Tenofovir-lamivudine-dolutegravir Combination as Second-line ART: a Randomised Controlled Trial (ARTIST)

AntiRetroviral Therapy In Second-line: Investigating Tenofovir-lamivudine-dolutegravir (ARTIST): a Randomised Controlled Trial

The strategy to support virological suppression on second-line antiretroviral treatment (ART) includes the provision of ART that has a low pill burden, good tolerability, low toxicity, is easily monitored, has a high barrier to resistance, and that is low cost. The fixed-dose combination of tenofovir-lamivudine-dolutegravir offers significant advantage as a potential second-line regimen compared to the World Health Organization standard of care second-line regimen of zidovudine-lamivudine-dolutegravir, in terms of cost, tolerability and monitoring requirements.

The ARTIST study is a phase 2, randomised, double-blind, placebo-controlled trial aiming to determine the proportion of patients achieving virological suppression when recycling the tenofovir-emtricitabine/lamivudine backbone with dolutegravir (tenofovir-lamivudine-dolutegravir fixed-dose combination) as a second-line with and without a lead-in supplementary dose of dolutegravir, in patients failing a tenofovir-emtricitabine/lamivudine-efavirenz first-line regimen.

There is evidence to suggest that even in the presence of resistance mutations to tenofovir and lamivudine (K65R or M184V/I), using this backbone with dolutegravir will provide an effective second-line regimen in patients who have failed a first-line regimen of tenofovir-emtricitabine/lamivudine-efavirenz. The strategy of giving a lead-in supplementary dose of dolutegravir is in view of the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks after efavirenz is stopped; the inducing effect decreases with time after efavirenz is stopped.

Given that these patients will have elevated viral loads, a high baseline risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance and efavirenz resistance, and the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks, this study will comprise two stages. The first stage will evaluate virological suppression in 62 participants initiated on the fixed-dose combination of tenofovir-lamivudine-dolutegravir with a lead-in supplementary dose of dolutegravir for the first 14 days. The study will progress to the second stage if this strategy proves effective, and 130 participants will then be randomised to receive the fixed-dose combination of tenofovir-lamivudine-dolutegravir with and without this lead-in dose.

The primary endpoint is virological suppression (viral load <50 copies/mL) at 24 weeks.

A pharmacokinetic sub-study will be conducted on 12 participants in stage 1 and 24 participants in stage 2, to assess the trough concentrations of dolutegravir and off-treatment concentrations of efavirenz at day 3, 7, 14, and 28. This is to evaluate the need for the lead-in supplementary dose of dolutegravir.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Dolutegravir 50 mg; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 192
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Western Cape
    • Cape Town, Western Cape, South Africa, 8001
      • Khayelitsha Site B/Ubuntu Community Health Clinic

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

HIV positive patients over 18 years old, who have failed first-line ART regimen of tenofovir-emtricitabine/lamivudine-efavirenz, are able to attend the study clinic for one year of scheduled visits and who have given written, informed consent will be enrolled in this study. In female patients of child-bearing potential, those willing to use effective and reliable contraception for the duration of the study will be eligible.

Failure of a first-line regimen is defined as a viral load (VL) of >1000 copies/mL (within the previous two months) and an immediately prior VL >1000 copies/mL, taken 2-24 months prior (based on data captured by National Health Laboratory Service).

Exclusion Criteria:

• If the patient has two VLs 2-3 months apart: >2 log drop in VLs between the most recent VL (within the previous two months) and the immediately prior VL (taken 2-3 months prior)
• CD4 count <100 cells/microlitre
• Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) formula
• Alanine aminotransferase >100 U/L or total bilirubin >twice the upper limit of normal
• Pregnant or desire to become pregnant during the study period (48 weeks)
• Breastfeeding
• Being treated for active tuberculosis (TB) or concern that patient has undiagnosed active TB (based on symptom screening) as rifampicin reduces the concentrations of dolutegravir and thus requires dose adjustments
• Any current diagnosis of malignancy
• Allergy or intolerance to one of the drugs in regimen
• Active, severe psychiatric disease judged likely to impact adherence
• Current substance abuse judged likely to impact adherence
• On treatment for AIDS-defining condition (not including secondary prophylaxis maintenance therapy)
• Any other clinical condition that in the opinion of an investigator puts the patient at increased risk if participating in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Supplementary dose; Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days.	Drug: Dolutegravir 50 mg; Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks).; Other Names: Dalimune 50 mg
Placebo Comparator: Placebo dose; Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with a matching placebo taken 12 hours later for the first 14 days.	Drug: Placebo; Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a matching placebo taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virological Suppression at 24 Weeks	Proportion of participants with HIV viral load <50 copies/mL at 24 weeks analysed by modified intention to treat (ITT) and according to the FDA snapshot algorithm	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virological Suppression at 24 Weeks (Sensitivity Analysis)	Proportion of participants with HIV viral load <50 copies/mL at 24 weeks using pre-specified sensitivity analyses	24 weeks
Virological Suppression at 12 Weeks (Modified ITT)	Proportion of participants with HIV viral load <50 copies/mL at 12 weeks analysed by modified ITT.	12 weeks
Antiretroviral Resistance Mutations by Genotypic Resistance Testing	To describe dolutegravir resistance or emergent resistance mutations to tenofovir or lamivudine in participants eligible for genotypic resistance testing by 24 weeks	24 weeks
CD4 Change at 24 Weeks	Change in CD4 count from screening to week 24	24 weeks
Adverse Events	To describe grade 3 or 4 adverse events and serious adverse events	24 weeks
All-cause Mortality	To describe all-cause mortality.	24 weeks
Adherence to Treatment	To describe tenofovir-diphosphate (TFV-DP) concentrations (ng/mL) at 24 weeks	24 weeks
Geometric Mean Ratio (GMR) of Dolutegravir Trough Concentrations on Day 7 Versus Day 28	To evaluate the geometric mean ratio (GMR) of dolutegravir trough concentrations on day 7 versus day 28	First 28 days

Collaborators and Investigators

• Sponsor: University of Cape Town
• Collaborators: Wellcome Trust; Médecins Sans Frontières, Belgium
• Investigators: Principal Investigator: Graeme Meintjes, PhD, University of Cape Town; Principal Investigator: Claire Keene, Médecins Sans Frontières, Belgium

Publications and helpful links

General Publications

• Zhao Y, Keene C, Griesel R, Sayed K, Gcwabe Z, Jackson A, Ngwenya O, Schutz C, Goliath R, Cassidy T, Goemaere E, Hill A, Maartens G, Meintjes G. AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir (ARTIST): protocol for a randomised controlled trial. Wellcome Open Res. 2021 Feb 17;6:33. doi: 10.12688/wellcomeopenres.16597.1. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): August 8, 2019
• Primary Completion (Actual): April 26, 2022
• Study Completion (Actual): October 27, 2022

Study Registration Dates

• First Submitted: May 31, 2019
• First Submitted That Met QC Criteria: June 16, 2019
• First Posted (Actual): June 19, 2019

Study Record Updates

• Last Update Posted (Actual): October 1, 2024
• Last Update Submitted That Met QC Criteria: September 4, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: dolutegravir; second line antiretroviral therapy
• 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; Urogenital Diseases; Genital Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Dolutegravir
• Other Study ID Numbers: ARTIST

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be shared with other organisations or individuals for further research upon a reasonable request to the University of Cape Town PI, provided that certain conditions are met (including but not limited to the ethical standards upheld by Human Research Ethics Committee (HREC) that approved the initial study).
• IPD Sharing Time Frame: From the time the final results are published
• IPD Sharing Access Criteria: Data will be shared with other organisations or individuals for further research upon a reasonable request to the University of Cape Town PI, provided that certain conditions are met (including but not limited to the ethical standards upheld by HREC that approved the initial study).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No