary analysis was repeated but with the end point as a confirmed HIV-1 RNA VL of ≥ 400 copies/ml. The estimated difference between arms (SCT – CT) in the proportion of virological failure was 2.1% in favour of SCT (90% CI –6.2% to 1.9%), which is consistent with the non-inferiority of SCT compared with CT (Figure 4).

FIGURE 4.

Adjusted Kaplan–Meier estimates of time to first detected HIV-1 RNA ≥ 400 copies/ml (confirmed) up to the week 48 assessment.

Adjusted for age range (8–12, 13–17 and 18–24 years), African site and African site × age range interaction.

Week 48 assessment
Treatment arm	Number of events	Person-years at risk	Estimated probability of failinga	90% CI
SCT	2	101.35	0.021	–0.000 to 0.044
CT	4	99.72	0.042	0.010 to 0.075
Difference (SCT – CT)			–0.021	–0.062 to 0.019
				Bootstrap p = 0.381

The results when analysing without adjusting for stratification factors remained qualitatively unchanged (data not shown).

The crude proportion (90% CI) of young people experiencing virological failure (≥ 400 copies/ml) was 0.020 (0.004 to 0.062) in the SCT arm and 0.040 (0.014 to 0.089) in the CT arm. Therefore, the estimated difference in crude proportion (90% CI) experiencing virological failure between arms (SCT – CT) was –0.020 (–0.060 to 0.020) (Table 8).

TABLE 8 - Difference in proportion of young people with HIV-1 RNA ≥ 400 copies/ml (confirmed) at any time from randomisation to the week 48 assessment

Fisher’s exact test.

Treatment arm	Number of events	Estimated proportion	90% CI	p-valuea
SCT	2	0.020	0.004 to 0.062
CT	4	0.040	0.014 to 0.089
Difference (SCT – CT)		–0.020	–0.060 to 0.020	0.683

Biochemistry

There were no significant differences between arms at any clinic visit after randomisation in creatinine, bilirubin, alkaline phosphatase, AST, ALT, glucose, triglycerides, very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or total cholesterol (data not shown). A significantly higher level of LDL cholesterol was observed in the SCT arm at week 24, but this difference appears to be transient, as there was no significant difference between arms at week 36 or week 48 (Table 9 and Figure 5).

TABLE 9 - Mean change in LDL cholesterol (mg/dl) from randomisation to week 48

adj, adjusted; SE, standard error; unadj, unadjusted.

Change in LDL cholesterol calculated using linear regression of LDL cholesterol after randomisation, adjusting for baseline LDL cholesterol, presenting mean change from a baseline LDL cholesterol of 92.04 mg/dl.

Linear regression adjusted for the stratification factors (age range, African site and African site × age range interaction) in addition to baseline LDL cholesterol.

Weeks since randomisation	SCT			CT			p-value (unadj)	Adjustedb difference
	n	Mean changea	SE	n	Mean changea	SE		Meanb	SE	95% CI	p-value (adjb)
12	20	2.9	8.0	18	8.2	8.2	0.65	–3.7	11.4	–26.9 to 19.4	0.75
24	81	4.3	1.8	83	–3.8	1.8	0.00	8.4	2.5	3.4 to 13.4	0.00
36	16	–0.9	4.0	16	–3.0	3.9	0.70	5.8	5.0	–4.6 to 16.1	0.26
48	89	1.3	1.7	92	–0.3	1.6	0.49	1.5	2.3	–3.1 to 6.1	0.52

FIGURE 5.

Mean change in LDL cholesterol (mg/dl) from randomisation to week 48.

Haematology

There were no significant differences between arms at any clinic visit after randomisation in haemoglobin level, white blood cell count, lymphocyte count or neutrophil count (data not shown). However, a significantly lower platelet count was observed in the SCT arm at each week after randomisation (Table 10 and Figure 6). Additionally, a significantly lower MCV was observed in the SCT arm each week after randomisation (Table 11 and Figure 7).

TABLE 10 - Mean change in platelet count (per l) from randomisation to week 48

adj, adjusted; SE, standard error; unadj, unadjusted.

Change in platelet count calculated using linear regression of platelet count after randomisation, adjusting for baseline platelet count, presenting mean change from a baseline platelet count of 300.68/l.

Linear regression adjusted for the stratification factors (age range, African site and African site × age range interaction) in addition to baseline platelet count.

Weeks since randomisation	SCT			CT			p-value (unadj)	Adjustedb difference
	n	Mean changea	SE	n	Mean changea	SE		Meanb	SE	95% CI	p-value (adjb)
12	95	–9.8	6.0	99	12.6	5.9	0.01	–21.7	8.2	–37.8 to –5.6	0.01
24	97	–13.2	5.2	99	4.3	5.1	0.02	–17.2	7.3	–31.6 to –2.9	0.02
36	98	–16.2	5.4	96	–1.0	5.5	0.05	–15.2	7.7	–30.4 to 0.1	0.05
48	95	–13.4	6.5	94	7.4	6.6	0.03	–20.9	9.2	–39.1 to –2.6	0.03

FIGURE 6.

Mean change in platelet count (per l) from randomisation to week 48.

TABLE 11 - Mean change in MCV (fl) from randomisation to week 48

adj, adjusted; SE, standard error; unadj, unadjusted.

Change in MCV calculated using linear regression of MCV after randomisation, adjusting for baseline MCV, presenting mean change from a baseline MCV of 93.48 fl.

Linear regression adjusted for the stratification factors (age range, African site and African site × age range interaction) in addition to baseline MCV.

Weeks since randomisation	SCT			CT			p-value (unadj)	Adjustedb difference
	n	Mean changea	SE	n	Mean changea	SE		Meanb	SE	95% CI	p-value (adjb)
12	92	–3.5	0.6	98	–1.0	0.6	0.00	–2.5	0.9	–4.2 to –0.8	0.00
24	95	–3.6	0.4	97	–0.9	0.4	0.00	–2.7	0.6	–4.0 to –1.5	0.00
36	94	–3.3	0.5	94	–1.3	0.5	0.00	–2.0	0.7	–3.3 to –0.7	0.00
48	94	–3.6	0.5	93	–1.6	0.5	0.01	–2.1	0.7	–3.5 to –0.6	0.00

FIGURE 7.

Mean change in MCV (fl) from randomisation to week 48.

Adherence

Analysis of questions on compliance to SCT strategy at follow-up visits showed good compliance, with 95% of weekend breaks being taken (99% excluding time after return to CT). Self-reported adherence was similar in both arms, with 7% (29/414) reports in the SCT arm versus 10% (40/409) reports in the CT arm of missing ART in the last week (excluding weekend breaks in SCT) (p = 0.42).

Additionally, a MEMSCap substudy on a subset of 61 young people (n = 31 SCT, n = 30 CT) showed a median (IQR) number of bottle openings per week of five (4–5) in the SCT arm and seven (6–7) in the CT arm. This suggested that there was good adherence to the protocol. When investigating the percentage of bottle openings by day, the SCT arm had < 20% of bottle openings on Saturday and Sunday and > 80% on Monday–Friday, whereas the CT arm had > 80% of bottle openings on each day (Figure 8).

FIGURE 8.

Bar graph comparing the proportion of days MEMSCap opened between arms.

Finally, there was a significantly higher MCV in the CT arm than in the SCT arm at each follow-up visit after randomisation (p ≤ 0.01) (see Table 11 and Figure 7), indicating that young people in the CT arm were taking ART. A raised MCV has been associated with ZDV and, when investigating the differences in MCV between arms in young people without ZDV in their ART regimen, there was no significant difference between arms. This suggests that young people in the CT arm had a higher intake of ART per week than young people in the SCT arm.

Safety

Twenty children had a total of 27 grade 3 or 4 AEs (SCT: 13 episodes in eight young people; CT: 14 episodes in 12 young people) up to the week 48 assessment. There were five treatment-modifying AEs (SCT, n = 1; CT, n = 4) and two new CDC stage B events (SCT, n = 1; CT, n = 1). There were fewer ART-related AEs in the SCT arm, with two episodes in two young people in the SCT arm compared with 14 episodes in 10 young people in the CT arm. There were 13 SAEs in nine young people: seven episodes in six young people in the SCT arm and six episodes in three young people in the CT arm (Table 16).

The most common type of grade 3 or 4 AE was an abnormal laboratory investigation, of which there were 14 episodes in 14 young people [episodes (young people): SCT 6 (6), CT 8 (8)]. There was no significant difference in the number of young people with any grade 3 or 4 AE (see Table 16), as well as no significant difference in the grade 3 or 4 AE rate ratio, both before (p = 0.886) and after (p = 0.720) adjustment for stratification factors (Table 17).

Fewer young people had an ART-related AE in the SCT arm than in the CT arm (2 vs. 10; p = 0.033). There were fewer ART-related AEs in the SCT arm both before (p = 0.017) and after (p = 0.018) adjusting for stratification factors (Table 18).

There were no significant differences between arms in how many young people had treatment-modifying AEs, with just five treatment-modifying events in the first 48 weeks (SCT, n = 1; CT, n = 4; p = 0.369) (Table 19).

There were no significant differences between arms in how many young people had SAEs (p = 0.331). Additionally, there were no significant differences between arms in the rate ratio, both before (p = 0.836) and after (p = 0.979) adjustment for stratification factors (Table 20).

The results were presented as an oral late breaker presentation at the Conference for Retroviruses and Opportunistic Infections in February 2015 (see Appendix 4). 45 Karina Butler was also interviewed at the conference. 46

Biomarkers substudy

The results for the linear regression model for each biomarker are presented in Table 21. At 48 weeks, the only inflammatory biomarker that showed a borderline significant difference between the arms was D-dimer (p = 0.048), with lower (favourable) levels seen in the SCT arm at week 48.

Immunology substudy

CD45 naive and memory cells were collected at baseline and week 48 from 119 individuals (SCT, n = 59; CT, n = 60) and CD8 naive and memory cells were collected at baseline and week 48 from 50 individuals (SCT, n = 24; CT, n = 25). The results from linear regression models of naive/memory cell ratios are provided in Table 22. There were no significant differences between arms at week 48 with respect to the ratios of naive/memory cells. The closest to significance was the ratio of CD8RA/RO (p = 0.135).

When fitting linear regression models with the outcome variable being naive or memory cells independently and not as part of a ratio, we also found no significant differences between arms (Table 23).

Virology substudy

In total, 194 young people attended a screening visit and a week 48 visit during the trial and were therefore eligible for this analysis (SCT, n = 98; CT, n = 96). Two young people in the CT arm who had their original blood tests using an assay with a lower cut-off of > 20 copies/ml could not be retested with an ultrasensitive assay, one because there was no sample available and the other because the sample was of an insufficient volume. However, all other individuals had samples tested using an assay with a lower cut-off of ≤ 20 copies/ml (SCT, n = 98; CT, n = 94). Fifteen individuals had a VL of ≥ 20 copies/ml at screening (or week 0 if the screening visit sample was unavailable), seven from the SCT arm and eight from the CT arm. At week 48, 27 (14.1%) young people had a VL of ≥ 20 copies/ml (SCT, n = 13; CT, n = 14); as expected, this is a slightly higher proportion of individuals than had a VL of ≥ 50 copies/ml (Table 24).

The estimated proportion of individuals with a VL of ≥ 20 copies/ml at 48 weeks was 13.3% in the SCT arm and 14.9% in the CT arm, giving an estimated difference in proportion between arms (SCT – CT) of 1.6% in favour of SCT (90% CI –9.9% to 6.6%; p = 0.836) (Table 25). The upper bound of this difference lies well below the 12% non-inferiority margin (Figure 9), which is interesting to note, although the trial was not powered to investigate the difference in the proportion of individuals with a VL of ≥ 20 copies/ml.

FIGURE 9.

Estimated difference between arms in the proportion of young people with a VL of ≥ 20 copies/ml at the week 48 visit.

Of the 15 young people with a baseline VL of ≥ 20 copies/ml, only one (CT arm) developed virological failure during the first 48 weeks of the trial. This indicates that a VL of ≥ 20 copies/ml but < 50 copies/ml at baseline is not predictive of virological failure within 48 weeks.

Finally, a comparison between arms of the number of young people with a VL of ≥ 20 copies/ml at week 48 who were virally suppressed (VL of < 20 copies/ml) at screening (or week 0) showed that 12 out of 91 (13.1%) young people in the SCT arm who were virally suppressed (VL of < 20 copies/ml) at screening (or week 0) had a VL of ≥ 20 copies/ml at 48 weeks, and 12 out of 86 (14.0%) young people in the CT arm who were virally suppressed (VL of < 20 copies/ml) at screening (or week 0) had a VL of ≥ 20 copies/ml at 48 weeks (Table 26).

Table 27 and Figure 10 show that the difference between arms (SCT – CT) in the proportion of young people with VLs of < 20 copies/ml at baseline and ≥ 20 copies/ml at week 48 was 0.8% in favour of SCT (90% CI –9.2% to 7.7%; p = 1.000).

FIGURE 10.

Estimated difference in the proportion of young people with a VL of ≥ 20 copies/ml at the week 48 visit who had a VL of < 20 copies/ml at baseline.

Qualitative substudy

Main study

Children and adolescents find the commitment to taking ART every single day difficult. Previously it has been accepted that, to achieve optimal virological suppression, > 95% adherence to a daily ART regimen is necessary. 53 Many of the data underlying that assumption were generated in the era before the advent of today’s more potent regimens, now often incorporating one or more of the longer-acting ARV agents such as EFV.

We hypothesised that the pharmacokinetic properties of a drug such as EFV might be exploited to permit very short interruptions in daily ART while effectively maintaining viral suppression, in effect allowing a break in pill taking without a real break in therapy. Such a strategy, that is, SCT, could reap several benefits. Allowing breaks in taking medications at particularly difficult times, for example weekends, could help normalise the life experience for young people, reduce the problem of gradual pill fatigue, reinforce adherence during the remainder of the week and obtain similar benefits to CT in terms of virological suppression but with reduced overall drug exposure.

In this study, the non-inferiority of viral suppression in young people on EFV-based first-line ART was demonstrated for SCT compared with CT.

This global, randomised, Phase II/III study recruited 199 young people across 11 countries. With just over one-third of participants from Africa, one-fifth from middle-income countries and the remainder from Europe and the USA, we were able to study the potential utility and applicability of the strategy in diverse geographical settings. The median age of young people enrolled was 14 years and, in total, 21% were young adults (aged 18–24 years). The generalisability of the results therefore extends not only to older children and adolescents but also to the important group of young adults for whom weekend socialising often leads to missed ARV doses.

The baseline characteristics of participants in the two study arms were well matched. The minor imbalance in CDC C events, with a greater number in the CT arm, is unlikely to be meaningful given the equivalence of CD4 counts and percentage at enrolment. A major strength of this study is the excellent follow-up, with only one participant lost to follow-up before the 48-week assessment and the median duration of follow-up being 86 weeks, with > 98% of clinic visits attended.

Assuring adherence to the randomised strategy was critical to the integrity of the trial results. If those randomised to the CT arm elected of their own accord to take breaks in therapy, non-inferiority of SCT and CT might be shown, but with both arms taking breaks and having similar treatment schedules. Four independent indicators of adherence to the assigned strategy provided reassurance in this regard. The results of the self-reported compliance in the SCT arm (95% of weekends off taken), the MEMSCap substudy (median cap openings 5 for SCT vs. 7 for CT), analysis of MCV levels in ZDV recipients and self-reported adherence questionnaires in both arms were all consistent in supporting the concept that young people in the SCT arm had appropriately less ARV exposure than those on CT arm and that young people were adherent to their assigned strategy.

The overall outcome for young people in the study was excellent, with 93% remaining virally suppressed to < 50 copies/ml and 97% remaining virally suppressed to < 400 copies/ml. This may well reflect that this was a selected population, all of whom had a record of good adherence prior to study entry and none of whom had experienced virological failure. The primary study end point, confirmed VL > 50 copies/ml, was reached by only six in the SCT arm and seven in the CT arm, representing a 1.2% difference in probability of failure in favour of SCT. The study hypothesis was thus confirmed: SCT was non-inferior compared with CT for viral suppression over 48 weeks.

Although viral suppression was the primary end point of this study, it was equally important to ensure that there were no other detectable indicators of potential hazard associated with the strategy in terms of immunological compromise, emergence of viral resistance or inflammatory change. No difference in CD4 counts or CD4%, or in the emergence of major resistance mutations was detected. Although viral sequence data were not available for four out of 13 participants meeting the primary end point criteria (n = 3 SCT, n = 1 CT), all four subsequently resuppressed suggesting that the presence of resistance was unlikely.

In a previous CD4-guided long-period interruption trial, the SMART study,22 the unanticipated excess of cardiovascular events highlighted the importance of HIV infection as an inflammatory state with the potential for re-emergence of chronic inflammation in the event of treatment interruption. Incorporation of the biomarker substudy was thus an important component of this trial and provided additional reassurances with regard to the safety of the strategy.

Inflammation and immunology substudies

As presented in Chapter 4, with the exception of the D-dimer results, no significant difference was seen between the trial arms in any of the 19 biomarkers. Patients randomised to SCT had slightly lower D-dimer levels at week 48 than at baseline, which is reassuring rather than worrying. The panel of biomarkers selected was comprehensive and these results add further reassurance that SCT is safe.

Similarly there was no evidence that CD4, CD8 or naive and memory subsets were affected by SCT. This contrasts with the findings reported in the PENTA 11 study,41 in which an interruption of 48 weeks was associated with marked changes in these parameters. This indicates that, at least for the duration of the study, there was no apparent inflammatory or immunological impact of SCT using markers that have previously been shown to be perturbed following treatment interruption.

Virology substudy

Recent evidence suggests that the HIV reservoir, which is not currently assessed with available routine diagnostic methods, plays an important role in disease progression. 55 Markers quantitatively evaluating residual viraemia56 and functionally assessing the ability of the reservoir to produce replication-competent virus57 are therefore emerging as additional necessary tools in patient stratification for prognosis and optimal management. The aim of the virological substudy was to evaluate the impact of SCT and CT on the reservoir as assessed by low-level residual viraemia and total HIV-1 DNA levels.

Although there was a slightly higher proportion of individuals with a HIV-1 RNA VL > 20 copies/ml at week 48 than > 50 copies/ml at week 48, reassuringly the number of young people with a HIV-1 RNA VL > 20 copies/ml at week 48 was comparable between arms (n = 14 CT, n = 13 SCT). There was no difference between the arms at baseline when the 20 copies/ml cut-off was used, which in addition was not predictive of virological failure.

These results indicate that young people in the SCT arm were not at risk of increased low-level viraemia at the end of the trial.

Qualitative substudy

The findings from the qualitative substudy indicate that those in the SCT arm, after taking some time to adapt, expressed a preference for taking the weekends off therapy, suggesting that SCT was acceptable to them. Although promising and preferred by those in the trial to CT, SCT may not, however, be a viable option for everyone, as even ‘exemplary adherers’ encountered initial challenges in adapting to the new 5 days on/2 days off routine.

Notably, SCT was preferred by the young people in the study in part because it enabled more effective hiding of their HIV status. As SCT reduces the risk of deductive disclosure through the witnessing of treatment taking, young people were able to engage in social activities that had previously been complicated by their desire to keep their HIV treatment and/or status secret. Although positive in the short term, it is of some concern in the longer term that denial about their HIV status might be perpetuated and disclosure postponed. At some point, these same young people will be encouraged to disclose their status as they transition to adulthood and begin their sexual lives. SCT might thus unintentionally support non-disclosure for a group of people living with HIV who will have to come to terms with disclosure in the not-so-distant future.

The study highlighted patterns of non-disclosure of adherence behaviours that often prevail among young people living with HIV. 58 In addition, our data have illustrated how young people use clinical indicators to interpret whether or not to share information and to justify non-disclosure, which contributes further insights to our current understanding. This relates to the limited reporting of missed doses. The lack of necessity to disclose missed doses appears to be reinforced by the confidence that young people invest in clinical monitoring; they interpret an undetectable VL as a demonstration that recent missed doses are not significant and do not need to be reported.

The impact of medication side effects on well-being were also consistently under-reported to clinicians and possibly within the trial. Some participants had come to perceive these side effects as ‘normal’ and as they considered them to be inevitable they did not consider it worth bringing them up and discussing them further. Once again, this illustrates the significant filtering that might be involved in young people’s conversations with clinic staff. Furthermore, discussion of treatment side effects may also provide valuable insight into the disparity between the common reporting of these side effects in the qualitative study and the rare reporting in the trial, where they may not have been described as unusual or severe.

The study participants clearly do not currently discuss many of their ongoing issues around their treatment and their condition with anyone and try instead to manage by themselves. They gain confidence in not needing to mention missed doses from the trust that they invest in what an undetectable VL signifies. This is particularly problematic in terms of their openness with clinicians, the lack of which might lead to health-related harms if treatment challenges are explored or revealed too late and medical options restricted. Reinforcing the reputation of young people as ‘exemplary adherers’ may paradoxically function as both an encouragement for young people to continue to take their treatment as prescribed and a disincentive to talk about any problem that might arise, including missed doses and side effects, for fear of damaging their reputation.

Importantly, therefore, an opportunity is opened up whereby SCT has the potential to signify the beginning of a change in the conversation around adherence in the clinic, within the family and within the broader social environments inhabited by young people living with HIV. As a therapy that specifically acknowledges the adherence challenges that pertain to childhood and adolescence, if framed thoughtfully health-care staff can use SCT to show a greater contextual understanding about how treatment can be disrupted for complex reasons. By encouraging more open discussions about ‘slippages’ and how these can be managed, SCT might be able not only to support improvements in communication between health-care staff and young people living with HIV but also to lessen the significant blaming and self-blaming that can at times characterise the experience of those who cannot achieve 100% adherence to ARVs.

The study findings suggest that SCT could be used as a ‘reward’ for those who can manage to adhere well and this could sustain them on the days when they are supposed to take their medication. In addition, SCT could also function as an incentive to put more effort into taking treatment and lowering VL for those who would not currently qualify for SCT. Thoughtful planning and framing of SCT to young people is necessary for these potential benefits to be realised.

However, study participants felt that SCT could also pose a significant risk to other young people who might try to take treatment breaks without clinical assessment and monitoring. This is a further reason to support the need for careful dissemination and communication of the results post trial. Recommendations for how the intervention and its results are to be communicated beyond the trial will be discussed in the concluding sections of this chapter.

Most of all, the initial challenges described by so many of the study participants need to be taken into serious consideration when planning any further interventions based on SCT. The findings suggest that the initial adaptation period, although different for different participants, was generally only short-lived but should not be underestimated. Provided that early adjustments are carefully managed and supported, however, the study has shown that SCT can be successfully transformed into a welcome ongoing treatment option for young people living with HIV, with great benefits for children’s and adolescents’ personal and social lives.

Conclusions: implications for health care and recommendations for research

The qualitative study within the BREATHER trial has uncovered and highlighted a number of important issues that are relevant for the treatment-related support that is needed for this cohort; the trial and possible subsequent interventions based on SCT; and the direction that future clinical and social research with this age group should take so that we can better understand and effectively respond to the challenges at hand.

PENTA Steering Committee

J-P Aboulker, J Ananworanich, A Babiker, E Belfrage, S Bernardi, R Bologna, D Burger, K Butler, G Castelli-Gattinara, P Clayden, A Compagnucci, T Cressey, M Debré, R de Groot, M Della Negra, A De Rossi, A Di Biagio, D Duiculescu (deceased), A Faye, V Giacomet, C Giaquinto (chairperson), DM Gibb, I Grosch-Wörner, M Hainault, L Harper, N Klein, M Lallemant, J Levy, H Lyall, M Mardarescu, L Marques, MJ Mellado Peña, M Marczynska, D Nadal, E Nastouli, L Naver, T Niehues, C Peckham, D Pillay, J Popieska, JT Ramos Amador, P Rojo Conejo, L Rosado, V Rosenfeldt (deceased), R Rosso (deceased), C Rudin, Y Saïdi, M Sharland, HJ Scherpbier, C Thorne, PA Tovo, G Tudor-Williams, A Turkova, N Valerius, A Volokha, AS Walker, S Welch and U Wintergerst.

BREATHER Trial Steering Committee

JT Ramos Amador, J Ananworanich, A Babiker, K Butler, P Clayden, J Darbyshire, V Leroy, V Musiime and I Weller (chairperson).

BREATHER Trial Management Group

J Ananworanich, A Babiker, S Bernays, T Bunupuradah, K Butler (chairperson), J Calvert, S Chalermpantmetagul, K Chokephaibulkit, R Choudhury, A Compagnucci, T Cressey, C Giaquinto, D Gibb, L Harper, J Inshaw, J Kenny, H Kizito, N Klein, E Menson, S Montero, V Musiime, A Nanduudu, E Nastouli, M Ndiaye, JT Ramos Amador, T Rhodes, Y Riault, Y Saidi, J Seeley, K Scott, S Storey and A Turkova.

Trials units

Immunology and Virology Advisory Group

A De Rossi, N Klein, MA Muñoz Fernandez, E Nastouli and N Ngo.

Qualitative Substudy Group

S Bernays, S Paparini, T Rhodes and J Seeley.

Independent Data Monitoring Committee

A Pozniak (chairperson), S Vella, G Chène and T Vesikari.

Endpoint Review Committee

K Butler, DM Gibb and V Musiime.

Communications

Magda Conway, CHIVA.

Recruiting sites

(L = Laboratory, P = Pharmacy, S = Social Scientist.)

Contributions of authors

Professor Karina Butler (Consultant Paediatrician, Infectious Diseases Specialist and University College Dublin Clinical Professor of Paediatrics, Paediatric Infectious Diseases) devised and conducted the main study.

Jamie Inshaw (Medical Statistician and Research Associate, Statistics) was the delegated statistician for the BREATHER trial and conducted the analyses for the main study and all substudies.

Deborah Ford (Senior Statistician) was a statistician for the BREATHER trial, conducted some analyses for the main study after Jamie Inshaw left the MRC CTU at UCL and contributed to the report.

Sarah Bernays (Lecturer, Medical Sociology) was the Chief Investigator on the qualitative substudy and devised and conducted the qualitative substudy.

Karen Scott (Clinical Trial Manager, Trial Management) managed the main trial and substudies and contributed to the development and production of the report.

Julia Kenny (Senior Clinical Research Fellow and Clinical Advisor, Immunology) devised and conducted the biomarkers substudy.

Nigel Klein (Consultant and Professor, Paediatric Infectious Diseases and Immunology) devised and conducted the immunology substudy and consulted on the immunological aspects of the main study.

Anna Turkova (Senior Paediatrician) contributed to trial management, report writing and follow-up of children at the UK sites.

Lynda Harper (Clinical Project Manager, Trial Management) managed the main trial and substudies, and contributed to the development and production of the report.

Eleni Nastouli, (Consultant Virologist, Virology) devised and conducted the virology substudy and consulted on virological aspects of the main study.

Sara Paparini (Research Fellow, Medical Anthropology) assisted with the data analysis for the qualitative substudy.

Rahela Choudhury (Clinical Trial Manager, Trial Management) managed the main trial and substudies, and contributed to the development and production of the report.

Tim Rhodes (Professor, Public Health Sociology) was the Chief Investigator on the qualitative substudy and codevised the qualitative substudy.

Abdel Babiker (Professor of Epidemiology and Medical Statistics, Statistics and Epidemiology) was the statistician for the BREATHER trial and oversaw all analyses and directed appropriate analyses to be carried out.

Diana Gibb (Professor in Epidemiology and Honorary Consultant Paediatrician, Epidemiology) played a role in all aspects of the trial as the lead of the paediatric programme at the MRC, including design, trial implementation, analysis and dissemination.

Publication

The BREATHER (PENTA 16) Trial Group. 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. [published online ahead of print 20 June 2016]. Lancet 2016.

Data sharing statement

Data sharing requests can be made to the corresponding author.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health.

Independent Data Monitoring Committee

• 28 October 2011.

• 5 September 2012.

• 31 July 2013.

• 7 February 2014.

Trial Steering Committee

• 16 December 2010.

• 16 December 2011.

• 16 December 2012.

• 19 December 2013.

• 18 December 2014.