REINItiation of Antiretroviral Therapy Using Oral bicTegravir, emtrIcitAbine and Tenofovir alafenamidE

A Multi-Center, Single-Arm, Open-Label, Prospective, Phase 4 Study to Investigate the Safety and Efficacy of Rapidly Restarting Oral Bictegravir, Emtricitabine, and Tenofovir Alafenamide (B/F/TAF) in Viremic and Virologically-Suppressed Male and Female HIV-Positive Patients Aged ≥18 Years Who Are Treatment-Experienced and Returning to Care After Experiencing a Treatment Interruption of ≥12 Weeks

Managing HIV well requires taking antiretroviral therapy (ART) every day, but many people living with HIV experience interruptions in their treatment. These pauses in medication can happen for many reasons, such as side effects, challenges with getting to the clinic, personal circumstances, stigma, or difficulties with everyday life. When HIV treatment is stopped, the viral load can increase, which may affect a person's health and make it easier for HIV to be passed on to others. Restarting treatment quickly after an interruption is important for both personal and public health. However, it can be difficult for people who miss doses to get back on treatment right away. There are often several steps and medical appointments required before restarting, such as waiting for lab results or reviewing medical history, which can cause further delays. These additional steps can make it even harder for people to re-engage and may discourage them from returning to care.

The REINITIATE study is designed for people living with HIV who have not taken any antiretroviral medications for at least the last 12 weeks. The study will offer participants a way to restart their HIV therapy quickly, by beginning treatment with B/F/TAF on the same day that they return to care. B/F/TAF is a widely used, once-daily HIV regimen, and is recommended in national treatment guidelines.

Researchers want to find out if this rapid restart approach is safe and effective, and whether it helps people regain control of HIV and remain in care. The study will also examine how many participants are able to keep the virus at a low level (viral suppression), stay engaged in their HIV care, and tolerate the medication after rapidly restarting treatment. In addition, the study will include interviews with some participants, to gain a better understanding of why they stopped taking their medications and what supported their return to treatment. These insights could help healthcare teams develop better ways to support people living with HIV in the future.

This prospective, multicenter, open-label, single-arm, Phase 4, interventional study aims to evaluate rapid antiretroviral therapy (ART) restart with bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in participants' routine clinical environments, facilitating data collection on treatment effectiveness and safety following same-day ART reinitiation amongst treatment-experienced people with HIV (PWH) who have had a treatment interruption of at least 12 weeks. This study will also characterize reasons for ART interruption and reinitiation.

B/F/TAF, a three-drug combination of bictegravir (B; a second-generation HIV-1 integrase strand transfer inhibitor [INSTI]), and emtricitabine (F) and tenofovir alafenamide (TAF), both nucleoside reverse transcriptase inhibitors (NRTIs), is a recommended initial ART regimen for most people with HIV in the United States. B/F/TAF is an oral, once-daily fixed-dose combination (FDC) that provides a potent and well-tolerated regimen for the treatment of HIV-1 infection in people, including those with some pre-existing resistance and subpopulations that are underrepresented in clinical trials, including Black, Hispanic, and Latine PWH, PWH ≥65 years old, and pregnant adults.

The rapid restart nature of this study involves the concurrent initiation of screening, baseline assessments, and administration of B/F/TAF on the same day. B/F/TAF is the only guideline-recommended single tablet regimen (STR) suitable for rapid restart, as it can be prescribed without prior knowledge of baseline laboratory parameters, including viral load, hepatitis B virus (HBV) status, or baseline genotypic resistance testing. This means the study treatment commences without baseline test results, provided the participant fulfills all eligibility criteria.

There will be two Cohorts of participants within this study: Cohort 1 will include viremic participants (defined by HIV-1 RNA ≥50 copies/mL) at baseline and Cohort 2 will include virologically suppressed participants (defined by HIV-1 RNA <50 copies/mL) at baseline. The study will aim to recruit 125 participants into Cohort 1 while simultaneously recruiting into Cohort 2 (it is assumed approx. 15-75 participants). The ratio of participants in Cohort 1 and Cohort 2 will be monitored during enrollment. Adherence and drop-out rates will be closely monitored throughout the study to mitigate the risk of insufficient sample sizes to power the planned analyses. Each participant's total study participation duration will be up to 48 weeks for data collection. Participants will be followed prospectively for 48 weeks in Cohort 1 and for 24 weeks in Cohort 2. Optional, semi-structured interviews will be conducted for a subset of participants in Cohorts 1 and 2 via teleconference at week 4 and week 24 after baseline screening and treatment reinitiation. While sample size will be informed by theoretical saturation, ~30 participants (15 per Cohort) is estimated to be sufficient.

Achieving viral suppression (defined as HIV-1 RNA <50 copies/mL) is the main goal of ART therapy for PWH who are viremic, and the primary objective of this study. It has been associated with improvements in CD4 cell counts, prevention of HIV drug resistance, AIDS- and non-AIDS-related events, and decreased transmission to sexual partners of PWH. Secondary outcomes include safety, resistance, persistence and adherence, and a range of patient-reported outcomes to understand patient experiences of ART.

Inclusion Criteria:

• ≥18 years of age at the time of signing the informed consent form (ICF)
• Diagnosis of HIV-1 confirmed by any positive HIV 4th generation test or detectable HIV-1 RNA level in >6 months
• Previously received ART for ≥30 consecutive days, as self-reported
• No ART dose received for ≥12 weeks prior to provision of informed consent, by any route of administration (i.e., injection or oral), as self-reported
• Returning to care with an interest to restart ART therapy
• Body weight ≥55.12lbs (25 kg)
• Signed ICF as described in the protocol which includes compliance with the requirements and restrictions listed in ICF and study protocol

Exclusion Criteria:

• Diagnosis of HIV-2 infection
• Known or suspected history of severe hepatic impairment (Child-Pugh Class C)
• Known or suspected history of severe renal impairment (estimated creatinine clearance [eCrCl] <30 mL/min)
• Concomitant medication that is contraindicated with B/F/TAF
• Known or suspected resistance to BIC (resistance-associated mutations [RAMs] include: G118R, Y143C/H/R, Q148H/K/R, N155H/S, or R263K in the integrase gene)
• Known/suspected resistance to tenofovir (TFV) (RAMs include: K65R/E/N, or K70E)
• Known/suspected history of 3 or more thymidine analog mutation (TAMs) (M41L, D67N, K70R, L210W, T215F/Y, and K219Q/E/N/R), T69-insertions, or K65R/E/N in reverse transcriptase (RT)
• History of B/F/TAF intolerance
• Unable to swallow whole tablets or swallow tablets cut into halves
• Unable to communicate in either English or Spanish