The purpose of this study was to compare the efficacy, safety, and durability of two different strategies to treat participants with a history of sub-optimal adherence and control of their HIV infection: long-acting (LA) antiretroviral therapy (ART) and all-oral standard of care (SOC).

This study compared the efficacy, safety, and durability of two different strategies to treat participants with a history of sub-optimal adherence and control of their HIV infection: long-acting (LA) antiretroviral therapy (ART) with rilpivirine (RPV) LA and cabotegravir (CAB) LA versus all-oral standard of care (SOC).

As the study was originally designed, the study included four steps.

Step 1, Induction

Previously non-adherent individuals were enrolled and underwent a period (up to 24 weeks) of induction SOC ART regimen using conditional economic incentives (CEI). Participants who achieved virologic suppression criteria at or after Step 1, week 4, defined as: a) HIV-1 RNA ≤200 copies/mL or b) HIV-1 RNA of 201-399 copies/mL followed by HIV-1 RNA ≤200 copies/mL by Step 1, week 24, were eligible to enter Step 2.

Step 2, Randomization

Eligible participants were randomized at Step 2 entry in a 1:1 ratio to either of the two treatment arms:

Arm A (LA ART): A combination of oral RPV + oral CAB for 4 weeks (optional) followed by the LA ART Phase, consisting of a two-drug regimen using RPV-LA + CAB-LA Q4 weeks until the end of Step 2 (Table 5.2.1-2). The option to initiate LA ART at the Step 2 Randomization visit without oral RPV + oral CAB was at the discretion of the site investigator of Record (IoR) and participant (see section 2.1, Direct-to-Inject).

Arm B (SOC): Continuation of the SOC for 52 weeks.

Step 3, Continuation/Crossover

Arm A participants continued on RPV-LA + CAB-LA Q4 weeks for 52 weeks until the end of Step 3. Arm B participants (continuation of SOC) who achieved virologic suppression (HIV-1 RNA ≤200 copies/mL) at Step 2, week 48, or HIV-1 RNA of 201-399 copies/mL at Step 2, week 48, followed by HIV-1 RNA ≤200 copies/mL by Step 2, week 52, had the option to cross over at the end of Step 2 to oral RPV + oral CAB for 4 weeks (optional) followed by RPV-LA + CAB-LA every 4 weeks until the end of Step 3 (Table 5.2.1-3). Arm B participants who did not wish or were not eligible to cross over completed study follow-up at Step 2, week 52.

If RPV-LA + CAB-LA became available before a participant finished Step 3, and the participant chose to continue RPV-LA + CAB-LA as part of their clinical care, their follow-up in the study ended at the completion of Step 3. If for some reason the participant chose not to continue LA ART at the end of Step 3 or if LA ART was not available, the participant registered to Step 4 and was followed on locally sourced oral ARV for 52 weeks.

Step 4, Observation

Participants who registered to Step 4 were followed for up to 52 weeks on oral ART. In addition, any participant who received at least one dose of CAB-LA or RPV-LA at any step, and prematurely discontinued the LA ART prior to the end of Step 3, completed their respective Step (either Step 2 or 3) on study/off study treatment, and registered to Step 4 and were followed to complete 52 weeks total on oral ART after their last dose of any LA injectable.

If LA ART became available during follow-up in Step 4, and the participant and provider decided to restart LA ART, they were allowed to do so. In that case, the participants were not followed by the study after restarting LA ART.

On February 12, 2024, based on the interim efficacy results, Data Safety and Monitoring Board (DSMB) recommended stopping randomization to Step 2 and transitioning all eligible participants in Steps 1 and 2 to LA-ART. Per recommendations from DSMB, randomization into Step 2 stopped on February 16, 2024, leaving three steps in the current study protocol 4.0:

In Step 1, participants will receive a SOC oral induction regimen consisting of an ART regimen that involves at least 3 drugs for 24 weeks. Participants who achieve milestones will receive conditional economic incentives. With randomization into Step 2 ended, all eligible Step 1 participants will register to Step 3 at the completion of Step 1.

Participants who are currently on Step 2:

Eligible participants in Step 2 Arm A (already on RPV-LA + CAB-LA) will register to Step 3 and continue on this regimen until the end of Step 3 (52 weeks; See protocol for more information). This should happen at the next scheduled study visit after approval of Version 4.0.

Eligible participants in Step 2 Arm B (SOC arm) will register to Step 3 and switch to oral RPV + oral CAB for 4 weeks (optional; see protocol for more information) followed by RPV-LA + CAB-LA Q4 weeks until the end of Step 3 (52 weeks). This should happen at the next scheduled study visit after approval of Version 4.0.

Eligible participants will enter Step 4 and be followed up to 52 weeks on locally sourced oral ART.

Participants will be followed for up to a total of 180 weeks. Study visits, which will occur throughout the study, may include physical examinations; blood, urine, and hair collection; liver function tests; questionnaires; and an electrocardiogram (ECG).

NOTE: Data summarized in the primary analysis report were based on evaluations undertaken at visits conducted prior to the implementation of Protocol v4.0 which incorporated February 12, 2024 DSMB recommendations. Primary analyses were outlined in the A5359 primary Statistical Analysis Plan (SAP) version 6.0 (dated August 5, 2024) focusing on follow-up in Step 1 and Step 2.

Step 1 Inclusion Criteria

HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.

NOTE: The term "licensed" referred to an FDA-approved kit, which was required for all IND studies.

WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandated that confirmation of the initial test result had to use a test that was different from the one used for the initial assessment. A reactive initial rapid test had to be confirmed by either another type of rapid assay or an E/CIA that was based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.

HIV-1 Plasma viral load (VL) greater than 200 copies/mL within 12 months prior to study entry by any US laboratory that had a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, unless the participant had been lost to clinical follow-up (see protocol for more information) and no viral load result was available within the last 12 months.

NOTE: Participants who satisfied non-adherence eligibility due to loss to clinical follow-up might not have had a viral load result available at the time of consideration for eligibility. Those participants could be screened and, regardless of their screening viral load result (either ≤ or >200 copies/mL), they would have been eligible for study entry if they met all other inclusion/exclusion criteria.

Evidence of non-adherence to ART according to at least one of the following criteria:

Poor virologic response within 18 months prior to study entry (defined as less than 1 log10 decrease in HIV-1 RNA or HIV-1 RNA greater than 200 copies/mL at two time points at least 4 weeks apart) in individuals who had been prescribed ART for at least 6 consecutive months.

Lost to clinical follow-up within 18 months prior to study entry with ART non-adherence for greater than or equal to 6 consecutive months.

NOTE: Lost to clinical follow-up was defined as either no contact with the provider or missing greater than or equal to 1 appointment in a 6-month period. ART non-adherence was defined as a lapse in ART greater than or equal to 7 days (consecutive or non-consecutive), in the 6-month period where they were lost to clinical follow-up per participant report.

No evidence of any clinically relevant RPV or INSTI resistance-associated mutations (see protocol for more information) through commercially available genotypic (or phenotypic, if available) analyses from any laboratory that had a CLIA certification or equivalent within 60 days of study entry (see protocol for more information), nor history of such mutations on review of prior HIV-1 drug resistance tests by the site investigator. For participants in whom a screening HIV-1 conventional genotype could not be resulted by the testing laboratory, review of historical genotypes and treatment history by the IoR could be used to satisfy this criterion as indicated in the protocol.

Ability of site clinician, in conjunction with the participant, to construct an oral induction antiretroviral (ARV) regimen that had to include at least three ARVs of which at least two had to be predicted to be fully active. The regimen had to include PI/cobi and/or an INSTI based on screening and/or historic resistance testing.

Laboratory values obtained within 60 days prior to study entry by any laboratory that had a CLIA certification or its equivalent:

Hemoglobin greater than or equal to 9.0 g/dL

Absolute neutrophil count (ANC) greater than or equal to 600/mm^3

Alanine aminotransferase (ALT) less than or equal to 3 x upper limit of normal (ULN)

Creatinine Clearance (CrCl) greater than or equal to 50 mL/min estimated by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-Epi).

For participants of reproductive potential, a negative serum or urine pregnancy test with a sensitivity of less than or equal to 25 mIU/mL at screening. This was repeated again at study entry.

NOTE: Participants were considered to be NOT of reproductive potential if: 1) they had had amenorrhea for at least 12 consecutive months prior to study entry (i.e., who had had no menses within 12 months prior to study entry), and had a documented follicle-stimulating hormone (FSH) greater than 40 IU/mL; OR 2) an FSH level was not available, but they had had 24 consecutive months of amenorrhea (in the absence of medications known to induce amenorrhea); OR 3) they reported having undergone surgical sterilization (e.g., hysterectomy, or bilateral oophorectomy, or bilateral tubal ligation/hysteroscopic tubal occlusion).

Contraception Requirements

Participants of Reproductive Potential: Participants of reproductive potential, who were participating in sexual activity that could lead to pregnancy, had to agree to use at least one of the listed highly effective methods for contraception from 30 days prior to the first dose of study medication, while receiving the study drugs, and for 30 days after stopping oral medications, or the duration specified in the product label if receiving study drugs not supplied by the study, or 52 weeks after stopping RPV-LA or CAB-LA. Acceptable methods of contraception included:

Contraceptive subdermal implant

Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive

Injectable progestogen

Contraceptive vaginal ring

Percutaneous contraceptive patches

Participants Who Were Not of Reproductive Potential: Participants who were not of reproductive potential were eligible to start study drugs without requiring the use of contraceptives. Any statement of self-reported sterility or that of her partner's had to be entered in the source documents.

NOTE A: Acceptable documentation of lack of reproductive potential was the participant's self-reported history of surgical sterilization, menopause, or male partner's azoospermia.

NOTE B: ALL participants in the study were to be counseled on safer sexual practices including the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV transmission to a partner without HIV.

Ability and willingness of participant or legal guardian/representative to provide written informed consent.

Step 1 Exclusion Criteria

Currently pregnant, planning to become pregnant during the study period, or currently breastfeeding.

Participants determined by the Site Investigator to have had a high risk of seizures, including participants with an unstable or poorly controlled seizure disorder.

NOTE: A participant with a prior history of seizure could have been considered for enrollment if the Investigator believed the risk of seizure recurrence was low. All cases of prior seizure history were to be discussed with the A5359 protocol leadership team (actg.leada5359@fstrf.org) prior to enrollment.

Advanced liver disease (as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) OR history of liver cirrhosis.

Chronic Hepatitis C (HCV) with planned or anticipated use of anti-HCV therapy prior to the completion of Step 2.

History of or current active hepatitis B (HBV) infection defined as a positive HBV surface antigen test or any detectable HBV DNA in participants with isolated HBcAb and HBV DNA as follows:

Participants positive for HBsAg were excluded.

Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and any detectable HBV DNA were excluded.

NOTE: Participants positive for anti-HBc (negative HBsAg status) and positive for anti-HBs (past and/or current evidence) were immune to HBV and were not excluded. If prior documentation of immunity was available, repeat testing at screening was not required.

Current or anticipated need for chronic anti-coagulation therapy.

Unwilling to receive injections, or unable to receive gluteal injections.

Tattoo or other condition over the gluteus region, which could have interfered with the interpretation of injection site reaction.

Previous use of CAB.

Any acute or serious illness, within 7 days prior to entry, requiring systemic treatment and/or hospitalization that could have rendered the participant unable to receive study medication, in the opinion of the site investigator.

QTc greater than 450 ms using either Bazett or Fridericia method within 60 days prior to study entry: Whichever method was used at screening had to be used throughout the study period.

Any serious medical or psychiatric condition, which could have rendered the participant unable to receive study medication in the opinion of the site investigator.

Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation.

Requirement for any medication that was prohibited with a study medication (refer to protocol-specific web page [PSWP]).

Step 2 Inclusion Criteria

Meeting virologic suppression criteria at or after Step 1, week 4, defined as:

1. HIV-1 RNA ≤200 copies/mL OR
2. HIV-1 RNA of 201-399 copies/mL followed by HIV-1 RNA ≤200 copies/mL by Step 1, week 24.

NOTE: The HIV-1 RNA viral load that was used to determine eligibility for randomization had to have been collected within 4 weeks (28 days) of the Step 2 randomization visit.

Step 2 Exclusion Criteria

Permanent discontinuation of study treatment for any reason during Step 1.

Participants who never started study treatment in Step 1 (see protocol for more information).

Step 3 Inclusion Criteria, Participants Registering from Step 1

Virologic suppression at or after Step 1, week 4, defined as:

1. HIV-1 RNA ≤200 copies/mL OR
2. HIV-1 RNA of 201-399 copies/mL followed by HIV-1 RNA ≤200 copies/mL by Step 1, week 24.

NOTE: The HIV-1 RNA viral load that was used to determine eligibility for Step 3 had to have been collected within 4 weeks (28 days) of the Step 3 registration visit.

Willingness to begin to receive LA ART.

Step 3 Exclusion Criteria, Participants Registering from Step 1

Permanent discontinuation of study treatment for any reason during Step 1.

Participants who never started study treatment in Step 1 (see protocol for more information).

Currently pregnant, planning to become pregnant during the study period, or currently breastfeeding.

Step 3 Inclusion Criteria, Participants Registering from Step 2

Willingness to continue LA ART (for those in Step 2 Arm A) or begin LA ART (for those in Step 2 Arm B).

Step 2 Arm B participants: HIV-1 RNA ≤200 copies/mL at the most recent Step 2 visit OR Confirmation of Virologic Failure visit.

NOTE: The HIV-1 RNA viral load that was used to determine eligibility for Step 3 had to have been collected within 4 weeks (28 days) of the Step 3 registration visit.

Step 3 Exclusion Criteria, Participants Registering from Step 2

Permanent discontinuation of study treatment (LA ART for Arm A and oral ART for Arm B) for any reason during Step 2.

Confirmed Virologic Failure during Step 2.

Step 2 Arm B Participants: Currently pregnant, planning to become pregnant during the study period, or currently breastfeeding.

NOTE: Step 2 Arm A participants who became pregnant and were permitted to continue on LA-ART could continue on that regimen in Step 3.

Step 4 Inclusion Criteria

Any participant who had received at least one dose of CAB-LA or RPV-LA AND did not have access to available LA ART through their provider, OR did not wish to continue LA ART.

Step 4 Exclusion Criteria

There were no exclusion criteria for Step 4.

Individual participant data that underlie results in the publication, after deidentification.

Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.

• With whom?

  • Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.

• For what types of analyses?

  • To achieve aims in the proposal approved by the AIDS Clinical Trials Group.

• By what mechanism will data be made available?

  • Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://submit.mis.s-3.net/. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.