Evaluating Long-Acting Antiretroviral Therapy in Non-Adherent HIV-Infected Individuals
a study on HIV/AIDS
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).
A Phase III Study to Evaluate Long-Acting Antiretroviral Therapy in Non-Adherent HIV-Infected Individuals
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 at Weeks 2, 4, 8, 12, 16, and 20.
In Step 2, eligible participants will be randomized to receive either oral RPV + oral CAB for 4 weeks followed by RPV-LA + CAB-LA every 4 weeks for 48 weeks 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 followed by RPV-LA + CAB-LA every 4 weeks for 48 weeks. 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).
HIV Infections Anti-Retroviral Agents Rilpivirine Standard of Care (SOC) Oral ART Oral RPV Oral CAB RPV-LA Loading Dose CAB-LA Loading Dose RPV-LA Maintenance Dose CAB-LA Maintenance Dose
For people ages 18 years and up
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 45 days prior to study entry by any US laboratory that has a Clinical Laboratory Improvement Amendments(CLIA) certification or its equivalent.
- 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 2 appointments 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 through commercially available genotypic (or phenotypic if available) analyses from any laboratory that has a CLIA certification or its equivalent within 45 days of study entry (see protocol for more information), nor history of such mutations on review of prior resistance tests by the site investigator.
- 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.
- NOTE: Site investigators will choose from among ART regimens available through the study listed in the protocol.
- Laboratory values obtained within 45 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/mm3
- 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 Cockcroft-Gault
- NOTE: A calculator for estimating the CrCl can be found at www.fstrf.org/ACTG/ccc.html.
- For women 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: Female 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
- Female Participants of Reproductive Potential: Female 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
- Female Participants Who Are Not of Reproductive Potential: Women 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 woman'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 an uninfected partner.
- 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 (email@example.com) 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 positive 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 positive for 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.
- 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 RPV or CAB.
- Active drug or alcohol use or addiction, with addiction score greater than or equal to 6 according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-V)Criteria for Diagnosis of Alcohol and Substance use (provided in the Manual of Procedures [MOPS]).
- NOTE: If addiction score less than 6 the participant will also be excluded if study participation would interfere with the participant's safety in the opinion of the site investigator.
- Acute or serious illness requiring systemic treatment and/or hospitalization within 7 days prior to entry.
- QTc greater than 450 ms using either Bazett or Fridericia method within 45 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
- HIV-1 RNA less than 50 copies/mL at Step 1, week 20, or HIV-1 RNA of 50-399 copies/mL at Step 1, week 20, followed by HIV-1 RNA less than 50 copies/mL by Step 1, week 24.
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
- 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.
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 commercially available LA ART,
- OR does not wish to continue LA ART.
Step 4 Exclusion Criteria
- There are no exclusion criteria for Step 4.
- UCSD Antiviral Research Center CRS not yet accepting patients
San Diego California 92103 United States
- Harbor-UCLA CRS not yet accepting patients
Torrance California 90502 United States
- not yet accepting patients
- Start Date
- Completion Date
- National Institute of Allergy and Infectious Diseases (NIAID)
- Phase 3
- Study Type
- Last Updated