Annual Implant Moves Closer to the Clinic | Nutrition Fit



A reformulated implant of investigational HIV prevention drug islatravir could protect people from HIV for a year.

Or at least results from a small, early trial suggest that’s a possibility.

“It’s a very exciting time for [preexposure prophylaxis],” Randolph Matthews, MD, PhD, a senior scientist at Merck, who presented the implant data, told Medscape Medical News. “It’s an option that we foresee for individuals who might be having difficulty with the daily pill, whether that’s because of forgetting [to take it] or for whom it’s difficult to get the pill, or there’s some stigma about having the pill around the house.”

Still, this trial was preliminary and small ― it included only 36 participants. Matthews told Medscape Medical News that he “hopes it will be available” in less than 5 years, but that depends on how the clinical trials go.

Right now, the US Food and Drug Administration has approved only generic tenofovir disoproxil fumarate/emtracitabine (Truvada) and its cousin, tenofovir alafenamide/emtracitabine (Descovy), for HIV prevention, and only Truvada has been approved for treatment of cisgender women.

But that looks to be changing, and rapidly, not just because of the data presented on the islatravir implant but also because of data presented on a monthly oral islatravir pill, weekly HIV prevention pills, monthly cabotegravir injections, vaginal rings, and monoclonal antibodies. Soon the HIV prevention space will look more like the contraception world, with options for different people at different stages of life and with different needs, Matthews said.

The comparison to contraception could be literal. Merck and others are considering ways to offer dual or sometimes triple protection through their formulations, with pregnancy prevention and HIV prevention.

Still, attendees at the Conference on Retroviruses and Opportunistic Infections (CROI) 2021 Annual Meeting could be forgiven for having data déjà vu. A year and a half ago, Matthews was on a similar stage, presenting similar data on an islatravir implant. At that time, the data were from 16 participants who received an islatravir/polymer implant loaded with one of two doses of the drug: 54 mg or 62 mg.

This time, Matthews’ data represented 36 participants — 12 of whom were control persons — who received either one of three doses of the drug or placebo in a reformulated implant that contained polymer and islatravir as well as barium for tracking. The barium allows researchers to track the implant with imaging, in the event that it slips or migrates under a muscle while being worn.

The previous implants presented at the 2019 International AIDS Society Conference on HIV Science “were much more a proof of concept,” Matthews told Medscape Medical News. “This is much closer to what will be brought forward.”

So instead of presenting phase 2 safety data on the previous implant, Matthews presented data on another implant prototype that had a slightly different design.

In this trial, researchers randomly assigned 36 healthy adults who were at low risk for HIV to one of three dose levels — 48 mg, 52 mg, and 56 mg. In each of these arms, four participants acted as controls. Researchers followed participants for the 12 weeks during which the implant was worn and for 8 weeks after removal. ECG data as well as data on pharmacokinetics, vital signs, and safety were collected.

“Because of the change in composition [of the implant], the release dynamics of islatravir also change,” said Matthews. “The 56-mg implant in this trial was expected to lead to concentrations similar to the 62-mg implant from the previous trial, while the 48-mg implant was expected to be similar to the 54-mg dose used in the previous trial.”

Indeed, that’s what they found. With an identified threshold of at least 0.05 pmol per million cells to simulate effectiveness — determined on the basis of monkey studies and other antiviral data — all three implant doses remained above the threshold throughout the active part of the trial. Notably, Matthews said, this implant was able to achieve with 56 mg of islatravir what the previous implant achieved with 62 mg. Concentrations in the blood reached levels that were expected to be effective “within hours” of implantation.

After the implants were removed, the 56-mg dose maintained effective half-life for about 198 hours, he said.

This half-life led Matthews to suggest that the “long tail” problem identified early on in the study of a long-acting cabotegravir-for-PrEP shot would likely not arise for people who discontinue the islatravir implant.

Also at this year’s meeting, Merck presented data on an oral islatravir pill that, at 60 mg, is projected to provide protection from HIV for 1 month.

“The half-life of islatravir and islatravir diphosphate after removal of the implant really is pretty much identical to the half-life of orally administered islatravir,” Matthews said. “So there’s really probably no need for an oral lead in or for anything afterwards.”

“Based on the islatravir parent and triphosphate data from this study and using a population PK model, we projected triphosphate concentrations out beyond the 3-month duration of the study,” Matthews said in his presentation. What’s more, “the 56-mg implant is expected to lead to islatravir triphosphate concentrations above the peak threshold, even for those at the low end of the concentration range, for at least 52 weeks.”

Matthews said that the final dosage of islatravir that will be investigated in phase 2 trials has not yet been determined, but “a dose similar to 56 [mg] or providing that degree of drug load is going to be important to the phase 2 protocol.”

There were adverse events in each arm of the study, though results were only presented for those patients who received active drug, not placebo. All adverse events were mild or moderate. The most common were implant-site reactions, such as tenderness, pain, and reddening or hardening of the skin. The most common non-injection-site reaction was headache. There was “no clear dose dependency” regarding headaches. He said that injection-site-related adverse events occurred with “a little bit lower frequency” among patients in the placebo arms than in the active-drug arm.

“Hopefully, the islatravir implant will be an option for people who are interested in PrEP, and that will increase the number of people taking it,” Matthews told Medscape Medical News. “And then that could have a positive impact on HIV.”

The presentation was met with excitement from people living with HIV. In comments about the virtual presentation, people expressed everything from having the daily pill available over the counter — provided systemic side effects continue not to occur — to simply exclaiming, “This is so exciting!”

For Sharon Hillier, PhD, of the University of Pittsburgh Medical Center and the Magee-Women’s Research Institute, Pittsburgh, Pennsylvania, who is a principal investigator of the use of vaginal rings for PrEP, it was significant, too.

“It’s not that this is going to be the answer,” she said. “Some people will want long-acting methods. Some people might want to take a tablet every month. Some people might want an injection every 2 months. The real point of this is that with a higher number of options, I think we have a lot better chance of impacting the epidemic with really at the broadest range of strategies.”

Still, the persistent gaps in PrEP referrals and PrEP prescriptions for people at highest risk for HIV remain are unlikely to be resolved entirely by a new method of HIV prevention. Shubha Rao, MPH, of the Centers for Disease Control and Prevention, presented partner services data at the conference that showed that in 48 US counties, only 7% of Black people in relationships with people with HIV were taking PrEP. In the South, where HIV rates are the highest, only a quarter of Black people in relationships with people with HIV received a referral to discuss PrEP with a provider.

“As the literature indicates, there are several social and structural barriers to PrEP use among Blacks,” Rao told Medscape Medical News. “While PrEP implants may help address some of the barriers to oral PrEP (eg, reduces adherence issues), we expect that most other social and structural barriers affecting oral PrEP uptake (eg, lack of PrEP providers, lack of insurance; low health literacy) may continue to affect the uptake of PrEP implants.”

Conference on Retroviruses and Opportunistic Infections (CROI) 2021 Annual Meeting: Abstract OA2-88LB. Presented March 8, 2021.

Heather Boerner is a science and medical reporter based in Pittsburgh, PA and can be found on Twitter at @HeatherBoerner. Her book, Positively Negative: Love, Sex, and Science’s Surprising Victory Over HIV, came out in 2014.

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