Overview

The purpose of this study is to evaluate the efficacy and safety of CABENUVA (Long-acting Cabotegravir Plus Long-acting Rilpivirine) in patients with HIV infection and severe renal impairment. This study is considered research and is voluntary.

Eligibility

Inclusion Criteria:

1. Aged 18 years or older, at the time of signing the informed consent.
2. A female participant is eligible to participate if she is not pregnant as confirmed by negative urine HCG test at screening and at each study visits), not lactating, and at least one of the following conditions applies:

Non-reproductive potential defined as:

• Pre-menopausal females with one of the following:
  1. Documented tubal ligation
  2. Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
  3. Hysterectomy
  4. Documented Bilateral Oophorectomy
• Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a

  blood test result of simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.

        Reproductive potential and agrees to follow one of the options listed in the Modified List
        of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential
        (see Appendix 6) from 30 days prior to the first dose of study medication, throughout the
        study, for at least 14 days after discontinuation of all oral study medications and for at
        least 52 weeks after discontinuation of CAB LA and RPV LA.
        The investigator is responsible for ensuring that participants understand how to properly
        use these methods of contraception. The study-sanctioned contraceptive method should be
        used consistently, in accordance with the approved contraceptive product label, before
        dosing of study medication and during the study intervention period
        For all participants receiving oral standard of care (SOC) treatment for HIV-1:
          1. Must be on uninterrupted current regimen (either the initial or second ARV regimen)
             for at least 6 months prior to Screening.
          2. Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12
             months prior to Screening: one within the 6 to 12-month window, and one within 6
             months prior to Screening
          3. Plasma HIV-1 RNA <50 c/mL at Screening
        Exclusion Criteria:
          1. Screening plasma HIV-1 RNA measurement > 50 c/mL
          2. Within 6 months prior to Screening, any plasma HIV-1 RNA measurement > 200 c/mL
          3. Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during
             the study
          4. Participants with severe hepatic impairment (Class C) as determined by Child-Pugh
             classification
          5. Any pre-existing physical or mental condition (including substance use disorder)
             which, in the opinion of the Investigator, may interfere with the participant's
             ability to comply with the dosing schedule and/or protocol evaluations or which may
             compromise the safety of the participant
          6. Participants who, in the investigator's judgment, pose a significant suicide risk as
             assessed via the Columbia Suicidality Severity Rating Scale (C-SSRS). In addition,
             participant's recent history of mental health, psychiatric history, suicidal behavior
             and/or suicidal ideation should be considered when evaluating for suicide risk.
          7. Evidence of active Hepatitis B virus (HBV) infection based on the results of testing
             at Screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody
             (anti-HBc), Hepatitis B surface antibody (anti-HBs) 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, not excluded if HBV DNA is
                  negative or not detected
               -  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
          8. Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be
             excluded, however Investigators must carefully assess if therapy specific for HCV
             infection is required; participants who are anticipated to require HCV treatment
             within 12 months must be excluded.
          9. Participants with HCV co-infection will be allowed entry into this study if:
               1. Liver enzymes meet entry criteria
               2. HCV Disease has undergone appropriate work-up, and is not advanced, and will not
                  require treatment prior to the Week 52 visit. Additional information (where
                  available) on participants with HCV co-infection at screening should include
                  results from any liver biopsy, fibroscan, ultrasound, or other fibrosis
                  evaluation, history of cirrhosis or other decompensated liver disease, prior
                  treatment, and timing/plan for HCV treatment.
               3. In the event that recent biopsy or imaging data is not available or inconclusive,
                  the Fib-4 score will be used to verify eligibility
               4. Fib-4 score >3.25 is exclusionary
               5. Fib-4 scores 1.45 - 3.25 will require review by site PI to ensure that
                  participant does not have severe liver disease and severe renal dysfunction.
                  Fibrosis 4 Score Formula: (Age x AST) / (Platelets x (sqr [ALT])
         10. History of liver cirrhosis with or without hepatitis viral co-infection
         11. Ongoing or clinically relevant pancreatitis
         12. Any condition which, in the opinion of the Investigator, may interfere with the
             absorption, distribution, metabolism or excretion of the study drugs or render the
             participant unable to receive study medications
         13. History or presence of allergy or intolerance to the study drugs or their components
             or drugs of their class. In addition, if heparin is used during PK sampling,
             participants with a history of sensitivity to heparin or heparin-induced
             thrombocytopenia must not be enrolled
         14. Current or anticipated need for chronic anti-coagulation or hereditary coagulation and
             platelet disorders such as hemophilia or Von Willebrand Disease. The exception are the
             use of low dose acetylsalicylic acid (≤325 mg) or if, clinically, is safe to hold the
             anticoagulant for 1-3 days prior to the target time of CABENUVA injections and to
             re-start it 12 hours after the IM injections (upon Pharmacist, cardiologist or
             hematologist opinion).
         15. Any evidence of primary resistance based on the presence of any major known INI or
             NNRTI resistance-associated mutation, except for K103N, (IAS, 2015) by any historical
             resistance test result. Note: Prior genotypic resistance testing is not required but
             if available it must be documented to provide direct evidence of no preexisting
             exclusionary resistance mutations. Details regarding baseline or prior resistance data
             must be noted in the source documentation
         16. Any verified Grade 4 laboratory abnormality except Creatinine level (See Appendix 11).
             A single repeat test is allowed during the Screening phase to verify a result
         17. Any acute laboratory abnormality at Screening, which, in the opinion of the
             investigator, would preclude the participant's participation in the study of an
             investigational compound
         18. Alanine aminotransferase (ALT) >=5x ULN, OR ALT >=3xULN and bilirubin >=1.5xULN (with
             >35% direct bilirubin)
         19. Exposure to an experimental drug or experimental vaccine within either 30 days, 5
             half-lives of the test agent, or twice the duration of the biological effect of the
             test agent, whichever is longer, prior to Day 1 of this study: Treatment with any of
             the following agents within 28 days of Screening:
               1. radiation therapy
               2. cytotoxic chemotherapeutic agents
               3. tuberculosis therapy with the exception of isoniazid (isonicotinylhydrazid, INH)
               4. Immunomodulators that alter immune responses such as chronic systemic
                  corticosteroids, interleukins, or interferons. (Note: Participants using
                  short-term (e.g., ≤21 days) systemic corticosteroid treatment; topical, inhaled,
                  and intranasal corticosteroids are eligible for enrolment)
         20. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening
         21. Use of medications which are associated with Torsade de Pointes.
         22. Participants receiving any prohibited medication and who are unwilling or unable to
             switch to an alternate medication.
         23. Unstable renal disease and/or anticipated need for renal transplant within 1 year of
             study entry.
        Note: Any prohibited medications that decrease CAB or RPV concentrations should be
        discontinued for a minimum of four weeks or a minimum of three half-lives (whichever is
        longer) prior to the first dose and any other prohibited medications should be discontinued
        for a minimum of two weeks or a minimum of three half-lives (whichever is longer) prior to
        the first dose.