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 and 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 and dolutegravir, in terms of cost, tolerability and monitoring requirements. The ARTIST study will be a randomised, open-label, active-controlled trial with 48 weeks of follow up, and will evaluate the viral load suppression achieved by participants taking the fixed dose combination of tenofovir, lamivudine and dolutegravir or zidovudine, lamivudine and dolutegravir as second-line therapy. 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 that includes a tenofovir and lamivudine or emtricitabine backbone and a non-nucleoside reverse transcriptase inhibitor (NNRTI). The trial will comprise two stages: the first will evaluate the viral suppression in 65 participants produced by the fixed dose combination of tenofovir, lamivudine and dolutegravir with a supplementary dose of dolutegravir for the first 14 days to mitigate the NNRTI effect in reducing dolutegravir concentrations when switching antiretrovirals. The study will progress to the second stage if this proves effective, and 130 participants will then be randomised to receive the fixed dose combination of tenofovir, lamivudine and dolutegravir (without a supplementary dose of dolutegravir) or the WHO standard of care second-line regimen of zidovudine, lamivudine and dolutegravir. The primary endpoint is viral suppression (viral load<50 copies/mL) at 24 weeks. A Pharmacokinetic sub-study will be conducted on 12 participants in stage 1 and in 12 patients in stage 2 who are randomised to the intervention arm, 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.
Name: TLD: fixed dose combination of tenofovir, lamivudine and dolutegravir antiretroviral therapy
Description: TLD fixed dose combination contains tenofovir 300mg, lamivudine 300mg and dolutegravir 50mg, administered once daily orally for 48 weeksType: DrugTLD
Name: ALD: combination of zidovudine, lamivudine and dolutegravir antiretroviral therapy
Description: ALD is the World Health organization standard of care second line regimen, and contains a combination of zidovudine 300mg and lamivudine 150mg, administered orally as a fixed dose combination twice daily, and dolutegravir 50mg administered orally once daily, for 48 weeks.Type: DrugALD
Description: VL< 50 copies/mL in the participants overall and stratified by presence or absence of resistance mutations at baseline, in stage 1
Measure: Virological suppression in stage 1 Time: 24 weeksDescription: VL< 50 copies/mL in the participants overall and stratified by presence or absence of resistance mutations at baseline, in stage 2
Measure: Virological suppression in stage 2 Time: 24 weeksDescription: To determine the proportion of patients who develop dolutegravir resistance mutations and new nucleoside reverse transcriptase inhibitors on second-line treatment
Measure: Proportion new ARV resistance Time: 48 weeksDescription: To evaluate the trough concentrations (ng/mL) of dolutegravir in the period after switching regimens
Measure: PK trough DTG Time: first 28 daysDescription: To evaluate the residual concentrations (ng/mL) of efavirenz in the period after switching regimens
Measure: PK residual EFV Time: first 28 daysDescription: To evaluate the proportion of patients with dolutegravir trough concentrations above the PA-IC90 value at all PK time points.
Measure: PK DTG above PA-IC90 Time: first 28 daysDescription: To describe tenofovir-diphosphate concentration (ng/mL - marker of adherence) in those with virological failure at 24 and 48 weeks by treatment arm and to compare to a group of matched controls.
Measure: Adherence in failures stage 1 Time: 24 and 48 weeksDescription: To describe dolutegravir concentration (ng/mL - marker of adherence) in those with virological failure at 24 and 48 weeks by treatment arm and to compare to a group of matched controls.
Measure: Adherence in failures stage 2 Time: 24 and 48 weeksDescription: To describe adverse events among the study cohort in stage one and in stage two by treatment arm
Measure: Description of adverse events Time: 48 weeksDescription: To describe all-cause mortality among the study cohort in stage one and in stage two by treatment arm
Measure: Description of all cause mortality Time: 48 weeksAllocation: Randomized
Parallel Assignment
There are 2 SNPs
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 that includes a tenofovir and lamivudine or emtricitabine backbone and a non-nucleoside reverse transcriptase inhibitor (NNRTI). --- K65R ---
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 that includes a tenofovir and lamivudine or emtricitabine backbone and a non-nucleoside reverse transcriptase inhibitor (NNRTI). --- K65R --- --- M184V ---