Comparative Study of Integrase Inhibitor Regimen Versus Boosted Protease Inhibitor Regimen in Late-Presenting Advanced HIV-1 Patients

The primary objective of this study is to demonstrate that an **Integrase Inhibitor** containing regimen is no better than a boosted **Protease Inhibitor** regimen in patients with advanced **HIV** infection. This comparison is clinically relevant as it aims to optimize treatment strategies for patients who present late during their acquisition of HIV-1, potentially improving therapeutic outcomes and resource allocation in clinical practice.

Secondary objectives include:

• Investigating the incidence of clinical events such as immunological and virological response, tolerability, resistance development, discontinuation of therapy due to tolerability, quality of life, and **Immune Reconstitution Inflammatory Syndrome (IRIS)**.
• Assessing whether virological response is better predicted by next-generation deep sequencing rather than the standard population sequencing currently performed.

The clinical trial involves a total of **90 participants** who are **HIV-1** infected and present late during their acquisition of the virus. The study population includes both male and female subjects, aged **18 years and older**, with a focus on individuals with advanced HIV infection. Participants are required to be **ART-naïve** prior to study enrollment and must have an **HIV viral load** greater than 1000 copies/mL. The trial includes individuals with a **CD4 cell count** of less than 200/μL or less than 100/μL, depending on the presence of symptoms or opportunistic infections. Participants must be able to take oral medications and are required to use acceptable methods of contraception. The selection process ensures that participants are capable of understanding and signing a written informed consent form and are willing to comply with all study requirements. The trial population is characterized by a vulnerable group, given the advanced stage of their condition and the specific health criteria outlined for inclusion.

The clinical trial is designed as an open-label, multi-centre, randomized study to evaluate the efficacy of an **integrase inhibitor** versus a boosted **protease inhibitor** antiretroviral therapy in patients with advanced **HIV** infection. The primary objective is to determine if the integrase inhibitor regimen is no better than the protease inhibitor regimen, with a secondary aim to assess if the integrase inhibitor regimen is superior. The trial is expected to run from March 5, 2019, to August 31, 2024, with a maximum treatment period of 48 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), **HIV-1** infection status, and ability to take oral medications. Following the screening, eligible participants will be randomized into one of the two treatment arms. Study visits will occur at regular intervals to monitor the primary endpoint, which is the time to failure due to virological or clinical reasons, and secondary endpoints, including viral load measurements, CD4 count changes, and incidence of immune reconstitution inflammatory syndrome (IRIS).

The trial will include follow-up visits at weeks 4, 8, 12, 24, 36, and 48 to assess the proportion of patients achieving specific virological and immunological milestones, as well as to monitor safety and tolerability. The end-of-study visit will occur at week 48, where final assessments will be conducted. Participant involvement is expected to last up to 48 weeks, with conditions for early termination including significant adverse events, non-compliance with study protocols, or withdrawal of consent.

Throughout the trial, participants will receive either Symtuza or Biktarvy, both administered as film-coated tablets taken orally. The study will ensure that all participants are ART-naïve prior to enrollment and are willing to use acceptable methods of contraception. The trial will not include patients with active tuberculosis or cryptococcal meningitis. The study aims to provide valuable insights into optimizing treatment strategies for patients presenting late with advanced **HIV** disease.

The clinical trial involves the administration of **Symtuza** 800 mg/150 mg/200 mg/10 mg film-coated tablets, which is an experimental medication. This pharmaceutical formulation is a combination of four active substances: **emtricitabine**, **tenofovir alafenamide**, **darunavir**, and **cobicistat**. The tablets are administered orally once daily, with a maximum treatment period of 48 weeks. The total maximum dose over the treatment period is 336 tablets. The medication is manufactured by Janssen-Cilag International NV and is authorized for use in the European Union under the marketing authorization number EU/1/17/1225/001. Participant compliance with the dosing schedule is monitored throughout the study.

Another experimental treatment used in the study is **Biktarvy** 50 mg/200 mg/25 mg film-coated tablets. This medication contains a combination of three active substances: **emtricitabine**, **tenofovir alafenamide**, and **bictegravir**. The tablets are also administered orally once daily, with a maximum treatment period of 48 weeks, and a total maximum dose of 336 tablets. Biktarvy is produced by Gilead Sciences Ireland UC and holds the marketing authorization number EU/1/18/1289/001. Compliance with the dosing regimen is similarly monitored to ensure adherence to the study protocol.

A second batch of **Biktarvy** 50 mg/200 mg/25 mg film-coated tablets is also utilized in the trial, identical in formulation and administration to the first batch. This batch is authorized under the marketing authorization number EU/1/18/1289/002. The administration and monitoring procedures remain consistent with the first batch, ensuring uniformity in treatment and compliance tracking across the study.

Efficacy in the clinical trial titled "An Open-Label, Multi-Centre, Randomised Study to Investigate Integrase Inhibitor Versus Boosted Protease Inhibitor Antiretroviral Therapy for Patients with Advanced HIV Disease" will be assessed using both primary and secondary endpoints. The primary endpoint is the time to failure, defined as the first occurrence of specified virological or clinical reasons. Secondary endpoints include the proportion of patients with HIV-RNA viral load less than 50 copies/mL at weeks 24, 36, and 48, and the time to reach a CD4 count greater than 200/μL. Additional secondary endpoints involve the proportion of patients with CD4 cell counts less than 200 μL and less than 350 μL at various timepoints (weeks 4, 8, 12, 24, 36, 48), the CD4/CD8 ratio at these same timepoints, and the incidence of **Immune Reconstitution Inflammatory Syndrome (IRIS)** through week 48.

Further assessments include the incidence and duration of hospitalizations, the rate of relapse of specific opportunistic infections or bacterial infections through week 48, and safety and tolerability measured by Grade 2, 3, and 4 signs and symptoms and laboratory toxicities. ART and opportunistic infection/bacterial infection treatment changes and dose modifications due to toxicities and drug-drug interactions with ART, and IRIS will also be monitored through week 48. Health care resource use, including total inpatient days and emergency room visits, will be evaluated, along with quality of life (QOL) and functional status outcomes, including overall self-reported QOL and functional status compared in the two groups at week 48. Discontinuation or modification of study medication due to insufficient virological response, resistance mutations at baseline, or resistance mutation development before week 48 will also be considered.