Triple vs. Double Therapy in naïves HIV-Infected Patients (TRIDUNA)

Effectiveness of a Dual Therapy (Dolutegravir + Lamivudine) on Reduction of the Viral Reservoir, Immune Recovery and Immune Activation Compared With a Triple Therapy (Dolutegravir + Tenofovir Alafenamide/Emtricitabine) in Treatment-naïve HIV-Infected Patients

The objective of this study is to clarify whether if starting antiretroviral treatment based on dual therapy (DTG + 3TC) could provide less control of residual HIV replication and, therefore, a detriment on immune activation and inflammation compared to starting with triple therapy, and could worsen the patients' long-term prognosis. For this purpose, the investigator has designed a randomized clinical trial where will assess the immunological recovery (CD4+/CD8+), immune activation, proliferation, senescence and apoptosis in T lymphocytes CD4+ and CD8+ cells by flow cytometry, the immune activation of monocytes/ macrophages and plasma concentrations of various inflammatory mediators by ELISAS, and the thymic function, the cellular reservoir of HIV and the degree of HIV DNA transcription by digital dropped PCR.

Study Overview

• Status: Unknown
• Conditions: HIV Infection
• Intervention / Treatment: Drug: Randomize

• Study Type: Interventional
• Enrollment (Anticipated): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Seville, Spain, 41013
    • Recruiting
    • Hospital Universitario Virgen del Rocío
    • Contact: Luis F Lopez-Cortes, MD, PhD; Phone Number: 34 - 955013096; Email: lflopez@us.es
    • Principal Investigator: Luis F Lopez-Cortes, MD, PhD
    • Principal Investigator: Alicia Gutierrez-Valencia, Pharm D
    • Sub-Investigator: Pompeyo Viciana, MD, PhD
    • Sub-Investigator: Rosa Ruiz-Valderas, MD, PhD
    • Sub-Investigator: Juan R Castillo-Ferrando, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Treatment-naïve HIV-1-infected patients ≥ 18 years of age.
• Plasma HIV-1 RNA >5000 and <500.000 copies/ml.
• T lymphocyte CD4+ count in peripheral blood >200/μl.

• Patients of childbearing age should consent to use a highly effective contraceptive method from 15 days before the time of inclusion of the study until 30 days after the end of it. It is considered a highly effective method:

  • Complete abstinence from penile-vaginal intercourse from 2 weeks prior to administration of Investigational Product, throughout the study, and for at least 2 weeks after discontinuation of all study medications;
  • Any intrauterine device with published data showing that the expected failure rate is <1% per year (not all intrauterine devices meet this criterion)
  • Male partner sterilization confirmed prior to the female subject's entry into the study, and this male is the sole partner for that subject.
  • Approved hormonal contraception.
  • Any other method with published data showing that the expected failure rate is <1% per year.
• Signed written informed consent prior to inclusion.

Exclusion Criteria:

• Acute HIV infection
• T lymphocyte CD4+ count in peripheral blood ≤ 200/µl
• Active opportunistic infection.
• Pregnancy at inclusion or during the follow-up
• Active hepatitis C and/or B virus co-infection.
• ALT ≥ 5 times the ULN, or ALT ≥ 3xULN and bilirubin ≥ 1.5xULN (with >35% direct bilirubin).
• Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (apart from hyperbilirubinemia or jaundice due to Gilbert's syndrome or asymptomatic gallstones).
• Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification.
• Current or past disease that requires the use subsidiary of treatment with corticosteroids, immunomodulatory agents, interferon or chemotherapeutic agents.
• Any laboratory abnormality grade 3 or 4 according to the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (Annex 3)
• Concomitant use of drugs with potential major interactions with the prescribed drugs according to the respective full prescribing information.
• Estimated creatinine clearance <50ml/min.
• History or presence of allergy to the study drugs or their components

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dual Therapy; Dolutegravir plus lamivudine	Drug: Randomize; Randomize to naive-treatment HIV-infected patients to receive dual o triple therapy as initial antiretroviral treatment; Other Names: Triple therapy
Active Comparator: Triple Therapy; Dolutegravir plus TAF/FTC	Drug: Randomize; Randomize to naive-treatment HIV-infected patients to receive dual o triple therapy as initial antiretroviral treatment; Other Names: Triple therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
proviral HIV-DNA	Mean changes in proviral HIV-DNA in PBMCs after 48 and 96 weeks of treatment	48 and 96 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune Recovery	Mean changes immune recovery assessed by CD4+/CD8+ T cell ratio.	48 and 96 weeks
Immune Activation	Mean changes immune activation assessed by the expression of HLA-DR and CD38 in both of CD4+ and CD8+ T cells.	48 and 96 weeks
Monocytes Activation	Mean changes monocytes activation (plasma sCD14 and sCD163).	48 and 96 weeks
Immunosenescense	Mean changes expression of markers for recent thymic emigrants (CD31), proliferation (Ki67), dysfunction (PD-1), senescence (CD57), and apoptosis (annexin A) in both CD4+ and CD8+ T cells.	48 and 96 weeks
Inflammation	Mean changes concentration of pro-inflammatory soluble mediator in plasma: TNF-α, IL-1β, IL-6, IP-10, IFN- γ, MIP-1α, MIP-1β, hsPCR y D-dímers.	48 and 96 weeks
Viral Reservoir	Mean changes viral reservoir size, evaluated by proviral HIV-DNA and HIV-RNA in peripheral blood mononuclear cells (PBMC) and CD4+ T cells isolate.	48 and 96 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Semen	Mean changes of HIV-RNA seminal plasma viral load	24 weeks
GALT	Mean changes of viral reservoir assessed as proviral HIV-DNA and HIV-RNA in GALT	48 weeks

Collaborators and Investigators

• Sponsor: Hospitales Universitarios Virgen del Rocío

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2020
• Primary Completion (Anticipated): January 1, 2022
• Study Completion (Anticipated): March 1, 2023

Study Registration Dates

• First Submitted: March 2, 2020
• First Submitted That Met QC Criteria: March 2, 2020
• First Posted (Actual): March 4, 2020

Study Record Updates

• Last Update Posted (Actual): August 18, 2020
• Last Update Submitted That Met QC Criteria: August 14, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: FIS-TAR-01-2019

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No