Phase 4, randomized, open-label study to evaluate the efficacy, safety and tolerability of switching virologically suppressed adults living with HIV on bictegravir/tenofovir alafenamide/emtricitabine to dolutegravir/lamivudine

Randomized, open-label, active-controlled study of virologically suppressed participants living with HIV

Participants who provide written informed consent and meet all the eligibility criteria will be randomized in a 2:1 ratio to one of the following 2 treatment groups:

Treatment Group 1 (n=148): FDC of DTG/3TC (50mg/300mg) administered orally, once daily (QD), without regard to food.

Treatment Group 2 (n=74): Stay on baseline regimen consisting of FDC of B/F/TAF (50mg/200mg/ 25mg) (taken as prescribed) without regard to food.

Randomization will be stratified by gender and race at entry given that this study aims to enroll at least 30% of participants who are female and African American.

All participants will be responsible for using their insurance plan to obtain coverage for DTG/3TC and or B/F/TAF, in addition to any labs required by the study. This expectation is clearly outlined in the informed consent. The study team will work with participants to minimize their co-pays for study medications and labs through the use of manufacturer and other external assistance programs.

Study duration will be 48 weeks.

Number of participants planned: Approximately 222 participants

Target Population: HIV-1 infected adult participants who are virologically suppressed (HIV-1 RNA<50 copies/mL) on FDC of B/F/TAF (50mg/200mg/ 25mg) ≥ 3 months prior to screening

Inclusion Criteria -

1. Aged 18 years or older at the time of signing the informed consent

   TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY

2. HIV-1 infected men or women.

3. Must have a stable form of insurance that is expected to continue without significant changes for at least 48 weeks

4. Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL at least 3 months apart prior to Day 1 (the screening HIV-1 RNA can count as the second measurement)

5. Plasma HIV-1 RNA <50 c/mL at Screening.

6. Must be on uninterrupted B/F/TAF for at least 3 months prior to screening

   SEX

7. Male or female A female subject is eligible to participate if she is not pregnant [as confirmed by a negative serum human chorionic gonadotrophin (hCG) test at screen and a negative urine hCG test at Day

1/Randomization (a local serum hCG test at Randomization is allowed if it can be done, and results obtained, within 24 hours prior to randomization)], 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:

     o Documented tubal ligation

     • Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
     • Hysterectomy
     • Documented Bilateral Oophorectomy

   • Post-menopausal 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 (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 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) (see Appendix 2) from 30 days prior to the first dose of study medication and for at least 2 weeks after the last dose of study medication.

The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. All subjects participating 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.

INFORMED CONSENT

8. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. Eligible subjects must sign a written Informed Consent Form before any protocol-specified assessments are conducted

b. Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

Exclusion Criteria -

CONCURRENT CONDITIONS/MEDICAL HISTORY

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

2. Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 3 disease [15], EXCEPT cutaneous Kaposi's sarcoma not requiring systemic therapy. Historical or current CD4 cell counts less than 200 cells/mm3 are NOT exclusionary.

3. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification [16].

4. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

5. 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 (antiHBc), Hepatitis B surface antigen antibody (anti-HBs) and HBV DNA as follows:

   • Subjects positive for HBsAg are excluded.
   • Subjects negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded.

   Note: Subjects positive for anti-HBc (negative HBsAg status) and positive for antiHBs (past and/or current evidence) are immune to HBV and are not excluded. AntiHBc must be either total anti-HBc or anti-HBc immunoglobulin G (IgG), and NOT anti-HBc IgM.

6. Anticipated need for any hepatitis C virus (HCV) therapy during the first 48 weeks of the study

7. Untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening without clear documentation of treatment). Subjects who are at least 7 days post completed treatment are eligible.

8. History or presence of allergy or intolerance to the study drugs or their components or drugs of their class.

9. 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.

10. Subjects who in the investigator's judgment, poses a significant suicidality risk.

    EXCLUSIONARY TREATMENTS PRIOR TO SCREENING OR DAY 1

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

12. Treatment with any of the following agents within 28 days of Screening

    • radiation therapy
    • cytotoxic chemotherapeutic agents
    • any systemic immune suppressant

13. Exposure to an experimental drug or experimental vaccine within either 28 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 the first dose of study medication.

14. Use of any regimen consisting of single or dual ART LABORATORY VALUES OR CLINICAL ASSESSMENTS AT SCREENING

15. Any evidence of major NRTI mutation (defined as history of 3 or more TAMs (M41L, D67N, K70R, L210W, T215F/Y, and K219Q/E/N/R), M184V/I, T69-insertions, or K65R/E/N) or presence of any major INSTI resistance-associated mutation [17] in any available prior resistance genotype assay test result

16. Any verified Grade 4 laboratory abnormality

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

18. Creatinine clearance of <50mL/min/1.73m2 via CKD-EPI method.

    EXCLUSIONARY CRITERIA PRIOR TO SCREENING OR DAY 1

19. Within the 6 to 12-month window prior to Screening and after confirmed suppression to <50 copies/mL, any plasma HIV-1 RNA measurement >200 c/mL.

20. Within the 6 to 12-month window prior to Screening and after confirmed suppression to <50 copies/mL, 2 or more plasma HIV-1 RNA measurements ≥50 c/mL.

21. Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on current ART regimen, any plasma HIV-1 RNA measurement ≥50 copies/mL.

22. Any drug holiday during the 12 months prior to Screening, except for brief periods (less than 1 month) where all ART was stopped due to tolerability and/or safety concerns.

23. Any history of switch to another regimen, defined as change of a single drug or multiple drugs simultaneously, due to virologic failure to therapy (defined as a confirmed plasma HIV-1 RNA ≥400 copies/mL.

48 weeks

Additional secondary endpoints included safety and tolerability which were evaluated through incidence and severity of AEs, laboratory abnormalities and discontinuations due to AEs at each study visit through Week 48.