Implants and injectables: PrEP in the future

Last month’s announcement that the Bill and Melinda Gates Foundation will give up to $140 million to a Boston drug device manufacturer to develop an implantable mini-pump to deliver drugs for pre-exposure prophylaxis (PrEP) against HIV infection has focused attention on the future of PrEP. Is the future all about implants, or will it offer multiple options for people who want to use PrEP?

Implants and other long-acting drug delivery systems have attracted interest as a means of delivering PrEP because studies show consistently that non-adherence – missing doses or not using an intravaginal ring – is strongly correlated with lack of protection from PrEP. Conversely, studies also show that people who maintain adequate levels of PrEP drugs are protected from HIV infection.


Intarcia is a Boston-based company developing an implantable mini-pump about the size of a matchstick to deliver a drug for control of blood sugar in people with Type 2 diabetes. Intarcia’s product – ITCA 650, which delivers the drug exenatide for Type 2 diabetes – is already under review by the United States Food and Drug Administration following successful phase III trials and could be licensed by late 2017.

Last month Intarcia announced that it had secured a $50 million grant from the Bill and Melinda Gates Foundation to develop its mini-pump technology to deliver antiretroviral drugs for PrEP. A further $90 million will follow to support access to the device in low- and middle-income countries if it is successful, subject to achieving a series of milestones.



In pharmacology, a medication which maintains its effects over a long period of time, such as an injection or implant.


Something (such as a graft or device) implanted in a body tissue. In a context of prevention (such as contraception), the word refers to a device that will deliver an active agent slowly, over several months or years. This technique might be used one day to deliver antiretrovirals in the body for HIV prevention (PrEP) or treatment. 

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

phase II

The second stage in the clinical evaluation of a new drug or intervention, in which preliminary data on effectiveness and additional information about safety is collected among a few hundred people with the disease or condition.


Refers to the mouth, for example a medicine taken by mouth.

Intarcia’s mini-pump technology is an implant that is placed below the skin, and which dispenses a controlled amount of drug each day. At this point Intarcia is not planning to use a specific antiretroviral product in its PrEP delivery system. Development tests will seek to identify which drugs can be delivered at high enough levels to prevent HIV infection.

Several other research groups and companies have reported on animal tests of subdermal implants, although Intarcia’s implant technology appears furthest advanced. Auritec, a Pasadena drug delivery company, has received National Institutes of Health funding to test intravaginal rings for delivery of antiretroviral prophylaxis, and has also tested an implant containing tenofovir alafenamide (TAF) in dogs. The 40-day study found that the implant maintained drug levels 30 times higher than those needed to protect against HIV infection throughout the study period.

PEPFAR (the US President's Emergency Plan for AIDS Relief) has also supported research into a subcutaneous implant for delivery of TAF, developed by the University of California, San Francisco, which is still at an early stage of development. A larger research project, the Sustained Long-Acting Protection from HIV (SLAP-HIV) partnership, based at Chicago’s Northwestern University and supported by a $17 million grant from the US National Institutes of Health, is working to develop an implant that can deliver either cabotegravir, rilpivirine, TAF or the tenofovir analogue tenofovir exalidex (TXL, formerly CMX-157, currently being developed for hepatitis B). The researchers also hope that their work will lead to the development of implants for long-acting antiretroviral therapy, doing away with the need for daily pill-taking.

Injectable PrEP

Injectable PrEP development is further advanced than PrEP implants, and may provide an interim step on the way to implants that deliver protection for up to a year. It may also provide shorter-term protection for people who need long-acting PrEP, but who, for whatever reason, do not want an impant. Unlike implants, which may be detectable under the skin and therefore unacceptable to some people, an injection is invisible to others and does not need to be removed or replaced when the active drug runs out.

The drawback of injectable PrEP – and perhaps for implants – is that long-acting formulations have been shown to linger in the body at low levels for months, risking drug resistance if HIV infection occurs. The ÉCLAIR study of cabotegravir as injectable PrEP found that almost a quarter of participants still had drugs levels that would probably prevent HIV infection six months after their last injection, while 41% still had detectable but suboptimal drug levels at this point.

Injectable PrEP is being tested at eight-week injection intervals, requiring quite a high frequency of clinic visits, which may not suit everyone. Intramuscular injections may also be unacceptable to some, although user satisfaction in the ÉCLAIR study was high.

Injectable PrEP development is focused on the use of two drugs, cabotegravir and rilpivirine, which are also being developed as long-acting injectable nanoformulations for treatment by ViiV Healthcare.

ViiV Healthcare is working on a long-acting injectable formulation of the antiretroviral cabotegravir, which recently entered a large phase III study in the United States, Latin America and Africa in men who have sex with men and trans women. The HPTN 083 study, sponsored by NIAID (National Institute of Allergy and Infectious Diseases), will randomise 4500 people to receive an injection of cabotegravir every eight weeks or to take Truvada (tenofovir/emtricitabine) every day, for an average of four-and-a-half years. Results are expected in 2021. A companion study, HPTN 084, will begin to test injectable cabotegravir in young women in sub-Saharan Africa later this year. Results from a phase II safety study (HPTN 077) are expected in early 2018.

PATH is testing injectable rilpivirine in women under licence from manufacturer Janssen, in a phase II safety study (HPTN 076) taking place in the United States, South Africa and Zimbabwe. Results are expected in February 2017. Rilpivirine injections are being given every eight weeks in this study.

Vaginal rings

Vaginal rings containing dapivirine, an NNRTI, have been tested in several phase III studies (ASPIRE and the RING study) and found to reduce the risk of infection by 65% in consistent users in the ASPIRE study. The rings were less effective in younger women due to less consistent use, indicating the need for longer-acting methods for this population in particular. The dapivirine ring is likely to undergo licensing review in 2018, and future developments will include experiments with rings containing other agents including TAF and maraviroc, an HIV entry inhibitor. Multi-purpose rings which act as both contraception and HIV PrEP are also in development.

Experiences from contraception emphasise value of multiple options

Although implants and injectable are likely to be attractive to many people, they won’t replace taking oral PrEP for everyone who needs it. Some people may want to use PrEP only for a short period, or may dislike the idea of an injection or an implant. Lessons from contraception show that getting the mix of options right, and delivering these options successfully, is important.

A global analysis of contraceptive uptake has shown that broadening the range of contraceptive options has increased the total usage of contraception – every new method made widely available increased total contraceptive use by 4-8% between 1982 and 2009. Studies in contraception suggest that a choice of method supports access and use.

Contraceptive studies in populations at risk for HIV infection show big variations in the type of contraception used from country to country among women taking part in microbicide studies. For example, whereas injectable contraception predominated in Malawi, oral contraception predominated in Zimbabwe. These historical patterns are structured by donor and health care provider influence over several decades, and may in turn influence the ways in which health services begin to offer different forms of PrEP. For example, greater experience with implantable and injectable contraception may lead to more rapid adoption of these modes when targeting women at higher risk of infection.

Nevertheless, it’s important to avoid assumptions about which type of product will be suitable for a specific population – this may act as a barrier to its subsequent use by other groups of people. For example, targeting a particular form of PrEP to sex workers may have the unintended effect of making other women reluctant to use it for fear of being identified as a sex worker.

It’s also important to remember that without a well-organised health system, any method of PrEP may fall short. For example, if systems aren’t in place to remind people to return for new injections or implants, many people will cease to be protected.