Evaluation of Doravirine, Tenofovir Disoproxil, and Lamivudine in Virologically Controlled HIV-1 Patients with Historical M184V/I Mutation: A Phase II Open-Label Study

The primary objective of this study is to evaluate the **efficacy** of the combination of Doravirine, Tenofovir Disoproxil Fumarate, and Lamivudine over a 24-week period in individuals living with HIV-1 who are virologically controlled and have a history of the M184V/I mutation, which is not present on the current proviral DNA. This is clinically relevant as it aims to assess the potential of this combination therapy to maintain virological control in a specific patient population with a history of resistance mutations.

Secondary objectives include assessing the effectiveness of the treatment at 48 weeks, evaluating immunological effectiveness, and describing changes after switching to the Doravirine/Tenofovir Disoproxil Fumarate/Lamivudine regimen in terms of proviral HIV DNA, weight, lipid profile, renal parameters, and quality of life. These objectives are important for understanding the broader impacts of the treatment on patient health and well-being over a longer duration.

The clinical trial involves **adult patients** living with **HIV-1** who are virologically controlled and have a history of the M184V/I mutation in a previous genotype. The study population includes both male and female participants, with an age range that encompasses young adults to older adults. Participants are required to have been on stable antiretroviral treatment for at least three months and must have maintained an HIV RNA viral load of less than 50 copies/mL for at least six months. The trial specifically targets individuals who have the M184V/I mutation in at least one previous genotype performed on plasma HIV-RNA, but not present in the current proviral DNA genotype. The trial population was selected based on these criteria, and all participants must have signed informed consent. The sponsor has not provided the total number of participants involved in the study. The trial includes a vulnerable population, and participants must demonstrate complete sensitivity to doravirine and tenofovir according to the genotype of the proviral DNA. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** of a combination therapy consisting of **doravirine**, **tenofovir disoproxil**, and **lamivudine** in individuals living with **HIV-1** who are virologically controlled and have a history of the M184V/I mutation. This is a phase II, open-label, non-comparative pilot study. The trial will span a total duration of 24 weeks, with an estimated end date of March 1, 2026. Participants will be required to attend several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as stable antiretroviral treatment for at least three months and an undetectable viral load for at least six months. The inclusion visit will also ensure the presence of the M184V/I mutation in a previous genotype but absent in the current proviral DNA.

Following the inclusion visit, participants will undergo regular follow-up visits to monitor the primary endpoint, which is the proportion of patients maintaining an undetectable viral load at 24 weeks. Secondary endpoints include the proportion of patients with an undetectable viral load at 48 weeks, changes in NGS genotype on proviral DNA, CD4 count, weight, lipid profile, and quality of life assessments. The end-of-study visit will occur at the conclusion of the 24-week period, where final assessments will be conducted.

Participant involvement is expected to last for the entire 24-week duration unless conditions arise that necessitate early termination, such as adverse events or withdrawal of consent. The trial will employ an intention-to-treat-exposed (ITT-e) analysis, with a sensitivity analysis conducted according to the FDA snapshot algorithm. The study is not categorized as low intervention and is conducted under the authorization of the relevant regulatory bodies. The investigational product, Delstrigo, is administered orally in the form of film-coated tablets, with a maximum daily dose of 100 mg. Participants will be closely monitored throughout the trial to ensure safety and efficacy of the treatment regimen.

The clinical trial involves the administration of **Delstrigo**, a combination medication formulated as **film-coated tablets**. Each tablet contains three active substances: **lamivudine**, **doravirine**, and **tenofovir disoproxil**. The pharmaceutical form is designed for oral administration. The dosage of the medication is specified as 100 mg of lamivudine, 300 mg of doravirine, and 245 mg of tenofovir disoproxil per tablet. Participants in the trial are required to take the medication orally once daily. The maximum treatment period is set at 52 weeks, with a maximum daily dose of 100 mg for each active substance. The medication is not a pediatric formulation and is not classified as an orphan drug.

**Lamivudine** is a chemical compound used as an active substance in the trial. It is part of the combination therapy provided in the Delstrigo tablets. The chemical origin of lamivudine is confirmed, and it is included in the formulation to contribute to the overall efficacy of the treatment regimen.

**Doravirine**, also known by the synonym MK-1439, is another chemical compound included in the Delstrigo tablets. It is utilized for its antiviral properties and is a critical component of the combination therapy aimed at managing HIV in participants with a history of the M184V/I mutation.

**Tenofovir disoproxil** is the third active substance in the Delstrigo formulation. Like the other components, it is of chemical origin and plays a significant role in the antiviral activity of the combination therapy. The inclusion of tenofovir disoproxil is intended to enhance the virological efficacy of the treatment.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for this study. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial's main objective is to evaluate the efficacy of the Delstrigo combination in individuals living with HIV who have a history of the M184V/I mutation and are virologically controlled.

The efficacy of the combination therapy consisting of **Doravirine**, **Tenofovir Disoproxil Fumarate**, and **Lamivudine** will be assessed in a phase II, open-label, non-comparative pilot study involving individuals living with HIV who have a history of the M184V/I mutation and are virologically controlled. The primary endpoint for evaluating efficacy is the proportion of patients achieving an undetectable viral load at 24 weeks. This will be analyzed per-protocol, excluding subjects who discontinue the experimental treatment without reaching a classifying event or are lost to follow-up. A sensitivity analysis will be conducted using the FDA snapshot algorithm on an intention-to-treat-exposed (ITT-e) basis.

Secondary endpoints include the proportion of patients with an undetectable viral load (<50 copies/mL) at 48 weeks, assessed using the FDA's ITT-e snapshot algorithm. Additional secondary measures involve the evolution of the NGS genotype on proviral DNA, changes in CD4 count, weight, and lipid profiles (LDL, HDL, triglycerides, and total cholesterol) between baseline, week 24, and week 48. The study will also evaluate changes in quality of life using the SF36 questionnaire at these timepoints. These assessments will provide comprehensive data on the virological and clinical efficacy of the treatment regimen over the study period.