Pharmacokinetic and pharmacokinetic/pharmacodynamic characterization of the dolutegravir/rilpivirine two‐drug regimen in SWORD‐1/‐2 phase 3 studies

Abstract

Aim: SWORD-1 and SWORD-2 phase 3 studies concluded that switching virologically suppressed participants with HIV-1 from their current three-or four-drug antiretroviral regimen (CAR) to the two-drug regimen of once-daily dolutegravir (DTG, 50 mg) and rilpivirine (RPV, 25 mg) was safe, well tolerated and noninferior for maintaining HIV-1 suppression at week 48 and highly efficacious to week 148. A secondary objective was to characterize drug exposure and exposure-efficacy/safety relationships.Methods: Adults with plasma HIV-1 RNA <50 copies/mL were randomized to switch to once-daily DTG + RPV on day 1 or to continue CAR for 52 weeks before switching. Trough plasma concentrations (C0) of DTG and RPV, the proportion of participants with HIV-1 RNA <50 copies/mL and adverse events to week 100 were summarized and subjected to exposure-response analyses in the overall population, in the subset of participants who switched from CAR containing enzyme-inducing drugs and by age category (≥50 and <50 years). The relationship between C0avg (individual average C0 across visits) and efficacy/safety was investigated.Results: Although week 2 DTG and RPV C0 were lower in participants switching from enzyme-inducing antiretroviral drugs, C0 and C0avg stayed above in vitro antiviral protein binding-adjusted IC90 and to week 100 with viral suppression >89%. DTG or RPV C0avg showed no relationship with virologic failures or safety. Participants ≥50 years had similar C0avg and safety response to younger participants. Conclusion:No clinically relevant relationship between DTG or RPV exposures and virologic or safety response was observed, confirming the DTG + RPV switch for participants as a safe and effective treatment.The primary efficacy and safety results of SWORD-1 and SWORD-2, two multicentre phase 3 trials conducted by more than 125 physician investigators in 13 countries, were previously published in Lancet. 1 Dr Josep Llibre and Dr Chien-Ching Hung, the two investigator signatories for the SWORD-1 and SWORD-2 study reports, were the lead authors on the primary manuscript, along with other high enrolling authors. The present manuscript reports on a secondary analysis: the integration of pharmacokinetic (PK) and pharmacodynamic (PD) data from the SWORD studies. The collation of these PK/PD results does not reflect the direct work of physician investigators, therefore the principal investigators are not included as authors of this manuscript.Clinical trial registration: ClinicalTrials.gov, NCT02429791 (SWORD-1) and NCT02422797 (SWORD-2).