The LATITUDE Study: Long-Acting Therapy to Improve Treatment SUccess in Daily LifE

A Phase III Study to Evaluate Long-Acting Antiretroviral Therapy in Non-Adherent HIV-Infected Individuals

The purpose of this study is 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 will 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) with rilpivirine (RPV) LA and cabotegravir (CAB) LA versus all-oral standard of care (SOC). The study includes four steps. 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. In Step 2, eligible participants will be randomized to receive either oral RPV + oral CAB for 4 weeks (optional) followed by RPV-LA + CAB-LA every 4 weeks for until the end of step 3 or to continue on SOC for 52 weeks. At the completion of Step 2, eligible participants randomized to SOC will have the option to register to Step 3 and receive LA ART, which includes oral RPV + oral CAB for 4 weeks (optional) followed by RPV-LA + CAB-LA every 4 weeks until the end of step 3. Participants already receiving RPV-LA + CAB-LA in Step 2 will continue on this regimen in Step 3 for 52 weeks. Eligible participants will enter Step 4 and be followed for 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).

In Step 1, participants will receive SOC oral ART regimen for up to 24 weeks. In Step 2, participants will receive oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks for 44 weeks. In Step 3, participants will receive a RPV-LA maintenance dose and a CAB-LA maintenance dose every 4 weeks until the end of Step 2. In Step 4, eligible participants will be followed until they complete 52 weeks on locally sourced oral ART.

In Step 1, participants will receive SOC oral ART regimen for up to 24 weeks. In Step 2, participants will continue SOC oral ART regimen for 52 weeks. In Step 3, participants will receive oral RPV once daily and oral CAB once daily for 4 weeks (optional), followed by a RPV-LA loading dose and a CAB-LA loading dose, followed in 4 weeks by an RPV-LA maintenance dose and CAB-LA maintenance dose every 4 weeks until the end of Step 3. In Step 4, eligible participants will be followed until they complete 52 weeks on locally sourced oral ART.

SOC oral ART regimen must include at least 3 drugs with 2 or more drugs predicted to be fully active, including a boosted protease inhibitor (PI) and/or an integrase strand transfer inhibitor (INSTI)

Regimen failure is defined as the occurrence of the first of the following two events at any time post randomization and Step 2, week 48, visit: Virologic failure (defined as confirmed HIV-1 RNA >200 copies/mL after Step 2 randomization) Permanent discontinuation of randomized study treatment

Virologic failure is defined as confirmed HIV-1 RNA greater than 200 copies/mL after Step 2 randomization

Occurrence of the treatment-related failure in Step 2 at any time post randomization and week 48 visit

Time will be measured from the Step 2 randomization to the first of the following events: virologic failure or treatment discontinuation due to adverse event (AE)

Virologic non-success will be defined by the US Food and Drug Administration (FDA) Snapshot algorithm

Number of participants with plasma HIV-1 RNA level less than 50 copies/mL and less than or equal to 200 copies/mL at scheduled study visits on Steps 1 and 2

AEs will be graded based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017

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" refers to a FDA-approved kit, which is required for all IND studies. WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is 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 has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, unless participant has been lost to clinical follow-up (see 4.1.3 NOTE) and no viral load result is available within the last 12 months 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 have 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 is defined as either no contact with provider or missed greater than or equal to 1 appointment in a 6-month period. ART non-adherence is 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 Manual of Procedures [MOPS] for list of exclusionary mutations) through commercially available genotypic (or phenotypic, if available) analyses from any laboratory that has 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 cannot be resulted by the testing laboratory, review of historical genotypes and treatment history by the IoR can be used to satisfy this criterion (see protocol for more information). Ability of site clinician, in conjunction with participant, to construct an oral induction antiretroviral (ARV) regimen that must include at least three ARVs of which at least two must be predicted to be fully active. The regimen must, 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 has 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, negative serum or urine pregnancy test with a sensitivity of less than or equal to 25 mIU/mL at screening. This will be repeated again at study entry. NOTE: Participants are considered to be NOT of reproductive potential if: 1) they have had amenorrhea for at least 12 consecutive months prior to study entry ((i.e., who have had no menses within 12 months prior to study entry), and have a documented follicle-stimulating hormone (FSH) greater than 40 IU/mL; OR 2) an FSH level is not available, but they have had 24 consecutive months of amenorrhea (in the absence of medications known to induce amenorrhea); OR 3) they report 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 are participating in sexual activity that could lead to pregnancy, must 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 include: Contraceptive subdermal implant Intrauterine device or intrauterine system Combined estrogen and progestogen oral contraceptive Injectable progestogen Contraceptive vaginal ring Percutaneous contraceptive patches Participants Who Are Not of Reproductive Potential: Participants who are not of reproductive potential are eligible to start study drugs without requiring the use of contraceptives. Any statement of self-reported sterility or that of her partner's must be entered in the source documents. NOTE A: Acceptable documentation of lack of reproductive potential is the participant's self-reported history of surgical sterilization, menopause, or male partner's azoospermia. NOTE B: ALL participants in the study should 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 Age greater than or equal to 18 years. 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 a high risk of seizures, including participants with an unstable or poorly controlled seizure disorder. NOTE: A participant with a prior history of seizure may be considered for enrollment if the Investigator believes the risk of seizure recurrence is low. All cases of prior seizure history should 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 positive HBV surface antigen test or any detectable HBV DNA in participants with isolated HBcAb and HBV DNA as follows: Participants positive for HBsAg are excluded Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and any detectable HBV DNA are excluded NOTE: Participants positive for anti-HBc (negative HBsAg status) and positive for anti-HBs (past and/or current evidence) are immune to HBV and are not excluded. If prior documentation of immunity is available, repeat testing at screening is 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 gluteus region, which may interfere with 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 hospitalizationthat may render 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 is used at screening must be used throughout study period. Any serious medical or psychiatric condition, which may render 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 is 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: HIV-1 RNA ≤200 copies/mL OR 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 will be used to determine eligibility for randomization must 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 Willingness to continue for those in Arm A or begin to receive LA ART for those in Arm B. Arm B participants: HIV-1 RNA less than 50 copies/mL at Step 2, week 48, or HIV-1 RNA of 50-399 copies/mL at Step 2, week 48, followed by HIV-1 RNA less than 50 copies/mL by Step 2, week 52. Step 3 Exclusion Criteria Permanent discontinuation of study treatment for any reason during Step 2. Confirmed Virologic Failure during Step 2. (Only for Arm B in Step 2) Currently pregnant, planning to become pregnant during the study period, or currently breastfeeding. Step 4 Inclusion Criteria Any participant who has received at least one dose of CAB-LA or RPV-LA AND does not have access to available LA ART through their provider, OR does not wish to continue LA ART. Step 4 Exclusion Criteria • There are no exclusion criteria for Step 4.

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.

Pluznik JA, Nijhawan AE, Spaulding AC. Does Anything Work? Improving HIV Care Engagement for Individuals Transitioning out of Correctional Settings. J Acquir Immune Defic Syndr. 2021 Mar 1;86(3):286-287. doi: 10.1097/QAI.0000000000002599. No abstract available.