HIV, HIV -1 Infection, HIV 1 Infection, HIV (Human Immunodeficiency Virus)
Conditions
Keywords
HIV-1, HIV Infections, Bictegravir, Emtricitabine, Tenofovir Alafenamide, Antiretroviral Therapy, Antiretroviral Therapy, Highly Active, Treatment Interruption, Virologically Suppressed, Treatment-Experienced, Returning to Care, Phase 4, B/F/TAF, B/F/TAF; bictegravir, emtricitabine, tenofovir alafenamide, drug combination, Rapid Restart
Brief summary
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.
Detailed description
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.
Interventions
DRUGBictegravir, emtricitabine, and tenofovir alafenamide
Oral, film-coated tablet containing 50 mg BIC, 200 mg FTC, and 25 mg TAF taken once daily with or without food administered for 24 or 48 weeks.
Sponsors
CAN Community Health
Gilead Sciences
Midway Specialty Care Center
Costello Medical Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is an open-label, non-randomized study without a control group. 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. The study treatment commences without all baseline test results being available, provided the participant fulfills all eligibility criteria. All eligible participants commence on the same oral, once-daily, fixed-dose combination of B/F/TAF which is a single-tablet regimen of 50 mg of bictegravir (BIC), 200 mg of emtricitabine (FTC), and 25 mg of tenofovir alafenamide (TAF). Once baseline assessment of viral load results are available participants are allocated into the relevant cohort which defines the duration of their study intervention. Cohort 1 (48 week follow up) will include viremic participants (HIV-1 RNA ≥50 copies/mL) at baseline and Cohort 2 (24 week follow up) will include virologically suppressed participants (HIV-1 RNA \<50 copies/mL) at baseline.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of participants in Cohort 1 with plasma HIV-1 RNA <50 copies/mL | Week 24 | Percentage of all participants who have plasma HIV-1 RNA Viral Load \<50 c/mL at W24 using FDA snapshot analysis, which defines a participant's virologic response status using only the viral load at the predefined timepoint within a certain window of time, along with study drug discontinuation |
| Percentage of participants in Cohort 2 with plasma HIV-1 RNA ≥50 copies/mL | Week 24 | Percentage of all participants who have plasma HIV-1 RNA Viral Load ≥50 c/mL at W24 using FDA snapshot analysis, which defines a participant's virologic response status using only the viral load at the predefined timepoint within a certain window of time, along with study drug discontinuation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of participants meeting protocol-defined virologic failure (PDVF) criteria in Cohort 1 | 48 weeks | Percentage of participants meeting PDVF criteria through Weeks 24 and 48. For Cohort 1, PDVF will be defined as Suboptimal Virologic Response, in which HIV-1 RNA ≥50 copies/mL and less than 1 log10 HIV-1 RNA reduction from Day 1 at the W12 visit, or Virologic Rebound, in which at any timepoint after achieving HIV-1 RNA \<50 copies/mL, a subsequent HIV-1 RNA measurement is noted to be ≥50 copies/mL, which is then confirmed at the following scheduled or unscheduled visit |
| Percentage of participants meeting PDVF criteria in Cohort 2 | 24 weeks | Percentage of participants meeting PDVF criteria through Weeks 24 and 48. For Cohort 2, PDVF will be defined as Confirmed Virologic Rebound, in which at any visit after Day 1, a rebound in HIV-1 RNA to ≥50 copies/mL, which is subsequently confirmed at the following scheduled or unscheduled visit, or any participant with HIV-1 RNA ≥50 copies/mL at the last on-treatment study visit (including E/D, lost to follow-up, or study endpoints) |
| Absolute and change from baseline in log10 HIV-1 RNA viral load of participants | 48 weeks | Absolute and change from baseline in log10 HIV-1 RNA viral load at Weeks 12, 24, and 48 |
| Absolute and change from baseline CD4 T-cell count of participants | 48 weeks | Absolute and change from baseline CD4 T-cell count at Weeks 12, 24, and 48. The CD4 T-cell count will be determined using the participant's blood sample. This test serves as a marker of immune system integrity and is used to evaluate immune suppression and disease progression, and monitor B/F/TAF efficacy |
| Percentage of participants discontinuing due to adverse events (AEs) or intolerability | 48 weeks | Percentage of patients discontinuing study treatment due to AEs or other intolerability through Weeks 24 and 48 |
| Percentage of participants experiencing treatment-emergent Grade 3-4 laboratory abnormalities | 48 weeks | Incidence of new Grade 3-4 lab abnormalities through Weeks 24 and 48 |
| Percentage of participants experiencing treatment-emergent Grade 3-4 drug-related adverse events | 48 weeks | Incidence of Grade 3-4 adverse events considered drug-related through Weeks 24 and 48 |
| Percentage of Participants experiencing Serious Adverse Events (SAEs) | 48 weeks | Incidence of SAEs through Weeks 24 and 48. All SAEs will be collected from the date of the first dose of the study drug until the end of on-study treatment + 30 days |
| Baseline resistance to B/F/TAF | 4 weeks | Proportion of participants with pre-existing genotypic or phenotypic resistance to any component of B/F/TAF at study entry |
| Treatment-emergent resistance in PDVF participants in Cohort 1 | 48 weeks | Proportion of participants with PDVF who develop treatment-emergent genotypic or phenotypic resistance to any component of B/F/TAF. For Cohort 1, PDVF will be defined as Suboptimal Virologic Response, in which HIV-1 RNA ≥50 copies/mL and less than 1 log10 HIV-1 RNA reduction from Day 1 at the W12 visit, or Virologic Rebound, in which at any timepoint after achieving HIV-1 RNA \<50 copies/mL, a subsequent HIV-1 RNA measurement is noted to be ≥50 copies/mL, which is then confirmed at the following scheduled or unscheduled visit |
| Treatment-emergent resistance in PDVF participants in Cohort 2 | 24 weeks | Proportion of participants with PDVF who develop treatment-emergent genotypic or phenotypic resistance to any component of B/F/TAF. For Cohort 2, PDVF will be defined as Confirmed Virologic Rebound, in which at any visit after Day 1, a rebound in HIV-1 RNA to ≥50 copies/mL, which is subsequently confirmed at the following scheduled or unscheduled visit, or any participant with HIV-1 RNA ≥50 copies/mL at the last on-treatment study visit (including E/D, lost to follow-up, or study endpoints) |
| Total satisfaction score on the HIV Treatment Satisfaction Questionnaire - Status Version (HIVTSQs) | 48 weeks | Total score at Weeks 4, 24, and 48 on the HIVTSQs on a scale of 0 (very dissatisfied) to 6 (very satisfied) |
| Change from Week 4 on the Total HIV Treatment Satisfaction Questionnaire - Status Version (HIVTSQs) score | 48 weeks | Change in total HIVTSQ satisfaction score from Week 4 to Weeks 24 and 48 on a scale of 0 (very dissatisfied) to 6 (very satisfied) |
| Total and change from baseline in the symptom distress score on the HIV-Symptom Index (HIV-SI) | 48 weeks | Total score and change from baseline at Weeks 4, 24, and 48 on the HIV-SI on a scale of 0 ("I do not have this symptom") to 4 ("It bothers me a lot") |
| Health-related quality of life by EuroQol 5-Dimension 5-Level (EQ-5D-5L) total score and change from baseline | Week 4 | Total EQ-5D-5L score and change from baseline at Weeks 4, 24, and 48 with a scale ranging from 0 (the worst health you can imagine) to 100 (the best health you can imagine) |
| Reasons for prior ART discontinuation and current reinitiation | Baseline | Participant-reported reasons for previous ART discontinuation and for reinitiation at study entry |
| Proportion of participants lost to follow-up | Week 48 | Participants with no study contact through Week 48 |
| Proportion of participants on study drug with documented clinic visit | Week 48 | Participants taking study drug at Week 48 who have a clinic visit within 90 days after their post-treatment safety follow-up visit (Week 48 + 30 days) |
| Adherence to B/F/TAF by pill count or dried blood spot (DBS) | Week 48 | Adherence rate as measured by pill counts or DBS at scheduled and/or unscheduled visits through Week 48 |
| Percentage of participants with plasma HIV-1 RNA <50 copies/mL | 48 weeks | Percentage of participants with HIV-1 RNA \<50 copies/mL assessed at Weeks 12, 24, and 48, using FDA snapshot analysis and missing values excluded |
| Participant experiences returning to care after HIV treatment interruption | Week 24 | Semi-structured qualitative interviews will be conducted at Weeks 4 and 24 to investigate the experience of PWH who are returning to care after interrupting treatment, including barriers to initial retention in care and reasons for disengagement, motivators for re-engagement with care, as well as barriers to this process, perceptions about future risk of disengagement with care following re-engagement, and impact of restarting treatment on first visit with B/F/TAF |
| Percentage of participants with plasma HIV-1 RNA <200 copies/mL | 48 weeks | Percentage of participants with HIV-1 RNA \<200 copies/mL assessed at Weeks 12, 24, and 48, using FDA snapshot analysis and missing values excluded |
Countries
United States
Contacts
CONTACTPrerak Shukla, MD
CONTACTMiranda Townsend
PRINCIPAL_INVESTIGATORJessica Altamirano, MD
CAN Community Health
PRINCIPAL_INVESTIGATORHector Bolivar, MD
Midway Specialty Care Center
Outcome results
None listed