Optimising Metabolic Management for People With Human Immunodeficiency Virus (HIV) on Integrase Based Antiretroviral Therapy (ART)

A Phase III/IV Factorial Randomized Double-blind Trial to Compare the Addition of Dapagliflozin vs Placebo and Rosuvastatin/Ezetimibe Versus Pitavastatin in Patients With HIV on Integrase Strand Transfer Inhibitor-based Antiretrovirals With Elevated Metabolic Risk

People with HIV are at a higher risk of cardiovascular diseases (CVD) due to the effects of the virus and its treatment. Integrase strand transfer inhibitors (INSTIs), a common HIV treatment, are associated with increased CVD risk and metabolic issues, such as weight gain and high blood pressure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, however, have been working well in reducing CVD events and hospitalizations due to heart failure, irrespective of diabetes presence. They also help in reducing weight and blood pressure. Pitavastatin has shown to work in lowering CVD events in people with HIV, but its availability is limited. This benefit is thought to be common to all statins, but this has not yet been confirmed. This study will examine the impact of dapagliflozin vs. placebo on metabolic parameters in people with HIV with high metabolic risk who are on INSTI-based ART.

This is a 2x2 factorial, randomised, placebo-controlled, double-blind, phase III/IV trial with two randomisations performed centrally via an on-line system, stratified by site. Participants will be randomised 1:1 to dapagliflozin 10mg vs. Placebo; this randomisation will be blinded. Participants will also be randomised 1:1 within each group to pitavastatin 4mg vs. rosuvastatin 10mg/ezetimibe 10mg; this randomisation will be open label.

Therefore, participants will be randomised to one of 4 groups:

1. Dapagliflozin 10mg + pitavastatin 4mg
2. Dapagliflozin 10mg + rosuvastatin 10mg/ezetimibe 10mg
3. Placebo + pitavastatin 4mg
4. Placebo + rosuvastatin 10mg/ezetimibe 10mg

With the following 2-arm randomised comparisons:

• Primary analysis hypothesis: a+b vs c+d (dapagliflozin vs placebo)
• Secondary analysis hypothesis: a+c vs b+d (pitavastatin vs rosuvastatin 10mg/ezetimibe 10mg)

The study's primary and secondary endpoints described will assess both efficacy and safety/tolerability across randomisation arms. Follow up will continue to 48 weeks and endpoint measures will be obtained at 4, 12, 24, and 48 weeks. Primary endpoint is at 24 weeks. The total number of participants is 300, with 75 randomised to each of the groups as listed above.

All randomised participants who have not withdrawn from the study will be invited to attend an optional observational follow-up visit at Week 96 (±6 weeks). The visit will collect longer-term post-treatment clinical, metabolic, cardiovascular risk, liver-related, medication use and safety data. No study drug will be supplied beyond Week 48, and no Week 96 CT coronary angiogram is planned. Week 96 data will be analysed separately as exploratory observational post-treatment follow-up data and will not alter the primary Week 24 or Week 48 analyses.

Inclusion Criteria:

1. Age 40-75 years and at least one of the following risk factors:

   1. BMI > 7% increase or > 5kg weight gain since INSTI commencement, or
   2. BMI ≥ 30 kg/m2

2. BMI ≥18 kg/m2 prior to INSTI commencement

3. Currently taking INSTI-based ART

4. Sustained virologic response, defined as viral load <200 copies/mL for at least 12 months

5. Current CD4 >250 cells/mm3

6. Informed consent for trial participation

Exclusion Criteria:

1. Currently taking a protease inhibitor
2. Indicated to take or already taking high intensity statin
3. estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2
4. Currently taking an SGLT-2 inhibitor or glucagon-like peptide 1 (GLP-1) agonist
5. Absolute contraindication or absolute indication to SGLT2 inhibitor therapy
6. Absolute contraindication to pitavastatin, rosuvastatin, ezetimibe or combination of rosuvastatin/ezetimibe
7. Pregnant or breast feeding
8. Severe hepatic impairment (Child Pugh B or C)
9. Participants receiving any excluded/contraindicated medication
10. Participants who are enrolled into an additional interventional study.
11. Expected inability or unwillingness to participate in study procedures.
12. In the opinion of the investigator, participation in a trial is not in the best interest of the patient.