Two studies published on Wednesday in the New England Journal of Medicine showed the effects of the monthly, long-acting injectable forms of cabotegravir and rilpivirine (Edurant). One study compared the injectable combination to standard oral therapy in people with HIV who were already virally suppressed. The other study compared the efficacy of the two drugs in injectable form to that of oral therapy for patients who were treatment-naive at the start of the study. Together, the studies showed that the injectable was noninferior to standard oral therapy both for people who were already virally suppressed and people who were just starting treatment.
The Injectable for Viral Suppression
The first study, called ATLAS, was a phase 3 open-label study. The researchers randomly assigned participants who had been virally suppressed (defined as HIV-1 RNA levels of less than 50 copies/mL) for six months on standard oral therapy into two arms of the study, of 308 participants each. Viral suppression had to have been documented at screening and within six and 12 months of screening.
One group stayed on their antiretroviral (ARV) therapy in pill form, and the other group received monthly injections of cabotegravir and rilpivirine. The median age for participants was 42 years old, and they were overwhelmingly white (68%) and cisgender male (67%).
At the end of 48 weeks, there were only five participants in the injectable group who still had detectable HIV levels (over 50 copies/mL), compared to three participants in the group receiving oral therapy, a difference that researchers determined showed the injectable was noninferior to pill-form therapy. They reported that 92.5% of people on long-acting injectables and 95.5% of those on standard oral therapy were virally suppressed at the end of the study. People who switched to the injectable reported being more satisfied with their treatment, with 91% reporting they preferred long-acting therapy to daily pills at 48 weeks.
“This trial shows successful treatment of HIV-1 infection with an all-injectable regimen as an alternative to daily oral treatment,” the authors write in NEJM. “Participants who received the long-acting therapy reported greater satisfaction and preferred the regimen over previous oral therapy. Although agreement to enroll in the trial implies willingness to try injectable therapy, most participants maintained a favorable view of the regimen even after 12 monthly injections.”
The Injectable for Those Starting Treatment
The FLAIR study was another phase 3, randomized, open-label trial, which was designed to study the noninferiority of injectable cabotegravir/rilpivirine to daily oral dolutegravir/abacavir/lamivudine (Triumeq) in patients who hadn’t been on any ARV therapy prior to entering the trial. The study enrolled 629 treatment-naive adults who had to have a viral load of at least 1,000 copies/mL and started everyone on the daily oral regimen, but 566 participants were randomly assigned to either study arm (the remaining 63 withdrew from the trial). In the long-acting injectable group, participants started a daily oral version of cabotegravir/rilpivirine to ensure there were no adverse effects, before being started on the monthly injectable for 12 doses (48 weeks). The median age for participants was 34 years old, and they were overwhelmingly white (74%) and cisgender male (78%).
At the end of 48 weeks, six of the 283 participants in the long-acting injectable arm and seven of 283 in the daily pill arm had viral loads above 50 copies/mL. The researchers concluded that monthly injectable cabotegravir/rilpivirine was noninferior to oral daily dolutegravir/abacavir/lamivudine in treatment-naive people.
“Efficacy results with long-acting therapy in this trial were similar to those seen in the ATLAS trial, which had a similar switch design but enrolled participants who had longer-term viral suppression, which had been achieved with the use of other standard three-drug oral therapies,” wrote the authors of the FLAIR study.
Implications for the Future
While these results show a long-acting injectable is just as good as daily pill-form ARV therapy, there still are some hurdles to overcome. In December 2019, the Food and Drug Administration (FDA) declined to approve ViiV Healthcare and Janssen’s new drug application for this novel regimen, citing manufacturing issues (not related to the safety of the medication). It is assumed that those will eventually be resolved and that the drug, after re-application, will likely be approved.
But there are also more practical issues around scale-up of long-acting injectable treatment for HIV. Echoing a talk given last year at the American Conference for the Treatment of HIV(ACTHIV) by Melanie Thompson, M.D., the NEJM also published an editorial by Judith S. Currier, M.D., accompanying the FLAIR and ATLAS results, that raises implementation challenges.
“Requiring monthly visits for injections will be challenging for busy HIV clinics,” she writes. “Experience in psychiatry with the use of long-acting injectable anti-psychotic agents for the treatment of schizophrenia has highlighted the important role that provider attitudes and clinic operations play in the use of this method of treatment.”
Currier goes on to raise questions about how to use oral pills as bridge therapy when people can’t make their monthly clinic visits, in order to prevent virologic failure. She also notes the need to understand why participants with treatment failure in FLAIR also had high rates of resistance, calling for further investigation. Lastly, she also calls out the need for more studies of long-acting injectable therapy during pregnancy and the postpartum period. But ultimately, Currier concludes this is a real advancement in treatment options.
“Version 1.0 of long-acting ART holds promise for the millions of people living with HIV if we make addressing the challenges involved a priority,” she concludes.