Triggered Escalating Real-time Adherence (TERA) Intervention
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional

Summary: 
      Youth Living with HIV (YLWH) often face unique challenges achieving high and sustained rates
      of adherence to their antiretroviral therapy (ART). Poor adherence can lead to unsuppressed
      virus, more advanced HIV disease and poorer health outcomes, eventually exhausting treatment
      options. To date however, there are few demonstrated interventions for youth failing first
      line therapy. This study evaluated a novel intervention that used remote coaching through
      video enabled counseling sessions, an Electronic Dose Monitoring (EDM) pill bottle that
      notified an adherence coach when youth failed to open/close the device around dose time, and
      problem solving outreach by the coach in response to not dosing from the EDM. This intensive
      'boot camp' strategy was implemented for 12 weeks followed by observation through 48 weeks.
    

Detailed description: 
      This was a Phase II, two-arm, randomized, open-label study. Eligible participants had failed
      ART therapy, defined as having a detectable plasma Human Immunodeficiency Virus - Type 1
      Ribonucleic Acid (HIV-1 RNA) ≥200 copies/ml within 45 days of enrollment despite having been
      prescribed ART for at least 24 weeks. They could continue the same ART regimen or start a new
      once daily regimen. Participants were stratified by age (<18 vs. ≥18 years of age) and
      randomized in equal proportions to receive the study intervention (TERA) or standard of care
      (SOC), with no enrollment limits in each stratum. Target accrual was 120 participants to be
      enrolled over one year.

      TERA was a time-limited (12 weeks) intervention approach that (a) used wireless electronic
      dose monitoring (EDM) to identify dose-times passing with no bottle opening, (b) sent a text
      asking about the delay, (c) evaluated response to the text and (d) initiated follow-up by an
      adherence coach depending on the response and if the bottle remained unopened for a
      designated period post dosing. Phone based outreach used problem solving discussion with an
      adherence coach, who could use an agreed-upon contact tree to reach the youth through other
      individuals. This "boot camp" strategy was used to unsettle or disrupt established
      non-adherence behaviors and factors promoting ongoing non-adherence.

      Participants were followed for 48 weeks, with clinic visits at entry and weeks 4, 12, 24, 36
      and 48. Audio computer assisted self-interviews (ACASI) were conducted every 12 weeks to
      collect information on adherence, motivation and skills, social support, mental and physical
      health functioning. Viral loads, medication and medical histories were also collected at each
      study visit.

      The primary objective of the study was to compare HIV-virologic suppression (VLS) rates at 12
      weeks. Secondary objectives included comparing VLS rates and EDM rates of ART adherence at
      24, 36, and 48 weeks as well as patterns of adherence over time.

      Major changes after the start of enrollment:

        1. To address lower than anticipated enrollment, the requirement that participants be
           failing first line ART was dropped in Protocol Version 2.0 (May 9, 2018).

        2. Accrual was closed before reaching the target enrollment of 120 participants on the
           recommendation of the Study Monitoring Committee (September 30, 2019).

        3. Coronavirus disease of 2019 (COVID-19) Updates: On March 20, 2020, the TERA study
           suspended all study activities due to COVID-19. On May 5, 2020, sites were allowed to
           resume TERA study activities whenever their institution allowed human subjects research
           to resume. Participants were encouraged to return for their final Week 48 clinic visits.

      At the time of the study pause, data collection for the Primary Outcome Measures was
      complete, so the analyses proposed in the original Statistical Analysis Plan were not
      affected. Follow-up for the Secondary Outcome Measures involving HIV-1 RNA measurements and
      adherence was incomplete, with 33% of participants still on study. Because of the possibility
      that participant behavior and adherence to ART would differ pre- and post-pandemic, and it
      would not be possible to collect HIV-1 RNA measurements within the required visit windows
      (sites were actively trying to keep patients from coming into care unless urgently needed),
      the Study Team decided to base analyses on data collected prior to the COVID-19 study pause.
      In addition, because the secondary virologic outcome measures were a combination of HIV-1 RNA
      levels and data completeness (classifying participants with no HIV-1 RNA measurement within
      the allowed visit window as "virologic failures"), the analysis population for these outcome
      measures only included participants with sufficient time on study to reach each study visit.

      These changes were implemented on June 2, 2020 in a Letter of Amendment (LOA) to TERA
      Protocol Version 3.1. The LOA detailed three modifications due to COVID-19 study visit
      suspension, but did not affect the existing protocol:

        1. Extension of Week 48 visit window through the end of data collection (October 12, 2020)
           for participants on-study as of March 20, 2020, due to COVID-19 study suspension.

        2. Changed all secondary outcome measures to apply only to data collected prior to COVID-19
           study suspension on March 20, 2020. Only participants who had been on study long enough
           to reach the Week 24, 36 or 48 study visits were included in the analyses.

        3. Virtual/remote site monitoring was implemented for all remaining site monitoring visits.

      On September 24, 2020, the Study Team released a memo to the sites extending the date for the
      Week 48 study visit to October 12, 2020.

      Results for secondary outcome measures 3 to 8 are based on the pre COVID-19 study pause
      database as of March 20, 2020.

      Results for secondary outcome measures 9 and 10 are based on the complete study database as
      of October 12, 2020.
    

Intervention name(s): TERA Intervention (TERA); Standard of Care (SOC)
Intervention type(s): Behavioral; Behavioral
Intervention description(s): A sequence of adherence support strategies implemented at care visits and as needed on the basis of EDM data. Components include: (1) remote education/preparation with an adherence coach conducted with VSee software (video conferencing) at site at baseline, week 4 and week 12; (2) one-way text alert at dose time when bottle has not yet been opened for that dosing window (users can disable this on request); (3) missed dose two-way outreach text asking "What's the plan?" which gets sent to both the participant's phone and a study phone; and (4) implementation of the coach-outreach (phone, text, remote counseling) triggered by missed doses or as a check-in to inquire about the well-being of the youth (once per week when no other contact with coach occurred the week prior).; Cell-phone reminders, patient-education, adherence planning (medication management), and checking-in on adherence at clinical care visits, as well as Viral load (VL) monitoring with patient feedback on VL, are used at sites. Less common, but available as a general service at some sites, on several websites, and at many pharmacies, youth may also receive text messages at dose times, for appointment reminders, and for refill reminders.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a Phase II, two-arm, randomized, open-label study.
Masking: None (Open Label)
Primary purpose: Supportive Care
Keywords: Adherence, Medication