Small implants containing islatravir that are inserted under the skin could one day be a long-acting option for PrEP (medication to prevent HIV), according to study results presented last week at the 30th Conference on Retroviruses and Opportunistic Infections (CROI 2023) in Seattle.
One group of researchers tested a refillable implant that could last for several years, while another team evaluated a biodegradable implant. Both implants protected female macaque monkeys against vaginal infection with SHIV – a hybrid simian-human virus similar to HIV – and the refillable implant also protected male monkeys against rectal infection.
Daily or on-demand oral PrEP and long-acting cabotegravir injections administered once monthly or every other month are highly effective at preventing HIV. But PrEP uptake has so far been limited, leading researchers to develop new methods including vaginal rings, dissolving rectal and vaginal inserts and long-lasting implants containing antiretroviral drugs.
More prevention tools are important so everyone at risk for HIV can find a method that fits into their life. “We need to increase PrEP access by providing multiple options to have better persistence and adherence,” Professor Alessandro Grattoni of Houston Methodist Research Institute in Texas told reporters at a CROI media briefing.
Long-acting injectables for PrEP have the drawback of waning drug levels over time, with an extended “long tail” in which levels are too low to prevent infection but may be high enough to cause drug resistance if a person does acquire HIV, Grattoni said. What’s more, they cannot be removed in the event of medical complications.
Another islatravir subdermal implant developed by Merck researchers contained enough of the drug to provide protection for at least a year, but continued use would require repeated minor surgical procedures to remove the old implant and replace it with a new one. That implant demonstrated favourable pharmacokinetics and safety in an early human study, but its current status is unknown.
Refillable islatravir implant
A refillable implant could overcome these limitations. Grattoni and colleagues developed a biocompatible implant based on nanofluidic silicon membrane technology. The experimental implant, which is about 20mm long by 10mm wide, is designed to be inserted under the skin, for example on the inside of the upper arm. To refill it, one needle is inserted through the skin to fill the first port in the implant while another needle is used to withdraw excess fluid from a second port, Grattoni explained. He said the procedure could be done by a trained nurse.
In a pharmacokinetic study, implants were inserted under the skin on monkeys’ backs and drug concentrations were measured over time. The implant produced sustained islatravir release, Grattoni reported, with a similar release rate in male and female animals. Constant islatravir plasma levels above those established for PrEP protection were maintained for more than 20 months. Levels of islatravir triphosphate in peripheral blood cells were also steady, but they were about twice as high in males compared with females (0.66 vs 0.33 pmol/106 PBMCs, respectively).
The implants were generally well tolerated, producing mild local tissue inflammation but no signs of systemic toxicity. There were no notable adverse events even at high islatravir doses, Grattoni said.
Next, the researchers challenged the animals with repeated low-dose SHIV exposures. Six male monkeys received 10 once-weekly rectal exposures while six females received the same number of vaginal exposures. None of the monkeys with islatravir implants were infected, leading the researchers to conclude that the implants “conferred 100% protection against rectal and vaginal infection.” In contrast, all control monkeys who did not get active implants were infected.
“Our nanofluidic islatravir implant is a promising technology for HIV prevention, which may improve PrEP uptake, adherence and implementation,” the researchers concluded.
Biodegradable islatravir implant
In a second study, Dr Michele Daly of the US Centers for Disease Control and Prevention and colleagues evaluated islatravir implants made of polycaprolactone, a biodegradable polymer. The implants contained about 46mg of islatravir with a release rate of 83mcg/day. Daly noted that islatravir could potentially be combined with contraceptives in the same implant.
Six female macaques received two 25mm implants, one under the skin of each upper arm. After five weeks of pharmacokinetic monitoring, they were vaginally exposed to SHIV twice weekly for six weeks. Next, one implant was removed, they were monitored for another five weeks, then repeatedly exposed to SHIV again.
Islatravir levels were higher when the monkeys had two implants, but they remained adequate even with one. Plasma concentrations were similar to those seen with once-daily oral islatravir in humans, Daly said. The researchers plan to measure islatravir triphosphate levels in peripheral blood cells.
Again, the implants were well tolerated. Most animals had no implant site reactions but one developed mild redness. Skin biopsies after implant removal were “unremarkable,” according to Daly.
None of the six monkeys became infected after 12 SHIV exposures while they had two implants. After one implant was removed, one of the six animals became infected. The single breakthrough occurred six weeks after the last SHIV exposure, and this monkey had the lowest islatravir level. All six monkeys with placebo implants were infected.
While findings from these studies are promising, the fate of islatravir remains unclear. In December 2021, trials of islatravir for HIV treatment were put on a partial clinical hold and PrEP trials were put on a full clinical hold after HIV-positive study participants experienced declines in their CD4 counts and HIV-negative volunteers had decreases in their total lymphocyte counts.
Last September, Merck announced that it would start new treatment trials using a lower islatravir dose, but studies of islatravir for PrEP would be discontinued. At that time, the company did not mention plans for islatravir implants. In a CROI presentation about islatravir’s effect on lymphocytes, Dr Kathleen Squires of Merck said the company is “looking at possibilities” for the implant and what the next steps would be.
Daly's study will expand safety assessments to include monitoring of lymphocytes and CD4 cells.
Grattoni told reporters that islatravir is a very promising drug with a good safety profile, and he thinks there are “opportunities to take it further.”
Grattoni A et al. Ultra long-acting refillable islatravir implant fully protects NHP against SHIV. Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 165, 2023.
Daly M et al. Vaginal prep efficacy of biodegradable islatravir implants in macaques. Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 989, 2023.