Tenofovir-lamivudine-dolutegravir Combination as Second-line ART: a Randomised Controlled Trial
Status:
Recruiting
Trial end date:
2022-10-01
Target enrollment:
Participant gender:
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.