Slow-release ARV implant a 'game changer development’

Organisation: Position: Deadline Date: Location:

An implant containing islatravir, which is inserted under the skin of the upper arm, should provide sustained levels of drug sufficient to prevent HIV infection for over a year, found one of the most keenly-awaited studies to be presented at the 10th International AIDS Society Conference on HIV Science (IAS 2019) in Mexico City.

Islatravir or MK-8591, originally called EFdA, has been developed by Merck (MSD), and is a new type of reverse transcriptase inhibitor which does not just block the transcription of HIV viral RNA into DNA that can be integrated into cells by acting as a ‘fake’ genetic base, as other NRTIs do, but also locks HIV’s reverse transcriptase enzyme into a conformation where it is more easily degraded by cellular processes. It has extraordinary affinity for reverse transcriptase and effectively stops viral replication at blood and intracellular levels 100 times lower than other HIV drugs, and with a half-life of as long as seven days, meaning that it could be dosed monthly.

In previous studies of an oral formulation of the drug, a dose of as little as 0.5mg was sufficient to block HIV replication for a week, and oral islatravir is under investigation as an HIV treatment in combination with another daily Merck drug, doravirine.

Merck’s Dr Randolph Matthews told the conference that the drug’s extraordinary persistence clearly made it suitable for long-acting formulations.

Merck has formulated the drug as an implant, a small plastic insert that is placed under the skin of the upper arm, a technology already used by the same company for contraceptives, and which has also been tried with other anti-HIV medications such as tenofovir. The Merck implant measures 4cm by 2mm and is not visible to others when implanted – an advantage for people who may fear being seen to take antiretrovirals. It has the advantage over long-acting injectable formulations of being removable, meaning not only that it can be taken out in the case of side-effects but also that there is less chance of resistance arising or being transmitted due to drug levels slowly tailing off in the body. Matthews said that once removed, levels of drug tailed off about as quickly as those of the oral dose.

The study of the pre-exposure prophylaxis (PrEP) implant announced only evaluated levels of the drug (versus placebo) in two different doses (54mg versus 62mg per implant) given to 16 individuals for a three-month period.

The purpose of the study was to assess the safety and tolerability of the implant, and to estimate the time at which the concentration of intracellular islatravir would fall below 0.05 picomols per million cells, the level previously determined to be the minimum effective level to stop HIV replication.

The higher dose (62mg) produced levels above this threshold in all trial volunteers for the three months the implant was in place, whereas levels fell below this for part of the time in a few people given the lower dose.

Although this was only a three-month study, projections based on the levels of drug seen show that the intracellular concentration of the drug produced by the implant should stay well above the prevention threshold for at least a year, and probably considerably longer.

The insertion of the implant is not totally without discomfort; nearly all participants said that the implant insertion initially produced some localised internal bleeding and discomfort, and a few complained of inflammation or itching in the implant area, but these side-effects were seen as tolerable by the participants.

Matthews told the conference that these initial safety results supported the development potential of the implant as a once-yearly PrEP option.

Background: Preexposure prophylaxis (PrEP) with antiretroviral drugs has demonstrated efficacy in reducing new HIV infections, although efficacy is tightly linked to good adherence, especially in women. HIV infection continues to be a global epidemic, however, with ~1.8 million new infections reported in 2018. MK-8591 is a nucleoside reverse transcriptase translocation inhibitor with high potency, high barrier to resistance, long t1/2, and distribution to sites of HIV sexual transmission at levels comparable to those observed in PBMCs. In addition, MK-8591 has demonstrated efficacy with weekly dosing in an SIV challenge prophylaxis study. Thus, MK-8591 appears to have potential as an agent for PrEP.
Methods: Drug-eluting implants were studied in preclinical species to establish general tolerability and pharmacokinetics (PK) of MK-8591 parent and of the active MK-8591-TP (triphosphate). These data, along with data from the SIV challenge study and from previous Phase 1 trials, formed the basis of models for predicting long-term exposures and for establishing a threshold concentration of 0.05 pmol/106 TP in PBMCs. In a double-blind placebo-controlled Phase 1 trial, a single MK-8591 (54mg or 62mg) or placebo implant was placed in subjects for 12 weeks. Safety and tolerability were assessed throughout the trial, and PK was collected for MK-8591 parent and MK-8591-TP until 4 weeks after implant removal. Modeling was conducted to extrapolate and predict MK-8591-TP concentrations.
Results: Implants were generally well tolerated, and PK showed concentrations above target for both implants throughout the study. PK parameter values for MK-8591-TP and the projected duration of the implant above the target are depicted in the table.

RP Matthews, SE Barrett, M Patel, W Zhu, KL Fillgrove, L Haspeslagh, G Chen, V Levine, S Zhang, A Goodey, SP Forster, R Vargo, JA Grobler, SA Stoch, M Iwamoto


According to a Health-e News report, Merck is the manufacturer of the implant, as well as the contraceptive implant known in South Africa as Implanon NXT. The pharmaceutical manufacturer’s experience with slow-release removable birth control implants, which are already widely used in some countries, puts them at an advantage of leading the way in the PrEP implant field. These small-scale results are promising, Matthews says, and show the need for larger-scale trials.

The report says a PrEP implant clinical trial will also start in South Africa, through the Centre for the Aids Programme of Research (CAPRISA) in KwaZulu-Natal. The trial will assess the safety and tolerability of an implant loaded with the ARV drug tenofovir alafenamide fumarate, which is produced by another pharmaceutical giant Gilead.

“Unlike the (islatavir) implant, which shows potential as a single implant, TAF may need more than one rod to be inserted (to be able to prevent HIV infection),” explains Dr Ariane van der Straten, a senior fellow and director at RTIs Women’s Global Health Imperative.

Researchers at IAS 2019 are forecasting that implant-driven HIV prevention technology could resolve some of the problems the one-a-day pill PrEP is facing at the moment, such as adherence.

The more correctly someone takes the PrEP pill, sold under the brand name Truvada, the more effective it is at preventing HIV infection. It needs to be taken more or less at the same time every day, which can be difficult for some people who are at risk of contracting, such as women. A 2015 study by researchers at the UNC Eshelman School of Pharmacy, University of North Carolina–Chapel Hill, showed that women who fail to take the pill daily have a higher chance of contracting HIV than men who have sex with men who skip doses.

The report says creating an implant that requires one or two implants and doesn’t need to be administered daily could help prevent new HIV infections in South African girls and young women who are infected by the virus at a rate that is four times higher than their male counterparts.

But implants – in particular, contraceptive implants – have a bad reputation in South Africa, van der Straten at the University of California San Francisco says. In 2014, the South African government introduced Merck’s Implanon NXT to increase contraceptive options in the public sector. The implant first boomed, but later, women removed them early, leading to a decline in the uptake, states a 2017 study. The report says women complained about side effects such as weight gain, acne, headaches, and mood swings.

It was reported that the women who wanted to remove the implant struggled because some health workers refused because they didn’t know how to. “Many people are complaining about the (contraceptive) implant. I even saw it on Checkpoint (reality TV programme). They are saying that they are having periods for a long time and when they go to the clinic to ask them to remove the implant, the nurses tell them that ‘we can’t remove it because we are not trained to remove it, we are only trained to insert it’,” said a young woman who was part of a 2018 study that assessed South African youth’s perception of an HIV-prevention implant.

The report says this hurdle could stand in the way of the success of an HIV-prevention implant. If the concerns and views of people who have or haven’t used Implanon NXT are not allayed by providing better information and fixing the mistakes of the Implanon NXT rollout, van der Straten says. She explains: “We need to learn from the South African situation and think about how we will make sure that the PrEP implant is not coercive, and when someone wants to remove it, they can get it out.”

But the study found that, despite challenging early stages of Implanon NXT, young people are open to the idea of a PrEP implant.

The study was conducted in Soshanguve (Tshwane) and Cape Town and suggests that young women and men between the ages of 18 to 24 show some kind of interest in using a PrEP implant. About a quarter (23%) of the women in the 105-person sample had previously used contraceptive implants. The study found that an HIV-prevention implant that offers long‐lasting protection could potentially be a hit.

“The reason why I feel excited is because it will be invisible when I have inserted it (PrEP implant). Nobody is going to see that it is there, unlike the one for pregnancy prevention,” Hlumelo, one of the study’s participants who has never used an implant, told researchers.

The report says while some participants preferred an implant that could prevent HIV for more than six months, size and the number of implants inserted also mattered. Additionally, a PrEP implant that’s flexible, discreet and is biodegradable – meaning it doesn’t need to be removed from the body – could also increase people’s chances of choosing the implant.

While the world could still be a few years away from a publicly available PrEP implant, the possibilities are endless and add to the increasing pot of biomedical innovations aiming to prevent new HIV infections.

Aidsmap material IAS 2019 abstract Health-e News report

Receive Medical Brief's free weekly e-newsletter

Related Posts

Thank you for subscribing to MedicalBrief

MedicalBrief is Africa’s premier medical news and research weekly newsletter. MedicalBrief is published every Thursday and delivered free of charge by email to over 33 000 health professionals.

Please consider completing the form below. The information you supply is optional and will only be used to compile a demographic profile of our subscribers. Your personal details will never be shared with a third party.

Thank you for taking the time to complete the form.