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.