Clinical trial NCT03991013: Tenofovir-lamivudine-dolutegravir Combination as Second-line ART: a Randomised Controlled Trial
Official title: AntiRetroviral Therapy In Second-line: Investigating Tenofovir-lamivudine-dolutegravir (ARTIST): a Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: second line antiretroviral therapy
dolutegravir
Lead sponsor: University of Cape Town
Sponsor class: OTHER
Collaborators: name: Wellcome Trust
name: Médecins Sans Frontières, Belgium
First posted: 2019-06-19
Enrollment: 192
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study will be a phase 2, randomised, double-blind, placebo-controlled trial of tenofovir-lamivudine-dolutegravir fixed-dose combination daily with a lead-in supplementary 50 mg dose of dolutegravir versus matching placebo taken 12 hours later for the first 14 days in patients failing a first-line tenofovir-emtricitabine/lamivudine-efavirenz regimen.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Virological Suppression at 24 Weeks
timeFrame: 24 weeks
Secondary outcomes:
measure: Virological Suppression at 24 Weeks (Sensitivity Analysis)
timeFrame: 24 weeks
measure: Virological Suppression at 12 Weeks (Modified ITT)
timeFrame: 12 weeks
measure: Antiretroviral Resistance Mutations by Genotypic Resistance Testing
timeFrame: 24 weeks
measure: CD4 Change at 24 Weeks
timeFrame: 24 weeks
measure: Adverse Events
timeFrame: 24 weeks
measure: All-cause Mortality
timeFrame: 24 weeks
measure: Adherence to Treatment
timeFrame: 24 weeks
measure: Geometric Mean Ratio (GMR) of Dolutegravir Trough Concentrations on Day 7 Versus Day 28
timeFrame: First 28 days
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: Khayelitsha Site B/Ubuntu Community Health Clinic
state: Western Cape
Study officials:
affiliation: University of Cape Town
name: Graeme Meintjes, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Médecins Sans Frontières, Belgium
name: Claire Keene
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.