With the recent U.S. Food and Drug Administration (FDA) approval of injectable cabotegravir/rilpivirine (CAB/RPV, Cabenuva), the first long-acting antiretroviral regimen is now available, letting people living with HIV (PLWH) opt for a safe and effective monthly shot instead of daily oral pills. But as game-changing as CAB/RPV is, it’s only the beginning.
“I’ve been a booster of long-acting injectables as an option,” said David Alain Wohl, M.D., a professor of medicine at the University of North Carolina-Chapel Hill. “Right now, we’re rolling out every-monthly injection. And if it wasn’t for the pandemic, there’d be a lot more buzz about this.”
But, he added, “I don’t think the majority of people will want to take an IM [intramuscular] injection.” For those individuals, offering additional administration methods and dosing alternatives may be key to further reducing HIV transmission.
“I’m big into people having choice,” Wohl said. And at the 28th Conference on Retroviruses and Opportunistic Infections (CROI 2021) in early March, we got a lot of new data on additional choices in development for long-acting HIV treatment and prevention.
Related: David Alain Wohl, M.D., on CROI 2021 research regarding long-acting antiretrovirals for HIV treatment
The Long-Acting HIV Treatment Pipeline: CROI 2021 Updates
Injectable Cabotegravir/Rilpivirine Every Two Months
CAB/RPV was approved in the U.S. as a monthly injection, but an every-two-months dose may be close on its heels. CROI 2021 brought 96-week data from ATLAS-2M, a phase 3b randomized (but open-label) trial comparing CAB/RPV IM injections given every four weeks (Q4W) to every eight weeks (Q8W). The findings were presented by Hans Jaeger, M.D., of MVZ München am Goetheplatz.
Prior 48-week ATLAS-2M findings indicated likely non-inferiority for the Q8W injections, and the new 96-week snapshot data continue to bear that out: In an intention-to-treat efficacy analysis, 91% of participants in the Q8W arm had a viral load below 50 copies/mL, compared to just over 90% in the Q4W arm.
Most participants who failed to meet virologic suppression criteria had no viral-load data available (usually due to study discontinuation); virologic non-response rates were 2% in the Q8W arm and less than 1% in the Q4W arm. Only one person was determined to have experienced virologic failure between weeks 48 and 96 (they were in the Q8W arm), but a retrospective data review indicated that person had a baseline resistance mutation to rilpivirine.
Drug-related adverse events were similar between the two study arms and did not change much from week 48 to week 96. Injection-site reactions remained common, though Jaeger noted in his presentation that they grew less frequent during the course of the study, and only one person dropped out of the study due to that side effect between weeks 48 and 96. (That person was in the Q8W arm.) Other severe drug-related events were rare.
While every-eight-week dosing of CAB/RPV appears promising, Wohl noted to TheBodyPro that his clinic is still adjusting to the nuances of administering periodic IM injections instead of writing prescriptions for oral medications. “I feel like we’re a little ill-prepared right now, most of us, for introducing this into the clinic, and need as much data as possible” on practical questions such as how to handle late or missed doses, he said.
But, regardless, injectable therapy is here, and it’s on providers to adjust to that reality. “CAB/rilpivirine is coming, and we’re going to be injecting people’s butts with this stuff,” Wohl said.
Injectable Lenacapavir With Six-Month Dosing
While CAB/RPV has been approved for use by people already on successful antiretroviral therapy, some people are on suboptimal therapy and have few treatment options remaining. Enter a long-acting formulation of the capsid inhibitor lenacapavir (LEN, formerly GS-6207), which is in clinical development for treatment and prevention of HIV. The hope is that the drug will not only be effective for treatment-naive people, but also offer new hope for people with multi-drug resistance.
Data were presented from the phase 2/3 CAPELLA trial to evaluate lenacapavir in heavily treatment-experienced people with multi-drug resistant HIV-1 infection. These interim efficacy results showed that lenacapavir injections every six months, when added to a failing regimen, achieved “clinically meaningful” rates of viral suppression with a “rapid and clinically relevant decline” in viral load. The findings were presented by Sorana Segal-Maurer, M.D., of New York-Presbyterian Queens Hospital.
Among the most noteworthy findings: 88% of the lenacapavir group achieved an HIV-1 RNA decline, compared to 17% of the placebo group. (Both groups also received an optimized background regimen using oral antiretrovirals.) In addition, 73% of participants given lenacapavir in combination with an optimized background regimen reached week 26 with undetectable viral load (<50 copies/mL).
The drug managed to maintain high rates of virologic suppression in a difficult-to-treat patient population with limited therapy options and high unmet medical need.
Oral Long-Acting Treatment
Long-acting oral treatments for HIV are also being developed to provide an alternative to both a daily pill regimen and injectables. At CROI 2021, two oral presentations explored the effectiveness of the NNRTI MK-8507.
Tracy Diamond, Ph.D., of Merck & Co., presented data on the in vitro resistance profile of MK-8507 for weekly oral use; the study indicated that the drug was active against common NNRTI resistance–associated variants. She added that MK-8507 would likely have a clinical virologic profile similar to doravirine (Pifeltro), only with less-frequent dosing.
Later this year, further study will begin on a once-weekly regimen using MK-8507 in combination with the NRTTI islatravir, another drug in development by Merck, Diamond said.
The Long-Acting HIV Prevention Pipeline: CROI 2021 Updates
No injectable or long-acting HIV prevention tools have yet been approved by the FDA. But several types of long-acting HIV prevention are in development, including extended oral antiretroviral PrEP (pre-exposure prophylaxis), intravaginal rings, injectables, implants, and antibodies. Several studies on the effectiveness and safety of these prevention methods were presented at CROI 2021.
Injectable PrEP: Dosing and Cost
As we already know from its recent approval as part of an HIV treatment regimen, injectable cabotegravir (CAB) has a long half-life, meaning it can potentially reduce the challenge of adherence for some people who experience obstacles to daily or on-demand oral PrEP.
Raphael Landovitz, M.D., of the University of California-Los Angeles, presented additional data regarding HIV infections that occurred in the HPTN 083 trial, a phase 2b/3 trial comparing long-acting CAB dosed every two months to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC, Truvada) in men who have sex with men and transgender women who have sex with men.
The last major set of data from this study were unveiled at the AIDS 2020 conference: researchers found that CAB-LA and TDF/FTC were both highly effective for HIV prevention, but CAB-LA was superior to daily oral TDF/FTC. (Of note, data presented at the 2021 HIV Research for Prevention conference found similar results in HPTN 084, a sibling study conducted among cisgender women.)
Landovitz and colleagues’ examination of the small number of incident HIV infections among participants in the long-acting CAB arm found that the majority occurred either during the initial oral lead-in phase of the study or after a delayed administration of a CAB dose (by more than two weeks). Four incident infections occurred despite on-time CAB administration—and Landovitz noted that, due to long-acting CAB’s ability to sustain viral suppression, it may be challenging to diagnose these incident infections early.
Emergent integrase resistance was rare, the study found, but did appear to occur when HIV infection occurred despite relatively high concentrations of CAB.
Ongoing research of long-acting CAB for PrEP will include evaluating the optional oral lead-in phase and use of viral load testing as a primary screen for HIV infection.
Meanwhile, as long-acting PrEP draws closer to becoming a reality in the U.S., discussion is brewing about implementation and affordability. At CROI 2021, Anne Neilan, M.D., M.P.H., from Massachusetts General Hospital, posed the question: How much should we be willing to pay for the improved efficacy of long-acting injectable CAB over daily oral TDF/FTC?
In an analysis of anticipated 10-year outcomes, given an estimated size of 1.9 million potential PrEP users and an off-PrEP HIV incidence of 1.5 per 100 person-years, Neilan and colleagues found that long-acting CAB led to the fewest total HIV transmissions—and by far the highest cost—when compared with branded TDF/FTC, generic TDF/FTC, and no PrEP at all.
Neilan et al concluded that if long-acting CAB for HIV prevention is priced comparatively to the long-acting CAB/RPV regimen used in HIV treatment, it would not be cost-effective. Instead, she suggested that long-acting CAB for PrEP should be priced to compete with generic TDF/FTC, noting that the availability of effective alternatives would limit the price premium that people would be willing to pay for long-acting CAB.
Vaginal Rings for PrEP
Polymer-based, long-acting intravaginal rings release one or more antiretroviral drugs over time when inserted into the vagina. Earlier this year, a ring containing dapivirine (DPV-VR) was added to the World Health Organization’s HIV prevention recommendations as an additional option for women at high risk for HIV. (The European Medicines Agency issued a “positive regulatory opinion” for the ring in July 2020, opening up pathways for its wider use.)
This initial iteration of DPV-VR was engineered to remain in the vagina for 28 days. At CROI 2021, Albert Liu, M.D., M.P.H., from the San Francisco Department of Health, presented findings from a phase 1 study comparing three-month DPV-VR formulations to the existing monthly DPV-VR. Researchers enrolled 49 HIV-negative cisgender women across two sites and compared the existing 25-mg ring (which was replaced after one month) with 100-mg and 200-mg rings (which were used continually for 13 weeks). DPV concentrations were determined via blood and cervicovaginal fluid at each follow-up visit and at one, two, and four hours after ring insertion and removal.
Researchers concluded that all DPV-VR formulations were well-tolerated and that the two extended-duration rings achieved higher DPV concentrations than the monthly DPV-VR, which is likely to translate into at least equal efficacy, Liu said.
In surveys, participants expressed high levels of satisfaction in the rings (an average of 8 on a 1-to-10 scale) regardless of dosing schedule—in fact, they generally rated the rings much more highly than male condoms. The largest percentage of those who gave DPV-VR the highest ratings were in the lowest-dose arm (25 mg monthly), though Liu hypothesized this may be because that was already the dose with which participants were most familiar.
Oral Long-Acting PrEP: Islatravir
Islatravir has a long shelf life, which can make it appropriate for longer-term dosing, be that for treatment or prevention. Munjal Patel, Ph.D., of Merck presented data on islatravir’s pharmacokinetic (PK) threshold and dose selection for monthly oral PrEP use. He said that a monthly oral dose of islatravir at 60 mg had been selected for phase 3 HIV-prevention clinical trials.
Patel added that protective islatravir-triphosphate concentrations are expected to exceed the drug’s PK threshold in just a few hours after administration and maintain that level from the first dose onward.
While a monthly PrEP pill has appeal, there’s another administration method for islatravir that also drew attention at CROI 2021: a subdermal implant.
Long-acting, subdermal implants for HIV prevention are at an early stage of development and have not yet been tested in humans, but if proven effective and safe, they would offer one more tool in the prevention toolbox. There is precedent for this method of prevention, of course—most notably the birth control medication etonogestrel (Nexplanon), which is a tiny plastic rod placed under the skin of a woman’s upper arm to prevent pregnancy.
At CROI 2021, Randolph Matthews, M.D., Ph.D., from Merck & Co., presented encouraging results from a phase 1 trial of implanted islatravir for PrEP. This trial, Protocol 008, involved a more advanced, radiopaque version of a prototype implant that was discussed in 2019 (in a study named Protocol 007). Participants received one of three subdermal islatravir doses for 12 weeks, followed by eight weeks of follow-up after the implants were removed.
Matthews et al found that, among the 36 total study participants, no serious adverse events or study discontinuations occurred, though mild to moderate events were reported by 61% and were typical of subdermal implants (e.g., inflammation, pain, or itching at the insertion site).
The highest-dose implant, 56 mg, was projected to have sufficient islatravir-triphosphate levels to prevent HIV transmission for at least one year. After the 56-mg implant was removed, islatravir maintained effective levels for 198 hours in study participants, Matthews said.
Myles Helfand contributed reporting to this article.