Comparative Study of Doravirine/Lamivudine Versus Dolutegravir/Lamivudine for Maintenance Therapy in HIV Patients with Suppressed Viral Load

The primary objective of the MODULO trial is to evaluate the **non-inferiority** of the doravirine/lamivudine (DOR/3TC) regimen compared to the dolutegravir/lamivudine (DTG/3TC) regimen in maintaining virological success at week 48 in people living with HIV (PLWH) who have achieved viral suppression under a three-drug regimen at inclusion. Virological success is defined as the absence of virological failure, characterized by two consecutive plasma viral loads (pVL) of 50 copies/mL or more, or a single pVL of 50 copies/mL or more followed by treatment discontinuation or loss to follow-up. This objective is clinically relevant as it seeks to determine if a two-drug regimen can effectively maintain viral suppression, potentially reducing drug exposure and associated side effects.

The secondary objectives include assessing various parameters between inclusion and week 48:

• Rate of virological failures
• Rate of therapeutic success using the FDA Snapshot approach
• Mutations of resistance in case of virological failure
• Rate of "blips" (single pVL ≥50 copies/mL, with next pVL <50 copies/mL)
• Residual plasma drug concentrations
• Incidence of clinical and biological side effects, with or without treatment discontinuation
• Evolution of CD4 T-cell counts, CD8 T-cell counts, and CD4/CD8 ratio
• Evolution of weight and BMI
• Evolution of metabolic biomarkers (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, and glycemia)
• Evolution of HIV reservoir (total HIV-DNA in blood)
• Proportion of participants with residual viremia (pVL <20 copies/mL with detectable RT-PCR signal)
• Evolution of the satisfaction associated with the study treatments (self-questionnaire)

The clinical trial involves **adults** aged 18 years and older, living with **HIV-1**. The study population includes both male and female participants who have maintained a suppressed HIV plasma viral load (pVL) of less than 50 copies/mL for at least 24 months. Participants are required to be on a stable three-drug regimen, including two NRTIs and one NNRTI, INSTI, or boosted PI, for a minimum of 12 months. The trial does not involve a vulnerable population. Participants must be affiliated with the French Social Insurance and have provided written consent to participate. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **non-inferiority** of two-drug regimens, specifically doravirine/lamivudine (DOR/3TC) and dolutegravir/lamivudine (DTG/3TC), in maintaining virological success in people living with **HIV** who have been successfully treated with a three-drug regimen. This trial is structured as a randomized, double-blind, controlled study, ensuring that neither the participants nor the researchers know which treatment is being administered, thus minimizing bias. The trial is expected to last until June 2028, with recruitment starting in December 2024, and involves a maximum treatment period of one year 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), stable HIV-1 infection with plasma viral load (pVL) <50 copies/mL for at least 24 months, and a stable three-drug regimen for at least 12 months. Follow-up visits will occur at regular intervals, including assessments at weeks 24, 48, 72, and 96, to monitor virological success, plasma drug concentrations, and other health markers such as CD4/CD8 T-cell counts, metabolic biomarkers, and body weight. The end-of-study visit will conclude the participant's involvement, assessing the primary endpoint of virological failure at week 48 and secondary endpoints at week 96.

Participant involvement is expected to last up to 96 weeks, with conditions for early termination including virological failure, severe side effects, or withdrawal of consent. The trial aims to provide comprehensive data on the efficacy and safety of the two-drug regimens, contributing valuable insights into HIV treatment strategies.

The clinical trial involves the administration of **LAMIVUDINE AND DOLUTEGRAVIR**, a combination of two active substances, **lamivudine** and **dolutegravir**. This experimental medication is provided in an oral pharmaceutical form, identified by the code PHF00082MIG. The maximum daily dose is one unit, with a total treatment period of one day. The administration route is oral, and the medication is classified under the ATC code J05AR25, indicating its use as an antiviral for systemic use, specifically for the treatment of HIV infections. Participant compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.

**DORAVIRINE** is another experimental medication used in the trial, provided as a film-coated tablet. The active substance, doravirine, is administered orally with a maximum daily dose of 100 mg. The treatment period is limited to one day. This medication is categorized as a chemical medicinal product, and its administration is closely monitored to ensure participant compliance with the prescribed dosing schedule.

The trial also includes the administration of **LAMIVUDINE** as a comparator treatment. This medication is provided in a coated tablet form and is administered orally. The maximum daily dose is 300 mg, with a treatment period of one day. Like doravirine, lamivudine is classified as a chemical medicinal product. Participant adherence to the dosing schedule is monitored to maintain the integrity of the trial results.

The efficacy of the MODULO trial will be assessed by evaluating the capacity of two-drug regimens, **DOR/3TC** and **DTG/3TC**, to maintain virological success in people living with HIV (PLWH) who have been successfully treated with a three-drug regimen. The primary endpoint for efficacy is the proportion of participants experiencing virological failure at week 48, defined as two consecutive plasma viral load (pVL) measurements greater than 50 copies/mL within a 2-4 week interval.

Secondary endpoints include the proportion of participants with virological failure at week 96, discontinuation of treatment or follow-up over 96 weeks, and the emergence of new resistance-associated mutations in cases of virological failure. Additional assessments will include plasma drug concentrations at weeks 24, 48, 72, and 96, and in cases of virological failure. Other parameters include CD4 and CD8 T-cell counts, CD4/CD8 ratio, body weight, BMI, metabolic biomarkers, levels of total HIV-DNA in PBMC, and residual viremia at baseline, week 48, and week 96. Patient satisfaction with study treatments will be measured using the HIVTSQ questionnaire at baseline, week 48, and week 96. For participants in the "genital compartment" sub-study, drug concentrations and levels of HIV-RNA in female genital secretions or semen will be measured at weeks 24 and 48.