An antiretroviral regimen consisting of only two drugs, the integrase inhibitor dolutegravir (Tivicay) and the NNRTI rilpivirine (Edurant), held up well as a maintenance approach in people with HIV who switched from more complex regimens, according to study findings presented on Feb. 14 at CROI 2017 in Seattle, Washington. The Phase 3 study results lend support to a switch strategy for people who may be on a virologically successful HIV treatment regimen but nonetheless desire a change to reduce their overall drug burden or curb the risk of certain adverse effects, such as changes in bone markers associated with the use of tenofovir (Viread).
"HIV infection so far requires lifelong antiretroviral treatment with standard regimens of three or four drugs," said Josep Llibre, M.D., a medical consultant in the HIV Unit of the University of Barcelona's Hospital Universitari Germans Trias i Pujol, at a Feb. 13 press conference prior to his presentation of the study data at CROI 2017. "It has been a long-term dream to try to identify safe strategies that can control the disease with a reduced number of drugs."
The studies in question, SWORD-1 and SWORD-2, are a pair of identically structured, open-label, multicenter trials that aim to determine whether that dream can become a reality with the combination of dolutegravir and rilpivirine. Dolutegravir was selected for its bioavailability, safety, potency and high barrier to resistance, while rilpivirine was selected for its efficacy and safety, Llibre said.
The two studies involve 1,024 people with HIV who were on their first or second antiretroviral regimen and had never before experienced virological failure. All volunteers had been on stable treatment for at least six months prior to joining the study, and all had an HIV-1 viral load below 50 copies/mL for the previous 12 months. Participants were randomized to either continue their current baseline regimen or switch to a once-daily regimen of dolutegravir and rilpivirine. This is a non-inferiority study, powered only to determine whether simplifying treatment is at least as beneficial for volunteers as continuing their baseline therapy. Volunteers hail from 13 different countries, including Argentina, Canada, Russia, Taiwan, the U.S. and several Western European nations.
The key measurement for non-inferiority in this study presentation was a snapshot analysis of viral suppression (HIV-1 RNA below 50 copies/mL) at week 48. On this front, volunteers who switched to the two-drug regimen appeared to perform as well as those who remained on their baseline regimens: Both study arms boasted a 95% virologic success rate.
Some other notable lab values similarly supported non-inferiority for the two-drug arm. "Through 48 weeks, the strategy proved beneficial in terms of bone biomarkers, and it had a neutral effect on lipids both in cholesterol and triglycerides," Llibre said.
Of note, the 95% success rate for each study arm did not mean that 5% of volunteers experienced virologic failure. In fact, extremely few study volunteers failed treatment: Only two people in each study arm had a confirmed loss of virologic control resulting in withdrawal from the study. Most non-successes were instead the result of study discontinuations for other reasons. Although such discontinuations occurred at roughly similar rates in both arms, the specific causes differed: Among the dolutegravir-rilpivirine recipients, most discontinuations (17 of 29) were attributed to adverse events, whereas among the baseline-regimen recipients, most were due to withdrawal of consent (14 of 34) or deviation from the study protocol (7 of 34).
At the press conference discussing the study results, moderator Joseph Eron Jr., M.D., suggested that the higher number of discontinuations in the two-drug arm attributed to adverse events was not an unusual finding for a study of this type, in which volunteers are informed of which drug regimen they are receiving. "In an open-label setting, someone's changed to something new, then if they have an adverse event, they're more likely to ascribe it to what they're changed to," he said. "So, I think there's a bias towards discontinuation in the new-therapy arm." Overall adverse event rates were similar in each study arm (77% in the two-drug arm versus 71% in the baseline-regimen arm).
Assessing the findings in sum, Llibre expressed optimism for the potential value of dolutegravir plus rilpivirine as part of a switch-maintenance strategy. The regimen is "given orally, it has no booster, it has no protease inhibitor, it has no NRTIs," he said. The regimen's success thus far in the study also "opens the door to new two-drug regimen strategies that will come in the future," Llibre added.
The study is slated to continue well beyond 48-week results. At week 52 of the study, participants in both arms move from the "early switch phase," whose results were presented here at CROI, to a "late switch phase" in which volunteers who had been randomized to begin the study on their baseline regimen are switched to two-drug therapy. At week 148, they transition to a continuation phase for longer-term monitoring. In the meantime, Llibre said the study findings thus far support a regulatory filing for U.S. Food and Drug Administration approval of a dolutegravir/rilpivirine coformulation -- one that, due to the low dosage required for each drug, has the potential to become the smallest single-tablet regimen on the market.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
Follow Myles on Twitter: @MylesatTheBody.