Study to Assess the Effects of Cabotegravir (CAB) and Rilpivirine (RPV) Long-Acting (LA) Injections Following Sub-cutaneous (SC) Administration Compared With Intramuscular (IM) Administration in Adult Participants Living With Human Immunodeficiency Virus (HIV-1) Infection in the FLAIR Study

This study will assess the pharmacokinetics, safety, tolerability, maintenance of virological suppression and patient reported outcomes for participants receiving CAB and RPV LA injections following SC administration in the anterior abdominal wall SC tissue compared with IM administration in the gluteus medius muscle in adult participants living with HIV-1 infection in the FLAIR study (NCT02938520).


Eligibility Criteria:
Inclusion Criteria:

* Capable of giving signed informed consent (FLAIR and Sub-study specific informed consent)
* Eligible participants must have been on CAB LA + RPV LA regimen for a minimum of 12 months while on the FLAIR study. Any disruptions in dosing during FLAIR must be discussed with the Medical Monitor for a final determination of eligibility into the sub-study.
* Plasma HIV-1 RNA \<50 c/mL at Sub-Study Screening.
* History of Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) vaccination (or booster dosing) is allowed prior to sub study screening and will be allowed during the conduct of the sub-study as long as the vaccine (or boosters) are not administered within 14 days of virologic load (VL) assessments.
* HIV-1 infected antiretroviral therapy (ART)-naive men or women aged 18 years or greater at the time of signing the informed consent.
* HIV-1 infection as documented by Screening plasma HIV-1 RNA \>=1000 cubic (c)/mL
* Antiretroviral-naive (less than or equal to (\<=10) days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection). Any previous exposure to an HIV integrase inhibitor or non-nucleoside reverse transcriptase inhibitor will be exclusionary
* Female Participants: A female participant is eligible to participate if she is not pregnant at Screening and first day of Induction Phase (as confirmed by a negative serum human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies

  1. Non-reproductive potential defined as:

     * Pre-menopausal females with one of the following:
     * Documented tubal ligation;
     * Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion;
     * Hysterectomy; Documented Bilateral Oophorectomy;
     * Postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause. 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 enrollment.
  2. 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 (FRP) from 30 days prior to the first dose of study medication, throughout the study, and for at least 30 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.
* All participants in the study should be counseled on safer sexual practices including the use and benefit/risk of effective barrier methods (example \[e.g.,\] male condom) and on the risk of HIV transmission to an uninfected partner.
* In France, a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

* More than 1 plasma HIV-1 RNA measurement 50 c/mL to \<200 c/mL (virologic blip) within 24 weeks prior to sub-study Screening visit that was investigated and found NOT to be associated with alternative causes including recent vaccinations received within 4 weeks of the viral blip or NOT associated with intercurrent illness that developed within 2-4 weeks of the viral blip.
* All viral blips that occurred within 24 weeks prior to screening should be discussed with the Medical Monitor to assess whether such a participant can enroll into the sub-study.
* Any Suspected Virologic Failure (HIV-RNA 200 c/mL) as defined during FLAIR study.
* Participants planning to require oral bridging during participation in the FLAIR sub study.
* The participant has a tattoo or any dermatological condition overlying the abdominal or gluteal regions which may interfere with interpretation of injection site reactions.
* 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 medication.
* Any woman of childbearing potential who is pregnant at screening will be excluded from entering the sub-study.
* Any women of childbearing potential who gets pregnant while on the sub-study will have to be withdrawn from the sub-study but will be allowed to transition back to the parent FLAIR study if a pregnancy specific Informed Consent Form (ICF) is signed, and commercial access is not available at the time of pregnancy
* Women who are pregnant, breastfeeding, or plan to become pregnant or breastfeed during the study.
* Any evidence at Screening of an active Centers for Disease and Prevention Control (CDC) Stage 3 disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy or historic or current cluster of differentiation 4+ (CD4+) cell count \<200 cells/ cubic millimeter (mm\^3) are not exclusionary.
* Participants with known moderate to severe hepatic impairment.
* Any pre-existing physical or mental condition (including substance abuse 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.
* Participants determined by the Investigator to have a high risk of seizures, including participants with an unstable or poorly controlled seizure disorder. 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 Medical Monitor prior to enrollment.
* Participant who, in the investigator's judgment, poses a significant suicide risk. Participant's recent history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk.
* The participant has a tattoo or other dermatological condition overlying the gluteus region which may interfere with interpretation of injection site reactions.
* Evidence of 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 Deoxyribonucleic acid (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.
* 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 prior to Week 48 of the Maintenance Phase must be excluded. HCV treatment on study may be permitted post Week 48, following consultation with the Medical Monitor. Participants with HCV co-infection will be allowed entry into Phase 3 studies if:

  * Liver enzymes meet entry criteria;
  * HCV Disease has undergone appropriate work-up, HCV is not advanced, and will not require treatment prior to the Week 48 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.
  * In the event that recent biopsy or imaging data is not available or is inconclusive, the Fib-4 score will be used to verify eligibility.
  * A Fib-4 score \> 3.25 is exclusionary;
  * Fib-4 scores 1.45 - 3.25 requires Medical Monitor consultation. Fibrosis 4 Score Formula: (Age \* AST)/ (Platelets \* \[square root of ALT\]).
* Unstable 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 otherwise stable chronic liver disease per investigator assessment).
* History of liver cirrhosis with or without hepatitis viral co-infection.
* Ongoing or clinically relevant pancreatitis.
* All participants will be screened for syphilis (rapid plasma reagin \[RPR\]). Participants with untreated syphilis infection, defined as a positive RPR without clear documentation of treatment, are excluded. Participants with a positive RPR test who have not been treated may be rescreened at least 30 days after completion of antibiotic treatment for syphilis.
* Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the study Medical Monitor for inclusion of the participant prior to enrollment.
* Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the drug or render the participant unable to receive study medication.
* 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 pharmacokinetic (PK) sampling, participants with a history of sensitivity to heparin or heparin-induced thrombocytopenia must not be enrolled.
* Current or anticipated need for chronic anti-coagulation.
* ALT \>=3 times upper limit normal (ULN).
* Clinically significant cardiovascular disease, as defined by history/evidence of congestive heart failure, symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty (PTCA) or any clinically significant cardiac disease.
* Exposure to an experimental drug and/or experimental vaccine within 28 days or 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of investigational product (IP).
* Treatment with any of the following agents within 28 days of Screening:

  * radiation therapy;
  * cytotoxic chemotherapeutic agents;
  * tuberculosis (TB) therapy, with the exception of treatment of latent TB with isoniazid;
  * Immunomodulators that alter immune responses (such as chronic systemic corticosteroids, interleukins, or interferons).
* Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
* Treatment with any agent, except recognized ART as allowed above, with documented activity against HIV-1 within 28 days of the first dose of IP.
* Use of medications which are associated with Torsades de Pointes
* Any evidence of primary resistance to non-nuclease reverse transcriptase inhibitors (NNRTIs) (except for K103N which is allowed), or any known resistance to Integrase inhibitors from historical resistance test results.
* Participants who are human leukocyte antigen (HLA)-B\*5701 positive and are unable to use an NRTI backbone that does not contain abacavir (participants who are HLA-B\*5701 positive may be enrolled if they use a nuclease reverse transcriptase inhibitors (NRTI) backbone that does not contain abacavir; HLA-B\*5701 positive participants may be excluded from the study if local provision of an alternate NRTI backbone is not possible).
* Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during the Screening Phase to verify a result.
* 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.
* Participant has estimated creatinine clearance \<50 mL/minute (min)/1.73 meter square (m\^2) via the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
* Participants who are currently participating in or anticipate to be selected for any other interventional study.