Elsevier

The Lancet

Volume 391, Issue 10123, 3–9 March 2018, Pages 839-849
The Lancet

Articles
Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies

https://doi.org/10.1016/S0140-6736(17)33095-7Get rights and content

Summary

Background

Lifelong HIV antiretroviral therapy (ART) has prompted an interest in two-drug regimens to minimise cumulative drug exposure and toxicities. The safety, tolerability, and efficacy of dolutegravir and rilpivirine suggest potential compatibility and effectiveness as a two-drug regimen. We aimed to investigate this two-drug regimen in a phase 3 study.

Methods

We identically designed SWORD-1 and SWORD-2, which were open-label, parallel-group, multicentre, phase 3, randomised, non-inferiority studies in 12 countries evaluating efficacy and safety of once-daily dolutegravir 50 mg plus rilpivirine 25 mg versus current ART regimen (CAR). We included participants aged 18 years or older who were on first or second ART with stable plasma HIV-1 RNA (viral load <50 copies per mL) for 6 months or longer at screening. We randomly assigned participants (1:1) with stratification by third-agent class, age, and planned participation in a bone mineral density substudy. The primary endpoint was proportion of participants with viral load lower than 50 copies per mL at week 48 among those individuals who received one or more doses of study medication. Investigators monitored adverse events to assess safety. These trials are registered with ClinicalTrials.gov, numbers NCT02429791 (SWORD-1) and NCT02422797 (SWORD-2).

Findings

We screened for participants from April 14, 2015, to Oct 15, 2015, for SWORD-1 and from April 21, 2015, to Sept 25, 2015, for SWORD-2. We randomly assigned 516 participants to dolutegravir-rilpivirine and 512 to continue with CAR. At week 48 (last patient visit was Nov 22, 2016), in the pooled analysis of the intention-to-treat population, 95% of participants had viral loads lower than 50 copies per mL in each group (486 of 513 in the dolutegravir-rilpivirine group vs 485 of 511 in the CAR group), with an adjusted treatment difference of −0·2% (95% CI −3·0 to 2·5) and showed non-inferiority with a predefined margin of −8%. 395 (77%) of 513 participants in the dolutegravir-rilpivirine group and 364 (71%) of 511 participants in the CAR group reported adverse events. The most common adverse events were nasopharyngitis (49 [10%] for dolutegravir-rilpivirine vs 50 [10%] for CAR) and headache (41 [8%] vs 23 [5%]). More participants taking dolutegravir-rilpivirine (17 [3%]) reported adverse events leading to withdrawal than did participants taking CAR (three [<1%]).

Interpretation

Dolutegravir-rilpivirine was non-inferior to CAR over 48 weeks in participants with HIV suppression and showed a safety profile consistent with its components. Results support the use of this two-drug regimen to maintain HIV suppression.

Funding

ViiV Healthcare and Janssen Pharmaceutica NV.

Introduction

Treatment guidelines for adults with HIV-1 infection recommend first-line and second-line antiretroviral therapy (ART) regimens comprising two nucleoside reverse transcriptase inhibitors (NRTIs) plus a third drug from the boosted protease inhibitor, integrase strand transfer inhibitor (INSTI), or non-NRTI (NNRTI) classes. It has been noted that NRTIs have been associated with long-term negative mitochondrial, renal, cardiovascular, and bone-health effects, prompting clinicians to seek NRTI-sparing options to treat HIV-1 infection.1

Research in context

Evidence before this study

We searched PubMed between April 17 and 27, 2017, for clinical trial publications, cohort studies, and review articles published in English from 2004 to 2017, using combinations, abbreviations, and variations of the search terms “HIV”, “antiretroviral therapy”, “dolutegravir”, “integrase strand transfer inhibitor”, “rilpivirine”, “non-nucleoside reverse transcriptase inhibitor”, “nucleoside reverse transcriptase inhibitor”, “dual therapy”, “two-drug regimens”, and “treatment simplification”. We used general Internet searches to acquire relevant practice guidelines and prescribing inserts from governmental, non-governmental, and corporate organisations. The evidence showed that two-drug regimens are being discussed and developed by investigators and clinicians to address emerging polypharmacy, lifelong cumulative drug exposure, ageing, and nucleoside reverse transcriptase inhibitor (NRTI) toxicity issues being faced by patients with HIV-1 infection. The notion for treatment in HIV for almost 20 years has been that three-drug regimens are required to provide adequate virological efficacy and a barrier to emergence of resistance. However, the development and regulatory approval of the potent integrase strand transfer inhibitor dolutegravir has facilitated development of two-drug regimens. The potency, safety, and high-resistance barrier of dolutegravir make it an optimal core drug for an NRTI, protease inhibitor, and booster-sparing two-drug regimen, and the efficacy, safety, and tolerability of rilpivirine suggest compatibility with dolutegravir.

Added value of this study

Results of the SWORD-1 and SWORD-2 studies show that dolutegravir-rilpivirine is non-inferior (predefined −8% non-inferiority margin) to the continuation of triple therapy, consisting of two NRTIs with a third drug belonging to the integrase strand transfer inhibitor, non-nucleoside reverse transcriptase inhibitor, or protease inhibitor classes in maintaining virological suppression through 48 weeks. To date, these studies comprise the largest trial population in which the efficacy and safety of a two-drug regimen have been evaluated. These findings provide a robust demonstration of the suitability of this two-drug regimen, dolutegravir-rilpivirine, for maintenance of HIV-1 suppression in treatment-experienced adults. These studies might also help with the development of new two-drug regimens following careful selection of antiretroviral drugs based on their potency, safety profile, and pharmacokinetic properties.

Implications of all the available evidence

After the early attempts at treatment of HIV infection with combinations of two antiretroviral drugs encountered mixed efficacy and toxicity results, the development and real-world use of this approach in recent years since the advent of combination therapy with three drugs has been sparse. A systematic review of contemporary two-drug regimen studies revealed that the bulk of these studies were insufficiently powered to support robust conclusions regarding efficacy or had no independent confirmation in separate studies. The SWORD studies highlight the potential benefit of two-drug regimens composed of drugs chosen on the basis of their favourable properties (eg, virological efficacy, pharmacokinetic and pharmacodynamic characteristics, and resistance barrier) in highly adherent patients who might need to minimise the number of concomitant medications they are taking. As the population with HIV ages, polypharmacy might become a more important treatment consideration. Treatment simplification strategies with two-drug regimens such as dolutegravir-rilpivirine might become more prominent in treatment decisions.

With combination ART resulting in longer lifespans, ageing patients with HIV are confronted by a constellation of interrelated comorbidities and drug–drug interaction risks.2 Regimens comprising two antiretroviral drugs have been proposed to minimise cumulative drug exposure and reduce risks for long-term drug-related toxicities.3 A systematic review2 of studies on two-drug regimens, from 2000 to 2014, showed mixed results. Most study populations were small, some trials had no active-control groups, or treatment durations were too short to support robust conclusions, and larger randomised trials had no independent confirmation from adequately powered follow-up trials.2 Concerns surrounding two-drug regimens include questions about how they compare with triple therapy in terms of barrier to treatment-emergent resistance and subsequent virological failure.4 Thus, the success of two-drug regimens might depend on choosing component drugs with complementary therapeutic, pharmacokinetic, and pharmacodynamic properties.3

The properties of dolutegravir make it a suitable candidate to investigate in two-drug regimens. Its 14-h plasma half-life and low-to-moderate pharmacokinetic variability between patients support once-daily dosing.5 The drug–drug interaction risks with dolutegravir are low because of its minimal effect on hepatic enzymes and its virological potency without pharmacokinetic boosters.6 The safety and efficacy of dolutegravir have been extensively studied in treatment-naive7, 8 and treatment-experienced9 patients with HIV-1 infection, and it has shown superiority or non-inferiority to comparator regimens, as well as efficacy, regardless of baseline viral load, in each of its phase 3 trials.7, 8, 9 Treatment-emergent resistance has not been reported in any previously ART-naive patient who received dolutegravir in these trials,7, 8 and dolutegravir has been shown to retain activity against most drug-resistance mutations selected by other INSTIs.10

Rilpivirine is an NNRTI with potent virological efficacy and favourable safety profiles when compared with other NNRTIs.11 Its 48-h half-life permits once-daily dosing12 and has shown unchanged virological effectiveness against some resistance mutations selected by other NNRTIs.13 The properties of rilpivirine suggest that it might be compatible with dolutegravir in a once-daily two-drug regimen that blocks viral replication at two stages, thereby enhancing its ability to achieve virological control and suppression. A retrospective cohort study14 of 152 treatment-experienced participants with HIV-1 infection provided preliminary evidence of the safety and efficacy of a once-daily two-drug regimen composed of dolutegravir 50 mg and rilpivirine 25 mg. Dolutegravir-rilpivirine was found to be well tolerated; 115 (99%) of 116 participants remained free of virological failure, and 105 (91%) remained free of therapeutic failure after 24 weeks. In the SWORD-1 and SWORD-2 studies, we aimed to evaluate the efficacy and safety of dolutegravir-rilpivirine compared with continuation of current ART regimen (CAR) for 48 weeks in a large randomised population with suppressed viral load.

Section snippets

Study design and participants

The SWORD-1 and SWORD-2 studies are identically designed, 148-week, phase 3, randomised, multicentre (12 countries; appendix), open-label, parallel-group, active-controlled, non-inferiority studies. The studies were done under approval of national, regional, or investigational site ethics committees in accordance with the 2008 Declaration of Helsinki. Summaries of the SWORD-1 and SWORD-2 protocols are available online.15, 16

We included participants who were 18 years or older, were on their

Results

We screened for participants from April 14, 2015, to Oct 15, 2015, for SWORD-1 and from April 21, 2015, to Sept 25, 2015, for SWORD-2. The week 48 analysis for both studies included data until Nov 22, 2016. Of 1339 participants screened across both studies, 1028 (77%) were randomly assigned to switch to dolutegravir-rilpivirine (n=516) or continue CAR (n=512; figure 1). The intention-to-treat and safety populations included 1024 participants (figure 1). Participant recruitment ended with about

Discussion

To our knowledge, the SWORD trials have enrolled the largest randomised study population for the evaluation of a two-drug regimen so far2 and both the individual SWORD-1 and SWORD-2 studies and the pooled SWORD data analysis showed non-inferiority in the maintenance of virological suppression over 48 weeks following a switch to dolutegravir-rilpivirine compared with continuing CAR. Notably, the non-inferiority margins (–10% for individual studies and −8% for pooled analysis) were more stringent

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