One of the most vibrant areas of HIV research these days is the search for new, more convenient ways to use antiretroviral medicines (ARVs) to prevent HIV infection. Such taking of ARVs to prevent HIV infection is referred to as pre-exposure prophylaxis, or PrEP for short. PrEP is one of a number of HIV prevention tools. Others include the correct use of condoms, medical male circumcision, and providing antiretroviral treatment to people living with HIV – the latter is a form of prevention since people living with HIV who are on treatment and in whose bodies the virus is suppressed are no longer infectious.
The current gold standard for HIV PrEP is a pill containing the ARVs tenofovir disoproxil fumarate (TDF) and emtricitabine – ideally taken daily. This pill is recommended both in World Health Organization and South African guidelines and, as Spotlight previously reported, is already available in South Africa’s public healthcare system.
But having to take a pill every day, or most days, is not convenient for everyone and some people may forget to take the pills. Some people might also wish to hide the fact that they are taking PrEP from their partners of families, which can be harder to do with pills than with other forms of PrEP. As with contraception, the vision is that people should have a choice of a variety of pills, implants, and injections so that they can choose the one that fits their lifestyle.
One alternative that the WHO is already recommending for women at substantial risk of HIV is the dapivirine vaginal ring (an ARV-containing ring worn inside the vagina). Landmark study findings presented last year also found a PrEP injection of a long-acting form of the ARV cabotegravir given every two months to be highly effective. Neither the ring nor the injection is available in South Africa yet. (Spotlight will soon publish an in-depth article looking at what needs to happen for the ring and injection to become widely available.)
As became clear at the 11th International AIDS Society (IAS) Conference, held virtually in July, yet more PrEP options are in the pipeline, including a bio-degradable implant and longer-acting injections, pills, and vaginal rings. We stress, however, that much of the products that we feature in this article are still in relatively early phases of research and may only reach clinics in a few years’ time, if ever. (All conference abstracts can be found here)
One broad theme from the conference was recognising the need for PrEP products that help mitigate the adherence challenges of different populations of PrEP users. As pointed out by Dr Kundai Chinyenze, Executive Medical Director at The International AIDS Vaccine Initiative (IAVI), PrEP products must be long-acting to mitigate these adherence challenges. Products should also support discreet use, have improved side-effect profiles and be able to support the reproductive health needs of women, and be more cost-effective and affordable.
1. Vaginal rings that last longer
As mentioned earlier, the WHO already recommends the use of the Dapivirine ring to women who are at substantial risk of HIV infection. During a presentation on the Dapivirine ring, Meg Doherty, director of Global HIV, Hepatitis, and STI programmes at the WHO, said that the ring had been submitted for regulatory approval in 2021 in a number of countries, including South Africa.
The next step for vaginal rings, according to the Richard Sweet Professor of Reproductive Infectious Disease at the University of Pittsburgh, Dr Sharon Hillier, are extended duration rings. One such option is a Dapivirine ring that lasts three months. The version currently recommended by the WHO only lasts one month.
She highlighted a Phase I pharmacokinetics and safety study of an extended duration dapivirine vaginal ring published in the Journal of the International AIDS society. This trial was a three-arm randomised trial and included 49 HIV-uninfected women. The first group used a 25mg dapivirine ring that was replaced every four weeks for a duration of eight weeks and then worn for an additional five weeks. The second group wore a 100mg dapivirine ring continuously for 13 weeks and the third group wore a 200mg dapivirine ring continuously for 13 weeks.
“The 90-day dapivirine ring safety was outstanding, with no differences in adverse events between the monthly and the three-monthly rings. And most of the adverse events were unrelated to the product use and almost all were mild,” she said. She added that the pharmacokinetics or drug levels of Dapivirine were higher in both plasma and cervical vaginal fluid when the higher concentration rings were used, which shows that there was sustained higher drug delivery in the three-month ring compared to the one-month ring.
“We think this really demonstrates that the three-month ring can not only be used safely but provided much higher levels of drug where it’s needed,” she said.
2. Multi-purpose rings
Hillier also stressed the potential value of multi-purpose rings which could serve as a contraceptive, protect against HIV, and protect against other sexually transmitted diseases. The Initiative for Multipurpose Prevention Technologies (IMPT) currently lists 11 such multi-purpose technology intravaginal rings that are in various stages of testing and development.
Hillier highlighted a Phase I trial of a 90-day Dapivirine and Levonorgestrel (a contraceptive) ring conducted by the University of Pittsburgh. The trial was randomised to compare results for 90 days of continuous ring use and ring use for 28 days and removal for the menstrual cycle once a month.
She said that overall, the ring was well-tolerated and delivered levels of Dapivirine similar to the Dapivirine only three-month ring. It was also found that the Levonorgestrel levels remained similar to the levels of Levonorgestrel-based contraceptives. Results from the group that removed the ring once a month for their menstrual cycle indicated that the removal of the ring led to rapid drug clearance, but levels were rapidly re-established when the rings were re-inserted.
3. A tenofovir ring
The only vaginal ring currently recommended by the WHO contains the ARV Dapivirine, but rings with other ARVs are also being developed. Director of the Clinical Research Center at CONRAD, a research organisation focused on developing new methods of contraception and HIV prevention, Dr Andrea Thurman, presented research data on studies for two new vaginal rings designed for PrEP use. These are a Tenofovir ring (which is designed to prevent HIV and Herpes Simplex Virus Two (HSV2), and the Tenofovir Levonorgestrel ring, which is designed to prevent HIV, HSV2, and act as a contraceptive.
She says that five Phase I early clinical studies have been completed on these two rings to assess safety. Four of these studies were conducted by CONRAD and one by the Microbicide Trial Network (MTN).
The results of these trials have been promising, according to Thurman. She said the incidence of adverse events was similar across treatment groups and similar to the placebo group. Evidence from all five studies shows that both rings are safe and do not cause genital ulcers. Both rings made enough of the drug(s) available to the body to suggest they will prevent infection, although further trials will be needed to determine whether the rings are actually effective.
4. A 3D-printed vaginal ring
One abstract presented at the conference reported how 3D printing technology can be used to produce multi-purpose vaginal rings. The researchers used Continuous Liquid Interface Production (CLIP), which is a 3D printing technology that uses ultra-violet light and photopolymerisation.
The prototype contained a triple-drug combination of the antiretroviral drug Islatravir as well as the contraceptive drugs etonogestrel and ethynyl estradiol – the latter two are already used in a contraceptive vaginal ring called the NuvaRing. The study compared the 3D printed ring’s contraceptive capabilities with that of the NuvaRing.
The early results showed that it was possible to manufacture 3D printed vaginal rings using CLIP that contained the required three drugs and that released the drugs as intended over a 90-day period in a manner comparable to the NuvaRing.
The abstract’s author, PhD candidate at the UNC Eshelman School of Pharmacy Isabella Young, was one of four recipients of the International AIDS Society (IAS) Prize for Research in HIV Prevention.
5. A biodegradable implant
While PrEP research on pills, rings, and injections has progressed quite far, there is still some way to go with implants such as those already used as contraceptives. That said, work is underway on an implant containing the experimental ARV islatravir. Such an implant would be implanted in the upper arm and could provide protection for as long as a year – after which it would have to be taken out by someone with medical training.
Now researchers have presented early work on a biodegradable implant, which could offer the benefit of not having to be taken out by a trained healthcare worker.
According to one of the study authors, Soumya Benhabbour, they tested a new process that allows for the manufacturing of biodegradable polymeric implants for the purpose of administering PrEP. These Polymeric Solid Implants (PSIs) were manufactured using a phased inversion and compression process and tested in mice. Their findings were published in the Journal of Pharmaceutics.
Benhabbour says the implant can be made into different shapes and sizes and can accommodate more than one drug in order to provide ultra-long-acting delivery of ARVs.
The researchers tested the PSIs containing the drugs Dolutegravir and Rilpivirine. Single and combination drug PSIs were tested to assess safety and pharmacokinetics in mice. Both the single and combination PSIs showed sustained drug release for 180 days and longer. The PSIs were well tolerated with no toxicity or adverse reactions at the implant site.
The PSIs do not require removal post-use, due to its biodegradable nature, according to the abstract, but can be removed quickly if treatment needs to be halted.
“This fabrication process is simple, scalable, and does not require high heat, high pressure, or use of high volumes of organic solvents. The fabricated PSIs are highly tunable, ultra-long-acting, and contain high drug loading to provide translatable human drug doses for HIV PrEP/ART,” the abstract concludes.
6. Long-Acting oral PrEP
One way in which PrEP taken in pill form might be made more convenient is if it could be taken less regularly. Instead of every day, researchers hope that a new formulation could provide protection when taken once a month.
Participants in a Phase IIA study received six once-monthly doses of either 60mg or 120mg of the experimental ARV Islatravir or a placebo. 60% of participants reported adverse events, the most common being headache, diarrhea, and nausea. The abstract reported that all drug-related adverse events were mild or moderate. With both doses of islatravir study participants were found to have the pre-specified drug levels in their bodies thought to be sufficient to prevent HIV infection.
In line with these results, a Phase III trial of oral islatravir 60mg once monthly is already enrolling. This trial will tell us whether once-monthly oral Islatravir is effective at preventing HIV infection.
7. Long-acting injectable PrEP
Injections of the long-acting form of the ARV cabotegravir administered every two months have already shown remarkably good outcomes in Phase III studies and it is likely only a matter of time until the WHO recommends these injections and they become more widely available.
But instead of injections every two months, injections every six months may be possible with a long-acting form of the experimental ARV lenacapavir.
Lenacapavir is being researched both for use as PrEP and HIV treatment.
The ongoing CALIBRATE study is looking at long-acting subcutaneous Lenacapavir dosed every six months as part of a combination regimen in treatment-naïve people with HIV. The interim 16 weeks results for the 182 participants of the study, which were divided into three groups, revealed that Lenacapavir either given orally or injected taken in combination with two other ARVs led to high rates of viral suppression in treatment-naïve people with HIV by week 16. The drugs were found to be generally safe and well-tolerated and the abstract states that results support the ongoing evaluation of the drug for HIV prevention and treatment.
Another study provided pre-clinical proof of concept that a single injection of Lenacapavir achieved long-acting protection against exposure to SHIV (simian-human immunodeficiency virus) in monkeys.
ClinicalTrials.gov lists a large, just-started study of lenacapavir for HIV PrEP in humans.
Read the original article on Spotlight.
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