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Gene Stollerman Professor of Medicine
Chief, Division of Infectious Diseases
Northwestern University Feinberg School of Medicine
Babafemi Taiwo, MBBS, has disclosed that he has received consulting fees from Gilead Sciences, Merck, and ViiV.
The IDWeek 2020 virtual conference included new data on the HIV regimen cabotegravir (CAB) plus rilpivirine (RPV) for the treatment of HIV, providing reassuring results regarding durability of responses, tolerability, and patient preference. Here is what I believe these results mean for clinical practice and how they may change the way we manage patients going forward.
Durability of Long-acting (LA) CAB Plus RPV
Three studies presented at this conference addressed the durability of LA CAB plus RPV for the treatment of HIV. First, the LATTE-2 study was a multicenter, open-label phase IIb study that assessed the long-term efficacy, safety, and tolerability of LA CAB plus RPV in treatment-naive adults. In this study, patients received oral CAB plus abacavir (ABC)/lamivudine (3TC) until they were virologically suppressed and then were randomized to continue the 3-drug oral regimen or switched to injections with LA CAB plus RPV monthly or every 2 months. At Week 96, patients receiving the oral regimen had the option to switch to monthly or bimonthly injections. Follow-up has now continued through 5 years.
Encouragingly, high rates of virologic suppression were observed at 256 weeks; indeed, 88% and 74% of patients who were randomized to injections bimonthly or monthly, respectively, maintained HIV-1 RNA < 50 copies/mL at this time point. In addition, 93% of patients who switched LA CAB plus RPV at Week 96 maintained virologic suppression at Week 256. Furthermore, I found it interesting that after Week 48, no participants in either arm experienced virologic failure, thereby indicating that LA CAB plus RPV is truly a durable maintenance therapy.
The POLAR study also addressed the durability of LA CAB plus RPV. In this rollover phase IIb study, patients from the LATTE-2 study who were suppressed on once-daily oral CAB plus ABC/3TC for at least 312 weeks could choose to switch to the new oral regimen of dolutegravir (DTG)/RPV or to LA CAB plus RPV administered every 2 months. Of interest, of the 97 participants in the study, 90 chose to switch to LA CAB plus RPV, and only 7 chose to switch to DTG/RPV. Although data were only reported out to 48 weeks, remember that these patients have essentially received CAB plus RPV for 7 years because they switched from the oral to LA regimen at Year 6. Promisingly once again, at this 48-week time point, no patient experienced either virologic rebound or protocol-defined virologic failure—showing that, in this population that had been receiving CAB plus RPV for 7 years, the regimen remained very durable, even after the switch to the injectable combination.
The third study to note examined the impact of the COVID-19 pandemic on ART interruptions for patients in the LA CAB plus RPV clinical trials. One potential disadvantage of this regimen is that patients have to visit a clinic to receive the injections. Initially, there was considerable apprehension on the part of researchers that the potential difficulties patients faced in accessing clinical sites due to the COVID-19 pandemic would result in many missed doses and therefore viral rebound. For this assessment, data from 1744 patients across 6 studies (LATTE-2, FLARE, ATLAS, ATLAS-2M, POLAR, and CUSTOMIZE) were aggregated and analyzed. Remarkably, investigators showed that the overwhelming majority (93%) of patients continued to receive their medications on schedule. Furthermore, those who did not receive their injections were able to transition to oral therapy—either oral CAB plus RBV or another oral regimen—for that short-term period when they didn’t have access to or didn’t receive the injection for whatever reason. Finally, no cases of virologic failure occurred as a result of the disruption.
Another study I would like to briefly mention examined the occurrence of HIV-1 RNA viral blips among patients receiving LA CAB plus RPV. It was reassuring in that patients on monthly or bimonthly injections experienced virologic blips at a rate similar to patients receiving an oral 3-drug current ART regimen, and the majority (89% to 100%) of patients with virologic blips were virologically suppressed at Week 48.
Taken together, these combined results show us that this investigational regimen offers both durability and flexibility—in the sense that patients could be switched to bridging oral therapy when needed—and it appears that low-level viremia blips are not a clinically significant concern.
Tolerability and Patient Satisfaction With LA CAB Plus RPV
One concern for HIV providers regarding LA CAB plus RPV is whether patients will wish to receive an intramuscular injection on a monthly or bimonthly basis. The CUSTOMIZE study, described as an implementation effectiveness hybrid study, examined patient perspectives on LA CAB plus RPV. Specifically, virologically suppressed patients from 8 clinical sites in the United States receiving monthly LA CAB plus RPV after a 4-week oral lead-in were surveyed at baseline and at 4 months regarding their overall perspectives and acceptability of the intervention. Of interest, at baseline, only 46.8% of patients said they had no trouble with oral ART, and concerns included forgetting to take their medication, hiding their medication from others, and running out of medication. Therefore, we must keep in mind a potential selection bias in this study, because many patients may have been highly motivated to take the injectable regimen because of their concerns with oral therapy.
That said, patients overwhelmingly reported positive impressions of the regimen, with > 91% of participants agreeing or completely agreeing that LA CAB plus RPV was acceptable and appropriate. Furthermore, whereas pain at the injection site was a concern at baseline for 57.8% of participants, only 27.6% reported this as a factor that interfered with their ability to receive treatment at Month 4. In addition, at Month 4, approximately 66% of participants reported no logistical challenges, and 89% reported that the amount of time spent in the clinic for each injection visit was very or extremely acceptable. Finally, no patients missed an injection or required oral bridging as of Month 4 of the analysis, and most of the injections were administered within a week of the target treatment date, indicating that a monthly injection schedule can be feasible.
Although these data are encouraging, approximately 34% of patients still perceived there to be logistical challenges to receiving the regimen. In an era where one of our goals as HIV providers is to help patients get to a point where HIV is essentially impactless in their overall lives, this is an area where there is room for improvement, and we must strive to address these logistical barriers. We may, therefore, need to work toward administering this regimen outside of the clinic and/or consider other ways in which we can optimize the implementation of this regimen so that patients are least affected.
Finally, it strikes me as very fitting that this study was called CUSTOMIZE, because the future of HIV medicine—and all medicine in fact—will be to try to customize our treatment to our patients’ wishes and really adopt a patient-centered approach. As we saw in this study, some patients perceive challenges with oral therapy, whereas others find injection therapy to be bothersome or inconvenient. Having this injectable treatment option in our armamentarium allows us to tailor the treatment to our patient’s unique circumstances and even switch between oral and injectable therapy, when appropriate.
Furthermore, although most of the current focus on LA regimens is inevitably on LA CAB plus RPV because of the many years of clinical development it has already undergone, it is very encouraging that other LA regimens are also in the ART pipeline, including lenacapavir (offering the benefit of subcutaneous injections) and islatravir (with the prospect of implants). In the foreseeable future, our patients may have the option of choosing among simple oral regimens and a range of LA regimens with varying characteristics, further increasing our ability to provide each patient with an optimal individualized regimen.
What are your thoughts about the clinical potential of LA ART? Join the discussion by posting a comment and sharing your experiences of what patients are telling you they would most like to see with LA ART strategies.