Evaluation of Safety in HBV Virological Control Using Darunavir, Ritonavir, Dolutegravir Sodium, and Lamivudine in HIV-1/HBV Co-infected Patients

The primary objective of this trial is to evaluate the **safety** of two treatment reduction strategies over 96 weeks in terms of chronic viral hepatitis B control in patients co-infected with HIV-1 and HBV who have previously achieved control on continuous triple therapy. This is clinically relevant as it aims to determine the feasibility of reducing treatment burden while maintaining effective control of chronic hepatitis B, which is crucial for long-term patient management and quality of life.

Secondary objectives include:

• Assessing HBV virological response at 48 weeks.
• Evaluating HIV virological response at 48 and 96 weeks.
• Identifying the selection of HBV resistance mutations at the time of virological failure.
• Determining predictive factors for virological rebound(s).
• Evaluating clinical and biological tolerance.
• Assessing participants' quality of life.
• Comparing HBV virological response at 96 weeks between treatment arms.

The clinical trial involves participants **co-infected with the HIV-1 and HBV viruses**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a stable health status, with specific criteria such as ALT levels below three times the normal range and CD4 lymphocyte counts greater than 250/mm³ at pre-inclusion. The trial does not involve a vulnerable population. Participants must have been on a consistent daily antiretroviral triple therapy regimen for at least 12 months, including specific medications such as tenofovir disoproxil fumarate or tenofovir alafenamide fumarate, combined with lamivudine or emtricitabine, and a choice of NNRTI, PI/r, or INSTI. The trial population was selected based on their ability to maintain virologic control, with HIV and HBV viral loads consistently low for at least two years. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is an interventional, multicenter, open-label, randomized, non-comparative study designed to evaluate the safety of two antiviral treatment reduction strategies in patients co-infected with **HIV-1** and **HBV**. The primary objective is to assess the safety concerning chronic viral hepatitis B control over a period of 96 weeks. The trial is categorized as Phase 4 and is not considered low intervention. The study involves the administration of **darunavir**, **ritonavir**, **dolutegravir sodium**, and **lamivudine**, all of which are administered orally. The trial is expected to commence recruitment on March 1, 2024, and conclude by June 30, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as confirmed HIV-1 and HBV co-infection, stable antiretroviral therapy, and specific virological and immunological parameters. Follow-up visits will occur at regular intervals, including assessments at weeks 0, 12, 24, 48, 72, and 96. These visits will monitor virological success rates, time to virological failure, and the incidence of adverse events. The end-of-study visit will evaluate the primary endpoint, which is the proportion of participants with HBV virological failure at 96 weeks.

Participant involvement is expected to last for the full 96-week duration unless early termination is warranted. Conditions for early termination include virological failure, defined as two successive HBV viral load measurements exceeding 10 IU/mL, or adverse events that necessitate discontinuation of the treatment strategy. The trial will also assess secondary endpoints such as the evolution of CD4 and CD8 T lymphocytes, metabolic parameters, and participants' quality of life. The study aims to provide valuable insights into the management of patients with HIV-1 and HBV co-infection, focusing on the safety and efficacy of treatment reduction strategies.

The clinical trial involves the administration of **PREZISTA** 800 mg film-coated tablets, which contain the active substance **darunavir**. This medication is provided in the form of film-coated tablets and is administered orally. The maximum daily dose is 800 mg, and the treatment period extends up to 96 weeks. **Darunavir** is a chemical substance, and its administration is part of a dual therapy regimen, boosted by **ritonavir** 100 mg, in combination with **lamivudine** 300 mg.

**Norvir** 100 mg powder for oral suspension, containing the active substance **ritonavir**, is also utilized in this trial. This medication is administered orally in the form of a powder for suspension. The maximum daily dose is 100 mg, with a treatment duration of up to 96 weeks. **Ritonavir** is a chemical substance and serves as a pharmacokinetic enhancer in the treatment regimen.

**Tivicay** 50 mg film-coated tablets, containing **dolutegravir sodium**, are included in the study. These tablets are administered orally, with a maximum daily dose of 50 mg, and the treatment period is up to 96 weeks. **Dolutegravir sodium** is a chemical substance, and its administration is part of a dual therapy regimen in combination with **lamivudine** 300 mg.

**Epivir** 300 mg film-coated tablets, containing the active substance **lamivudine**, are administered orally. The maximum daily dose is 300 mg, with a treatment duration of up to 96 weeks. **Lamivudine** is a chemical substance and is used in combination with either **dolutegravir sodium** or **darunavir** boosted by **ritonavir** 100 mg as part of the dual therapy regimen.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of participants experiencing **HBV virological failure** at 96 weeks. Virological failure is defined as two successive HBV viral load measurements exceeding 10 IU/mL or a single measurement above the detection threshold followed by permanent discontinuation of the treatment strategy or follow-up in the trial.

Secondary endpoints include the **HBV virological success rate** at 48 weeks, the **HIV virological success rate** at both 48 and 96 weeks, and the time to virological failure, which encompasses rebound in HBV and/or HIV viral load. Additional secondary endpoints involve the rate of participants with at least one HBV viral load blip until weeks 48 and 96, the selection of HBV resistance mutations at the time of virological failure, and the incidence of grade 3 or higher adverse events, as well as the incidence of strategy discontinuation at weeks 48 and 96.

Further assessments will include the evolution of CD4 and CD8 T lymphocytes, and the CD4/CD8 ratio from baseline to weeks 48 and 96, as well as changes in metabolic parameters such as total cholesterol, LDL-c, HDL-c, triglycerides, and fasting blood sugar over the same period. Participants' compliance with treatment will be evaluated using a self-questionnaire at multiple timepoints: baseline, weeks 12, 24, 48, 72, and 96. Additionally, participants' quality of life will be assessed using the Pro-Qol self-questionnaire at the same intervals. The HBV virological success rate at 96 weeks will also be compared between different treatment arms.