Inclusion Criteria:
1. 18 years of age and above
2. HIV-1 infection confirmed in clinic records or by study team.
3. Two consecutive HIV-1 VL \<200 copies/mL ≥3 months apart prior to randomization.
4. On an oral regimen of 2NRTI + DTG as part of first line ART
5. Is identified as a participant with a history of, sub-optimal ART adherence or engagement in care based on one or more of the following criteria:
1. Documented detectable HIV-1 VL (\>1000 c/mL) on all-oral ART (EFV/NVP or DTG-based) in the prior 2 years despite being ART-experienced for
≥3 months.
2. History of being lost to follow-up from care (\>4 weeks elapsed since a missed scheduled clinic appointment or refill in the prior 2 years).
3. Failed to link to HIV care despite ≥3 months elapsed since HIV diagnosis.
6. Females: human chorionic gonadotrophin (HCG) negative and willing to use one highly effective form of contraception if woman of reproductive potential
7. Must sign informed consent form (ICF) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
8. Willing and able to attend all clinic appointments.
Exclusion Criteria:
1. Not virologically suppressed (VL\<200 c/mL) for ≥3 months at the end of the screening process.
2. Previous use, or intention to use, protease inhibitor-based ART at any time.
3. Evidence of prior HIV-1 resistance test with NNRTI drug resistance mutations (other than K103N) and/or INSTI drug resistance mutations.
4. Unwillingness to receive 2 injections on a 2 monthly basis.
5. Unwilling to use a form of contraception.
6. Pregnant, breastfeeding or planning to become pregnant during the study period.
7. Requires tuberculosis therapy or other drug with clinically relevant drug interaction
8. High risk of seizures, including participants with an unstable or poorly controlled seizure disorder.
9. Has active TB or other mycobacterial disease and requires treatment.
10. Advanced liver disease, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or history of cirrhosis.
11. Chronic Hepatitis C with planned or anticipated use of Hep C therapy
12. 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 (HBcAb), Hepatitis B surface antibody (HBsAb) as follows:
* Participants positive for HBsAg are excluded
* Participants negative for HBsAg but positive for HBcAb, with no evidence of HBsAb are excluded NOTE: Participants positive for HBcAb due to prior infection (negative HBsAg status) and with evidence of HBsAb have some immunity to HBV and have low risk of reactivation so are not excluded.
13. Current or anticipated need for chronic anticoagulation therapy.
14. Previous use of oral or injectable CAB or RPV.
15. Any Grade 4 laboratory abnormality at the conclusion of screening process.
16. Creatinine clearance (CrCl) \<50 mL/min/1.732 by Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation.
17. Alanine aminotransferase (ALT) \> 3×upper limit of normal (ULN).
18. Has a tattoo or other dermatological condition overlying the gluteus region that may interfere with interpretation of ISRs.
19. Has ongoing or clinically significant medical conditions that in the opinion of the investigator may interfere with the absorption, distribution, metabolism or excretion of the study interventions or could affect participant safety.
20. Has pre-existing physical or mental condition 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.
21. Known allergies, hypersensitivity, or intolerance to cabotegravir or rilpivirine or its excipients.
22. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 30 days before the planned first dose of study intervention or is currently enrolled in another interventional study.
23. Has received any prohibited medication listed in Section 6.8.2, Prohibited Medications and Non-drug Therapies and is unwilling or unable to switch to an alternate medication.
24. Has been treated 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 (isonicotinyl hydrazid, INH).
4. Anticoagulation agents (e.g., warfarin and direct oral anticoagulants).
25. Is using immunomodulators that alter immune responses (such as chronic systemic corticosteroids, interleukins, or interferons). Note: Participants using short-term steroid tapers, topical, inhaled and intranasal corticosteroids, topical imiquimod are eligible for enrolment.
26. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
27. QTc interval \>450 ms (if QTc interval is \>450 ms on the ECG read out, then it should be corrected according to Fridericia; https://www.mdcalc.com/corrected-qt-interval-qtc) within 90 days prior to study entry.
