In January, the U.S. Food and Drug Administration (FDA) approved cabotegravir/rilpivirine (CAB/RPV, Cabenuva) monthly injections for antiretroviral treatment (ART), marking a major leap forward in treatment options and thereby reducing dosing days from 365 to 12—and, likely soon, six—days per year. Next up: injections for pre-exposure prophylaxis (PrEP).
For many patients, drastically reducing dosing days—the promise of long-acting injectables—outweighs the potential inconvenience of multiple clinic visits. However, while injectables are a game-changing new option for people dealing with pill fatigue, there are some yet-to-be-resolved clinical and practical questions about CAB/RPV and the long-acting PrEP injectable, cabotegravir (CAB). A handful of those questions were raised during the interactive session, “From Daily Pills to Monthly Shots for HIV Prevention and Treatment: Can Efficacy Be Translated Into Effectiveness?” presented at the 28th Conference on Retroviruses and Opportunistic Infections (CROI 2021) in early March. While panel participants agreed there were more questions than clear answers—we need more data was a refrain—some offered creative thinking about how to implement a plan for injectables that centers the needs of people living with and impacted by HIV.
Who Are the Most Suitable Patients for Long-Acting ART and PrEP?
The CROI panel agreed that long-acting injectables shouldn’t be considered automatic replacements for daily pills, but rather an option for some people. But for whom, exactly? Hyman Scott, M.D., M.P.H., the clinical research medical director at Bridge HIV at the San Francisco Department of Public Health, said that adherence to long-acting ART for some is really about adherence to medical visits—but noted, “I have many patients who are adherent to visits but not adherent to daily pills. These people might benefit from long-acting treatment.”
Adolescents might also benefit from monthly injections, said Charles Flexner, M.D., an infectious-disease specialist and professor at Johns Hopkins University School of Medicine, adding, “This is a group that, worldwide, has shown difficulty in adhering [to oral treatment].”
Once-a-month visits could be ideal as part of integrated health management, said Gary Blick, M.D., chief medical officer and HIV specialist at Health Care Advocates International, in an email to TheBodyPro. “CAB may be appropriate for patients who must be seen monthly; for instance, those receiving monthly injections of Vivitrol [naltrexone] or long-acting testosterone.”
Will Monthly Visits Be Too Much for People?
For some, yes. The panel agreed not everyone will choose to come in every month, or even every two months, for an injection. Session attendee Jim Pickett, the senior director of prevention advocacy and gay men’s health at AIDS Foundation Chicago, said that medical distrust is one issue to contend with.
“When we started oral PrEP, many people were suspicious about what was in the pill,” said Pickett. “If we’re giving them an injection, they might be more reluctant. With a pill, it’s out of your system quickly. With the injection, if you want to stop or you have a bad reaction, you’re stuck for a month or more.”
There’s also the issue of reliable transportation. If a clinic offering CAB or injectable PrEP isn’t conveniently located, that could cause some people to think twice, or skip the visit altogether.
Another potential deterrent is wait time, given that providing many injections may put a strain on the flow of clinics. To address this, health care facilities need to be prepared for the added influx of people, said Francois Venter, M.D., Ph.D., FCP, the head of Ezintsha, an HIV research organization based in Johannesburg, South Africa. “(CAB) presents some operational challenges and complexity for clinics, who will really have to up their game,” added Venter. “But we’ve seen from delivery of contraception, people are OK with injections as long as there’s not a long queue.”
The panel discussed possible workarounds for appointment overload, such as delivery of CAB at infusion centers. Panel participant Nittaya Phanuphak, M.D., Ph.D., executive director of the Institute of HIV Research and Innovation in Bangkok, Thailand, said that “de-medicalizing” treatment and prevention—one example is injections at a pharmacy, similar to how flu shots are administered—might be ideal for some, especially for injectable PrEP. “But [long-acting] PrEP might not fit well into the de-medicalization concept unless there is research into whether they can be administered by non-medical personnel, or self-injection,” added Phanuphak. Right now, there’s no such field data.
One key point to consider in de-medicalizing treatment or prevention: A pharmacy might not be the ideal spot if the injection is given in the buttock, as many pharmacies may not have a private space to drop your drawers. And yet another roadblock: Doctors might put up resistance to pharmacy injections. In 2019, the California Medical Association initially opposed a bill allowing PrEP to be purchased without a prescription, until an amendment was added to limit purchase to a 60-day supply.
How Can Virologic Failure and Drug Resistance Be Prevented?
Beyond delivery methods and convenience, providers need to keep an eye on possible drug resistance. While CAB/RPV was found to be well tolerated and not inferior to daily pills, virologic failures were documented in the recent ATLAS-2M phase 3 study, conducted in 1,049 adults living with HIV. In the monthly arm of the study, 0.4%, or two out of 523 participants, developed confirmed virologic failure (CVF), and in the every two months arm, 1.5%, or eight of 522 participants, developed CVF. (CVF is defined as the inability to suppress and sustain a person’s viral load to less than 200 copies/mL.)
In addition to risk of virologic failures, there’s resistance that could potentially arise from missed or delayed visits, or any number of other reasons. “There are at least 50 ways to fail at treatment [with CAB/RPV],” said Flexner. “And there are many long-acting agents in development that will be available in three to five years, and all formulations will be different in risk of resistance.”
A possible complicating factor is that CAB/RPV requires two sizable injections—ViiV Healthcare’s cabotegravir and Janssen’s rilpivirine—every month, and those drugs must be delivered into a muscle. Panel members noted that there are few parts of the body that can accommodate the required 2-mL injections. “What about people with high BMI?” Flexner asked. “It may be harder to reach the muscle and therefore lead to low drug concentration, which could lead to resistance.”
One resistance-related question is: How much forgiveness is there in four-week and eight-week dosing? Long-acting agents have a long half-life, but there is a drop-off in effectiveness at some point. But at what point? “Clearly there is a point where the concentration is too low to maintain suppression,” Flexner said. “You want to define that sweet spot, low enough to select resistance but not high enough to prevent the virus from replicating.”
The panel agreed that real-world effectiveness and implementation data are needed to understand whether there are patients who are more susceptible to virologic failure and resistance.
Might There Be Other LA-ART and LA-PrEP Concerns?
The session surfaced a number of other issues surrounding the rollout of injectables for treatment and prevention. Among them:
- Will injectable PrEP require more sophisticated monitoring of HIV status? Consensus: Maybe.
- Would such sophisticated HIV monitoring, including pooled viral load testing, be feasible? Consensus: Maybe not.
- Can injectable CAB be used for post-exposure prophylaxis (PEP)? Consensus: In theory, yes, but, again, more data are needed.
- Could HIV subtypes play a role in resistance? Consensus: Yes, maybe, and data are needed.
One other compounding issue not covered by the panel—who pays for it?—was addressed by Blick in an email. According to Blick, because injectables will be administered in a clinical setting, payers are likely to cover it as a medical, rather than a pharmacy, benefit. “Drugs covered under a health insurer’s medical benefit may require a flat coinsurance rate of the cost of the drug,” said Blick. “The Centers for Medicare and Medicaid Services [CMS] may designate Cabenuva as covered under Medicare Part B or Part D. Medicaid coverage policies will be determined on a state-by-state basis.”
TheBodyPro will be wrestling with these topics and more as CAB/RPV is rolled out, and as CAB moves through approval.
Bottom Line: Focus on Benefits, But Make It Easy for the Patient
All considerations and possible challenges shouldn’t deter health providers or their patients from considering injections for treatment—or PrEP, when it’s available—and panelists agree, the potential benefits outweigh the potential downsides. One additional, perhaps undersold benefit for the user, added Pickett: long-acting treatment may reduce internal stigma. “Studies showed, instead of thinking about HIV daily, you think about it once a month and get on with your life,” said Pickett. “That led to high rates of retention.” But he added, for injectable ART and PrEP to work well, health providers need to reduce the hassles, or “friction” that keep patients from getting shots. “We need to be thinking, right now, about ways to make this easier.”