One of the most vibrant areas of HIV research these days is the search for new, more convenient ways of using antiretroviral (ARV) medicines to prevent infection.
Taking ARVs as a precautionary – rather than curative – measure is referred to as pre-exposure prophylaxis (PrEP). Other preventive measures include the correct use of condoms, medical male circumcision and providing ARVs to people living with HIV. Those 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 and emtricitabine – ideally taken daily. This is recommended both in World Health Organisation (WHO) and South African guidelines, and is already available in the South African public healthcare system.
However, taking a pill every day (or most days) is inconvenient for some people, while others may forget to do so. One alternative that the WHO is already recommending for women who are at substantial risk of HIV infection is the dapivirine vaginal ring (an ARV-containing device worn inside the vagina). In a landmark study last year, a PrEP injection of a long-acting form of the ARV cabotegravir given every two months was also found to be highly effective. However, neither the ring nor the injection is available in South Africa yet.
As became clear at the eleventh International Aids Society conference, held virtually last month, more PrEP options are in the pipeline, including a biodegradable implant and longer-acting injections, pills and vaginal rings. Many of the products featured 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.
Dr Kundai Chinyenze, executive medical director at the International Aids Vaccine Initiative, pointed out that these products needed to be long-acting to mitigate the adherence challenges of different populations. They also needed to support discreet use, have improved side-effect profiles, be able to support the reproductive health needs of women, and be more cost-effective and affordable.
Vaginal rings that last longer
Meg Doherty, director of global HIV, hepatitis and sexually transmitted infection programmes at the WHO, said the dapivirine ring had been submitted for regulatory approval this year in a number of countries, including South Africa.
The next step, according to Dr Sharon Hillier, the Richard Sweet professor of reproductive infectious diseases at the University of Pittsburgh, US, is extended duration rings. One option is a dapivirine ring that lasts for three months. The version currently recommended by the WHO only lasts for one month.
Hillier 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 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 eight weeks and then worn for an additional five weeks. The second group wore a 100mg dapivirine ring continuously for 13 weeks, while 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 three-monthly rings. Most of the adverse events were unrelated to the product use and almost all were mild,” said Hillier.
Hillier also stressed the potential value of multipurpose rings, which could serve as a contraceptive and protect against HIV and other sexually transmitted diseases. The Initiative for Multipurpose Prevention Technologies currently lists 11 such multipurpose 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 of 90 days of continuous ring use, 28 days of continuous ring use 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 those in levonorgestrel-based contraceptives. Results from the group that removed the ring once a month for their menstrual cycle indicated that this led to rapid drug clearance, but levels were rapidly re-established when the rings were reinserted.
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. Dr Andrea Thurman, director of the Clinical Research Centre at Conrad (an organisation focused on developing new methods of contraception and HIV prevention) presented research data on studies for two new vaginal rings designed for PrEP use. These are a tenofovir ring designed to prevent HIV and herpes simplex virus two (HSV2), and a tenofovir levonorgestrel ring designed to prevent both HIV and HSV2 and act as a contraceptive.
Thurman said that five phase I early clinical studies had been completed on these two rings to assess safety. Evidence from all five studies showed that both rings were safe and did not cause genital ulcers. Both rings delivered enough of the drug(s) to the body to suggest that they would prevent infection, although further trials would be needed to confirm their effectiveness.
A 3-D-printed vaginal ring
One abstract presented at the conference explained how 3-D printing technology could help produce multipurpose vaginal rings. The researchers used continuous liquid interface production, a 3-D printing technology that uses ultraviolet 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 3-D-printed ring’s contraceptive capabilities with those of the NuvaRing.
Early results showed it was possible to manufacture 3-D-printed vaginal rings using continuous liquid interface production that contained the required three drugs and released them over a 90-day period, similar to the NuvaRing.
A biodegradable implant
There is still some way to go with implants, such as those already used as contraceptives. Work is under way on an implant containing islatravir, which could be implanted in the upper arm and provide protection for up to a year.
Thereafter, it would need to be removed by someone with medical training.
Researchers have also presented early work on a biodegradable implant that might not need to be removed by a trained healthcare worker.
According to one of the study authors, Soumya Benhabbour, a new process was tested that allowed for the manufacturing of biodegradable polymeric solid implants for the purpose of administering PrEP. These implants were manufactured using a phased inversion and compression process, and tested in mice. The research findings were published in the Journal of Pharmaceutics.
Benhabbour said the implant could be made into different shapes and sizes and could accommodate more than one drug to provide ultralong-acting delivery of ARVs.
The implants used in the test contained the drugs dolutegravir and rilpivirine. Single- and combination-drug implants were tested to assess safety and pharmacokinetics in mice. Both the single- and combination-drug implants showed sustained drug release for 180 days and longer, with no toxicity or adverse reactions at the implant site.
Due to their biodegradable nature, the implants do not require removal post-use, but can be removed quickly if treatment needs to be halted.
Long-acting oral PrEP
PrEP in pill form could be more convenient if it needed to be taken less regularly.
Participants in a phase IIA study received six once-monthly doses of either 60mg or 120mg of the experimental ARV islatravir or a placebo. Adverse events were recorded in 60% of the participants, the most common being mild or moderate headaches, diarrhoea and nausea. 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.
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.
However, injections every six months may also be possible with a long-acting form of the experimental ARV lenacapavir.
An ongoing study is looking at long-acting subcutaneous lenacapavir administered every six months as part of a combination regimen in treatment-naive people with HIV. The interim 16-week results for the 182 participants of the study, who were divided into three groups, revealed that the ARV – given either orally or injected, taken in combination with two other ARVs – led to high rates of viral suppression in treatment-naive people with HIV by week 16. The drugs were found to be generally safe and well tolerated.
This article was produced by Spotlight – health journalism in the public interest.