Triggered Escalating Real-time Adherence (TERA) Intervention

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:

• 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).
• Accrual was closed before reaching the target enrollment of 120 participants on the recommendation of the Study Monitoring Committee (September 30, 2019).
• 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:

• 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.
• 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.
• 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.

Inclusion criteria

• Confirmation of HIV-1 Infection as documented in the participant's medical record by at least two of the following criteria:

• Reactive HIV screening test result with an HIV antibody or HIV antibody/antigen-based, Food and Drug Administration (FDA)-licensed assay followed by a positive supplemental assay (e.g., HIV-1 Western Blot, HIV-1 indirect immunofluorescence, HIV-1/HIV-2 discriminatory immunoassay);
• Plasma HIV-1 quantitative ribonucleic acid (RNA) assay >1,000 copies/mL;
• Positive HIV-1 deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) assay; or
• Positive plasma HIV-1 RNA qualitative assay
• Participant aware of his or her HIV infection, as determined by site staff
• Documented plasma HIV-1 RNA plasma ≥200 copies/mL within 45 days of the date of the enrollment visit
• Prescribed antiretroviral therapy for at least 24 weeks or more prior to documented plasma HIV-1 RNA plasma ≥200 copies/mL.
• Prescribed a once-daily (one or more pills once a day) ART regimen with at least two active agents (per clinician judgment or genotype evidence) at enrollment
• Able to communicate in spoken and written English
• Currently has a cellular phone that is also able to send and receive text messages
• Willing and able to provide at least one additional contact phone number (preferably two) to contact participant
• Able and willing to provide written informed assent/consent and able to obtain written parental or guardian permission (if required as specified by the site, by state law, and/or Institutional Review Board policy, and detailed in each site's Protocol Implementation Plans) to be screened for and to enroll in this study

Exclusion criteria

• Gross cognitive limitations, acute emotional instability, or medical or mental health illness that in the opinion of site personnel would impair the individual's ability to provide informed consent and/or interfere with the protocol's objectives
• Concurrent participation in interventional studies addressing adherence unless approved in advance by study team
• Positive pregnancy test at the time of enrollment. If participant becomes pregnant while on study, they may continue on study
• Currently using or planning to use an electronic dose monitoring and reminder device outside of the study