As 2019 draws to a close, TheBodyPro takes stock of the year's most noteworthy developments in HIV. And not just any developments: We're looking specifically at those with the largest impact for people who provide HIV care and services in the U.S. In this series, veteran clinician-researcher David Alain Wohl, M.D., guides us through the new research and other important moments of 2019 that have the greatest potential to alter the HIV clinical landscape in the months and years to come.
Injectable cabotegravir (CAB) and rilpivirine (RPV) will certainly make the 2020 edition of our Top 10 list. Anticipated to be available early next year, a guaranteed big story will be how smoothly the rollout of this long-acting HIV therapy goes.
The data supporting a regimen consisting of injectable CAB/RPV were presented at CROI 2019 in the form of a pair of open-label trials named FLAIR and ATLAS. In FLAIR, people who were treatment-naive were started on abacavir/dolutegravir/lamivudine (Triumeq) and, if they achieved viral suppression at 20 weeks, were randomized to either stay on this oral regimen or add oral CAB and RPV (to demonstrate tolerability) before switching to a regimen consisting solely of intramuscular CAB/RPV. The design of ATLAS was similar, but participants were not treatment-naive: Instead, they entered the study with suppressed viremia on an oral antiretroviral regimen, and were randomized to either continue these or switch to intramuscular CAB/RPV.
Both trials found intramuscular CAB/RPV non-inferior to continued oral therapy, with upwards of 90% of participants in all arms achieving virologic suppression at week 48.
However, among the handful of people with suboptimal virologic response, a combined total of six people across the CAB/RPV arms of both studies were found to have drug resistance. All but one of these participants had NNRTI and integrase inhibitor drug resistance detected at the time of failure; the remaining participant had only NNRTI resistance.
Baseline specimens in some participants were subsequently found to harbor viral DNA with mutations that may have handicapped the injectable regimen. Also, all were subtype A viruses: Five of the six drug resistance failures occurred among participants enrolled in Russia, where this subtype is more common than it is in the U.S.; these five all had a pre-existing L74I mutation in their baseline DNA sample. This mutation had not previously been considered highly consequential, but it now appears to be a risk factor for regimen failure, at least for people with subtype A virus.
Satisfaction with the injections was high in these studies, despite universal mild to moderate injection site reactions. A bevy of data are reporting high patient preference for long-acting HIV therapies.
The Bottom Line on Injectable Antiretroviral Research
There are two important ramifications from ATLAS and FLAIR:
- They will probably pave the way for U.S. Food and Drug Administration approval of this novel and, arguably, revolutionary therapeutic approach.
- They demonstrate much of what we need to know about how well CAB/RPV will work in near-ideal settings.
For the motivated participants in the trials, efficacy was impressive and on par with standard daily oral comparators. As we saw in the SWORD trials (which examined the potential for switching to a two-drug oral regimen of dolutegravir plus rilpivirine), while few people experienced virologic failure, emergent drug resistance was a risk when failure did occur. Also similar to SWORD, in these studies we saw that despite a greater number of reported adverse effects after the switch, participants preferred the new regimen compared to what they were on previously.
The launch of CAB/RPV will be interesting. Incorporating monthly injections into clinic operations will require some major adjustments in the way HIV therapy is delivered, even if it's administered to a minority of patients who both desire and are eligible for this new combination.
A follow-on study, ATLAS-2M, is ongoing; it will compare a schedule of one intramuscular dose taken every four weeks with one taken every eight weeks. For sure, a spoonful of less frequent administration will help this injectable medicine go down -- not only for our patients, but also for the clinic staff that will have to schedule, administer, and track them.