This is a multicentre study carried out in participants living with human immunodeficiency virus type 1 (HIV-1) who have not previously been treated with any antiretroviral therapies. The study will investigate two 2-drug regimens for the treatment of HIV-1: a fixed-dose combination oral tablet of dolutegravir/lamivudine (DTG/3TC) and cabotegravir plus rilpivirine long-acting agents (CAB + RPV LA). All participants will initially receive DTG/3TC once daily, and once virologic suppression is attained (plasma HIV-1 <50 c/mL), participants will be offered a choice to switch to CAB + RPV LA or to continue taking oral DTG/3TC. This study will provide important data on the efficacy, safety, implementation effectiveness, and patient-reported outcomes of these two regimens in a study where participants have the option to choose between them based on individual preference. The aim of the study is to evaluate the antiviral effectiveness at 11 months after switching to CAB+RPV LA following initial virologic suppression on DTG/3TC and to provide data on how long it takes participants to suppress their viral load on DTG/3TC.

Inclusion Criteria:

1. Participants with plasma HIV-1 RNA ≥1,000 c/mL at Screening.
2. Antiretroviral-naïve participants (defined as no prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection) prior to enrolment.
3. Participant is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
4. Participants enrolled in France must be affiliated to, or a beneficiary of, a social security category.

Exclusion Criteria:

1. Women who are pregnant or breastfeeding or plan to become pregnant or breastfeed during the study.

2. Participants with any evidence of a current Center for Disease Control and Prevention (CDC) Stage 3 disease; with the exception of cutaneous Kaposi's sarcoma not requiring systemic therapy, and CD4+ count <200 cells/cubic millimetre (mm^3) (neither is exclusionary).

3. Participants with history or presence of allergy or intolerance to the study drugs or their components or drugs of their class, or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates study participation.

4. Participants with ongoing or clinically relevant pancreatitis.

5. Participants with Clinically significant cardiovascular disease, as defined by recent history (within the last 6 months) or current 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.

6. Corrected QT (QTc) interval >450 milliseconds (msec) (or QTc >480 msec for participants with bundle branch block).

7. Participants with ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the Investigator and the Medical Monitor for inclusion of the participant prior to enrolment.

8. Participants with hereditary coagulation and platelet disorders (e.g., haemophilia or von Willebrand Disease); or current or anticipated need for chronic anti-coagulation, with the exception of the use of low-dose acetylsalicylic acid (≤325 mg).

9. Participants with severe hepatic impairment (Class C) as determined by Child-Pugh classification.

10. Participants with unstable liver disease as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice or cirrhosis, or decompensated cirrhosis (e.g., ascites, encephalopathy, or variceal bleeding), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per Investigator assessment).

11. Participants with history of liver cirrhosis with or without hepatitis viral co-infection.

12. 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 enrolment 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 enrolment.

13. Participants who, in the Investigator's judgment, pose a significant suicide risk. Participant's recent history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk.

14. Participants with signs and symptoms which, in the opinion of the Investigator, are suggestive of active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 14 days prior to enrolment.

15. 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), and hepatitis B surface antibody (anti-HBs) as follows:

    • Participants positive for HBsAg are excluded
    • Participants negative for HBsAg and negative for anti-HBs but positive for anti-HBc are excluded only if HBV DNA is detected [either detected below lower limit of quantification (LLOQ); detected above upper limit of quantification (ULOQ); or numerical value (i.e. between LLOQ and ULOQ)];
    • Participants negative for HBsAg but positive for anti-HBc and positive for anti-HBs (past and/or current evidence) are immune to HBV and are not excluded.

16. Participants with hepatitis C virus (HCV) co-infection at Screening are eligible only if:

    • liver enzymes meet entry criteria; and
    • HCV disease is not anticipated to require on-study treatment with any agent(s) that have potential adverse drug-drug interactions (DDIs) with the study interventions; and
    • HCV disease has undergone appropriate work-up and is not advanced or associated with cirrhosis

17. Participants with untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening without clear documentation of completed treatment at least 7 days prior to enrolment) are excluded. Participants with a false positive RPR (with negative treponemal test) or serofast RPR result (persistence of a reactive nontreponemal syphilis test despite history of adequate therapy and no evidence of re-exposure) may enroll after consultation with the Medical Monitor. Participants who completed treatment at least 7 days prior to enrolment are eligible.

18. Known or suspected presence of any major resistance mutations as defined by the international AIDS society (IAS)-United States of America (USA) resistance guidelines to DTG, 3TC, CAB or RPV in any resistance test result.

19. Participants with 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 first dose of study treatment.

20. Participants with treatment with any of the following agents within 28 days of Screening:

    • radiation therapy
    • cytotoxic chemotherapeutic agents;
    • tuberculosis therapy with the exception of isoniazid (isonicotinylhydrazid, INH);
    • anti-coagulation agents, with the exception of the use of low dose acetylsalicylic acid (≤325 mg);
    • 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

21. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.

22. Treatment with any agent with documented activity against HIV-1 in vitro within 28 days of first dose of study treatment. Treatment with acyclovir/valacyclovir is permitted.

23. Use of medications which are associated with Torsade de Pointes

24. Participants receiving any protocol-defined prohibited medication and who are unwilling or unable to switch to an alternate medication.

25. Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 lipid abnormalities.

26. Any acute laboratory abnormality at Screening, which, in the opinion of the Investigator, would preclude the participant's participation in an interventional clinical trial.

27. Participant has estimated creatine clearance <30 milliliter per minute (mL/min) per 1.73 square meter (m^2) using the refitted, race-neutral Chronic Kidney Disease Epidemiology Collaboration (CKDEPIcr_R) method.

28. Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN); or ALT ≥3xULN and bilirubin ≥1.5xULN (with >35 percentage (%) direct bilirubin).

29. Participants known or suspected to have acquired HIV-1 concurrent with use of protease-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP) must be discussed with the Medical Monitor prior to enrolment.

30. Participant has a gluteal implant/enhancements (including fillers); or tattoo or other dermatological condition overlying the gluteus region which may interfere with interpretation of injection site reactions.

31. 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 drugs.

32. 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.

33. Participant is currently participating in, or anticipates being selected for, any other interventional study.

Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en-gb/innovation/trials/data-transparency/

Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.

Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months.