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

Study Overview
=================
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.

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

Conditions
-----------------
HIV Infections

Intervention / Treatment
-----------------
* Drug: Dolutegravir 50 mg
* Drug: Placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Supplementary dose<br>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<br>* 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).<br>* Other names: Dalimune 50 mg;|
| Placebo Comparator: Placebo dose<br>Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with a matching placebo taken 12 hours later for the first 14 days. | Drug: Placebo<br>* 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).<br>|

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, overall and stratified by the presence or absence of resistance to tenofovir and lamivudine at baseline. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antiretroviral resistance mutations by genotypic resistance testing | To describe resistance profile at baseline (NRTI and efavirenz resistance), and treatment-emergent resistance to integrase inhibitor and NRTI in participants who experience virological failure. | Baseline, 24 and 48 weeks | 
| Residual efavirenz concentrations and dolutegravir trough concentrations | To evaluate the trough concentrations (ng/mL) of dolutegravir and the residual concentrations (ng/mL) of efavirenz in the period after switching regimens. To evaluate the proportion of participants with dolutegravir trough concentrations above the protein-adjusted 90% inhibitory concentration (PA-IC90) value at all pharmacokinetics time points. | First 28 days | 
| Virological suppression at 12 and 48 weeks (modified ITT) | Proportion of participants with HIV viral load <50 copies/mL at 12 and 48 weeks analysed by modified ITT. | 12 and 48 weeks | 
| Virological suppression at 12, 24 and 48 weeks (per protocol) | Proportion of participants with HIV viral load <50 copies/mL at 12, 24 and 48 weeks analysed per protocol. | 12, 24 and 48 weeks | 
| Adherence to treatment | To describe tenofovir-diphosphate concentration (ng/mL) in participants who experience virological failure and matched controls from among those who are suppressed at 24 and 48 weeks. | 24 and 48 weeks | 
| CD4 change at 24 and 48 weeks | Change in CD4 count from screening at week 24 and 48. | 24 and 48 weeks | 
| Adverse events | To describe grade 3 and 4 drug-related adverse events, serious adverse events, and any adverse event requiring discontinuation of any drug in the ART regimen. | 48 weeks | 
| All-cause mortality | To describe all-cause mortality. | 48 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
second line antiretroviral therapy, dolutegravir