Antiretroviral Treatment Guided by Proviral Genotype: Pilot Trial of Proof of Concept.

Phase IIa, open clinical trial, pilot, single arm and proof of concept.

Study Overview

• Status: Unknown
• Conditions: HIV-1-infection
• Intervention / Treatment: Drug: Dolutegravir (DTG); Drug: Lamivudine (3TC)

Detailed Description

Proof of concept trial evaluating safety and efficacy of treatment with Dolutegravir (DTG) + lamivudine (3TC) once daily in suppressed participants with history of previous treatment with 3TC or emtricitabine (FTC). Half of the participants will have history of failure with 3TC or FTC and M184V/I or K65R/E/N mutations in previous plasma genotypes, although to be eligible these mutations cannot be detectable at study entry in proviral DNA.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28041
    • Hospital 12 de Octubre

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:

1. HIV-1 infected patients.
2. Age> 18 years.
3. Receiving stable antiretroviral treatment for at least 3 months.
4. Current or historical treatment with 3TC or FTC.
5. Willing to change antiretroviral treatment due to intolerance or interest in simplification.
6. Undetectable viral load (<50 cop/mL) for at least 1 year prior to the inclusion. A single viral load >50cop/ml (≤500 copies/ml) is allowed before the three months prior to inclusion in the study, preceded and followed by an undetectable determination.
7. Current level of CD4> 350 cells/μL.
8. Naïve to integrase inhibitors.
9. Patient able to understand and give written informed consent.
10. For those included in group 1 (20 patients): No previous history of virological failure with ART regimen that included 3TC or FTC or previous virological failure had a population genotype without M184V/I or K65R/E/N mutations.
11. For those included in group 2 (20 patients): previous history of virological failure with ART regimen that included 3TC or FTC and historical genotype with M184V/I or K65R/E/N mutations.

Exclusion Criteria:

1. Detection of any of the following mutations in proviral DNA in peripheral blood by conventional sequencing: M184V/I or K65R/E/N.
2. Pregnant, lactating or child-bearing women who do not commit to using an adequate contraceptive method.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dolutegravir (DTG) + Lamivudine (3TC); Eligible subjects will receive one 50 mg tablet of DTG plus 300 mg 3TC tablet orally once daily upto 48 weeks	Drug: Dolutegravir (DTG); DTG 50 mg tablet will be orally administered once daily with or without food upto 48 weeks; Other Names: Tivicay; Drug: Lamivudine (3TC); Lamivudine will be dispensed as 300 mg white, diamond shaped, scored, film coated tablets. It will be orally administered once daily with or without food upto 48 weeks.; Other Names: Epivir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with undetectable viral load (<50 copies / mL) at 48 weeks	- Efficacy: Proportion of patients with undetectable viral load (<50 copies / mL) at 48 weeks of follow-up, according to the FDA snapshot algorithm in the population "by intention to treat-exposed". The intention-to-treat population includes all patients who have received at least one dose of DTG and 3TC.	Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with virological failure at 24 weeks	Proportion of patients with viral load <50 copies/ml at week 24, according to the FDA snapshot algorithm in the population "by intention to treat-exposed".	Week 24
Proportion of patients with virological failure at 48 weeks	Proportion of patients with virological failure at week 48 according to the FDA snapshot algorithm.	Week 48
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Incidence of adverse events and discontinuation of treatment due to toxicity or intolerance.	Since baseline visits to week 48
Evaluation of the appearance of genotypic resistance mutations (1)	Incidence of genotypic resistance mutations in patients with virological failure at week 48. Description and frequency of genotypic resistance mutations.	Week 48

Collaborators and Investigators

• Sponsor: Instituto de Investigación Hospital Universitario La Paz

Publications and helpful links

General Publications

• De Miguel R, Rial-Crestelo D, Dominguez-Dominguez L, Montejano R, Esteban-Cantos A, Aranguren-Rivas P, Stella-Ascariz N, Bisbal O, Bermejo-Plaza L, Garcia-Alvarez M, Alejos B, Hernando A, Santacreu-Guerrero M, Cadinanos J, Mayoral M, Castro JM, Moreno V, Martin-Carbonero L, Delgado R, Rubio R, Pulido F, Arribas JR; ART-PRO, PI16/00837-PI16/00678 study group. Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a non-randomized, pilot clinical trial (ART-PRO). EBioMedicine. 2020 May;55:102779. doi: 10.1016/j.ebiom.2020.102779. Epub 2020 May 11.

Study record dates

Study Major Dates

• Study Start (Actual): November 2, 2017
• Primary Completion (Anticipated): May 31, 2021
• Study Completion (Anticipated): July 31, 2021

Study Registration Dates

• First Submitted: April 2, 2018
• First Submitted That Met QC Criteria: May 25, 2018
• First Posted (Actual): May 29, 2018

Study Record Updates

• Last Update Posted (Actual): July 7, 2020
• Last Update Submitted That Met QC Criteria: July 6, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Lamivudine; Dolutegravir
• Other Study ID Numbers: ART-PRO; 2017-000151-10 (EudraCT Number)

Drug and device information, study documents

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