Phase II Pilot Study on Dual Antiretroviral Therapy with Long-Acting Cabotegravir and Lenacapavir in HIV-Infected Patients

The primary objective of this study is to evaluate the **efficacy** of maintenance dual antiretroviral therapy with cabotegravir/lenacapavir over a 48-week follow-up period in individuals with **HIV infection**. Efficacy is defined by the absence of virological failure, characterized by two successive viral loads (CVs) of ≥50 copies/mL, a CV of ≥50 copies/mL followed by definitive cessation of treatment or follow-up, or a CV of ≥50 copies/mL at week 48. This objective is clinically relevant as it aims to assess the potential of long-acting antiretroviral therapy to maintain viral suppression, which is crucial for the long-term management of HIV.

Secondary objectives include:

• The rate of virological failure between weeks 24 and 48.
• The rate of participants achieving therapeutic success at week 48, defined as the absence of virological failure and no definitive discontinuation of treatment or study follow-up due to intolerance.
• Resistance profile at the time of virological failure.
• Frequency of minority resistance variants archived in DNA at day 0 and their impact on the risk of virological failure and on the selection of resistance mutations.
• The evolution of the proportion of intact and defective proviruses in PBMC between day 0 and week 48.
• The rate of participants with at least one "blip" (viral load greater than 50 copies/mL with a control less than or equal to 50 copies/mL) between day 0 and week 48.
• Change in CD4 and CD8 T lymphocytes and CD4/CD8 ratio between weeks -2 and 48.
• Plasma concentrations of antiretroviral treatments between day 0 and week 48.
• Assessment of the incidence of grade 3 or higher clinical and laboratory adverse events.
• Assessment of the incidence of adverse events and discontinuation in the study up to week 48.
• Development of weight and BMI between day 0 and week 48.
• Changes in metabolic parameters (total cholesterol, LDL-c, HDL-c, triglycerides, and fasting plasma glucose) between day 0 and week 48.
• Changes in participants' symptoms (self-report) between day 0 and week 48.
• Assessment of participant satisfaction (self-questionnaire) between day 0 and week 48.

The clinical trial involves participants diagnosed with **HIV infection**, with both male and female subjects included. The study population comprises adults aged 18 years and older, with no specific vulnerable populations selected. Participants are required to have a stable oral antiretroviral treatment history for at least six months and must have an undetectable viral load, defined as less than 50 copies/mL, in the last six months. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants are expected to maintain certain lifestyle considerations, such as the use of effective contraception for women at risk of pregnancy and preventive measures during sexual intercourse throughout the trial duration. Key health criteria include ASAT and ALAT levels below three times the normal range, creatinine clearance above 60 mL/min, hemoglobin levels greater than 10 g/dL, and platelet counts exceeding 100,000/mm³. The selection process for the trial population is based on a collegial decision by clinicians, virologists, and pharmacologists, particularly for those with resistance mutations, oral drug intolerance, or drug-drug interactions.

The clinical trial is designed to evaluate the efficacy of maintenance dual **antiretroviral** therapy with **cabotegravir** and **lenacapavir** over a 48-week follow-up period in individuals with **HIV infection**. This study is an open-label, multicenter, Phase II pilot trial. The trial will assess the absence of virological failure, defined as two consecutive viral loads (CVs) of ≥50 copies/mL or a CV ≥50 copies/mL followed by definitive cessation of treatment or follow-up, or a CV ≥50 copies/mL at week 48. Participants will be randomly assigned to receive either **Vocabria** 600 mg prolonged-release suspension for injection or **Sunlenca** 464 mg solution for injection, with the option of **Sunlenca** 300 mg film-coated tablets or **Vocabria** 30 mg film-coated tablets as oral formulations.

The trial will commence with a screening visit to confirm eligibility based on inclusion criteria such as age ≥18 years, stable oral antiretroviral treatment for at least six months, and undetectable viral load with CV <50 copies/mL in the last six months. Participants must provide informed consent and meet specific health criteria, including ASAT and ALAT <3N, creatinine clearance >60 mL/min, and haemoglobin >10 g/dL. The study will include regular follow-up visits to monitor virological response, safety, and tolerability, with assessments at baseline, week 24, and week 48. The end-of-study visit will occur at week 48, where the primary endpoint of virological failure will be evaluated.

Participant involvement is expected to last approximately 48 weeks, with conditions for early termination including virological failure, adverse events, or withdrawal of consent. Secondary endpoints will include the percentage of participants with virological failure between weeks 24 and 48, therapeutic success at week 48, and the incidence of adverse events. The trial will also explore the presence of resistance mutations and changes in metabolic parameters, CD4 and CD8 T lymphocytes, and participant satisfaction. The estimated recruitment start date is October 4, 2024, with an anticipated end date of May 4, 2026.

The clinical trial involves the administration of **Vocabria 600 mg prolonged-release suspension for injection**, which contains the active substance **cabotegravir**. This pharmaceutical form is a prolonged-release suspension intended for injection. The maximum daily dose is 600 mg, with a total dose of 600 mg administered via injection. The treatment period for this medication is up to 44 weeks. The suspension is manufactured by VIIV Healthcare B.V. and is classified as an antiretroviral agent. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another experimental medication used in the trial is **Sunlenca 300 mg film-coated tablets**, containing the active substance **lenacapavir**. These tablets are administered orally, with a maximum daily dose of 600 mg and a total dose of 600 mg. The treatment period for this formulation is 2 weeks. Sunlenca is produced by Gilead Sciences Ireland Unlimited Company and is also classified as an antiretroviral agent. Compliance with the oral dosing schedule will be closely monitored.

The trial also includes the administration of **Sunlenca 464 mg solution for injection**, which also contains **lenacapavir** as the active substance. This solution is administered via injection, with a maximum daily dose of 927 mg and a total dose of 927 mg. The treatment period for this formulation extends up to 48 weeks. This product is manufactured by Gilead Sciences Ireland Unlimited Company and is categorized as an antiretroviral agent. Participant adherence to the injection schedule will be assessed throughout the study.

Additionally, **Vocabria 30 mg film-coated tablets** are used in the trial, containing **cabotegravir sodium** as the active substance. These tablets are administered orally, with a maximum daily dose of 30 mg and a total dose of 30 mg. The treatment period for this formulation is 4 weeks. The tablets are produced by VIIV Healthcare B.V. and are classified as an antiretroviral agent. Monitoring of participant compliance with the oral dosing schedule will be conducted during the trial.

The efficacy of the clinical trial will be assessed by evaluating the maintenance of dual antiretroviral therapy with **cabotegravir** and **lenacapavir** over a 48-week follow-up period. The primary endpoint for efficacy is defined by the absence of virological failure, which includes two successive viral loads (CVs) of ≥50 copies/mL, a CV of ≥50 copies/mL followed by definitive cessation of treatment or follow-up, or a CV of ≥50 copies/mL at week 48. For participants with detectable viral loads at baseline, virological failure will be assessed starting from week 24.

Secondary endpoints include the percentage of participants with virological failure between weeks 24 and 48, the percentage achieving therapeutic success at week 48, and the percentage of participants with viruses harboring resistance mutations at the time of virological failure. Additional assessments involve the proportion of minority resistance variants archived in DNA, changes in CD4 and CD8 T lymphocytes, and the CD4/CD8 ratio. The study will also describe the evolution of intact and defective proviruses in PBMC, plasma concentrations of antiretroviral treatments, and the incidence of clinical and laboratory grade 3 or higher adverse events. Other parameters include changes in weight, BMI, metabolic parameters, and participant-reported outcomes such as symptoms and satisfaction, assessed via questionnaires from day 0 to week 48.