Mark Mascolini is a medical journalist who writes about HIV news, research and global policies for the International AIDS Society and many publications. Emily Bass is the Director of Strategy & Content at AVAC.

A medicine you get only every two months to reduce your risk of acquiring HIV sounds like a great deal. And that could be an option in the future. But only if two big efficacy trials of long-acting injectable cabotegravir (CAB-LA) show that it is safe and effective. The strategy in question is one shot of this long-acting antiretroviral (ARV) in the buttocks every 8 weeks. The questions the two trials are asking are whether this type of PrEP is safe and well tolerated and whether it will help shield trial participants—women, men who have sex with men (MSM), and transgender women (TGW)—from HIV.

We already know that long-acting CAB, an investigational HIV integrase inhibitor, prevents rectal, vaginal, and intravenous infection with simian HIV (SHIV) in monkeys. Studies in animals aren’t a guarantee of results in humans, but these and other data have helped move the candidate into human studies. A Phase 2 trial of CAB-LA for prevention (ECLAIR) was recently completed among men; the HPNT 077 Phase 2 trial among women and men is due to present results soon; and the drug is now moving into two efficacy trials (HPTN 083 and HPTN 084).

A combination of CAB-LA and another investigational injectable, the nonnucleoside antiretroviral rilpivirine (RPV), is being studied for treatment in people living with HIV and showing good results. In the treatment context, injectable ARVs are given to people who have undetectable viral loads using standard, pill-based regimens. So far it looks like long-acting injected CAB plus RPV every 4–8 weeks safely maintains HIV suppression. The combination has entered Phase 3 trials in people living with HIV who have been on antiretroviral therapy before, and those who have not. (RPV was also studied for long-acting PrEP in the HPTN 076 trial but is not moving forward into efficacy trials at this point.)

Despite this early run through the research gauntlet, pressing questions remain about the safety and routine use of long-acting injected antiretrovirals. Initial questions about acceptability can be partially explored now in the trials, but for injectable PrEP, as for any new strategy, there would need to be a robust agenda of follow-up investigation, should the efficacy trials show positive results. Some of the questions include:

• Will there be adherence advantages of shots given every two months over daily pills in practice—and/or will intermittent injections raise other problems?
• Will the good early side-effect scores of CAB-LA hold true outside clinical trials—or will the almost-routine injection reactions turn off possible bi-monthly-shot recipients?
• Will the striking staying power of CAB-LA and RPV in a person’s body—the long duration that makes infrequent shots possible—lead to side effects whose risks outweigh the benefits and convenience of the tool?
• In people with HIV who use long-acting CAB-LA and RPV, will HIV spawn resistant mutants during the months-long low-level drug “tail” that lingers when a long-acting dose is not followed by another?
• In people who are HIV-negative and using CAB-LA for PrEP, what’s the strategy for dealing with the tail when coming off PrEP? Oral PrEP is one option but could be unpopular with people who opt for the injection. Yet exposure to HIV during the period when the drug is still in the body could lead to drug resistance, if infection occurs. In other words, will the tail wag the drug?

This report considers the evidence so far, with a focus on long-acting injectable CAB for pre-exposure prophylaxis (PrEP) to prevent HIV infection. Here’s what we know and don’t know right now.

We know an injection won’t be perfect for everyone.

Easier adherence remains the premier promise of long-acting antiretroviral PrEP or treatment. For lots of people, getting a shot in the butt every two months sounds much simpler than popping a Truvada (TDF/FTC) tablet every single day—or remembering to dose up before and after sex. But experience from many arenas—particularly contraceptives—tells us it won’t be the simpler choice for everyone. Countless people have no trouble remembering to swallow a multivitamin every day; they might more easily lose track of an every-eight-weeks multivitamin shot. Some women like a daily birth control pill; others prefer a long-acting method such as an implant or an injection. There will almost certainly be people who can take a daily PrEP pill with calendrical consistency but find the eight weeks between PrEP shots a slick slope to dosing amnesia.

The trials can’t predict preferences or the chances that people will fall into this two-month memory trap. Clinical trials of injectable PrEP or treatment require people to come to a clinic for their injections. We do know that women taking hormonal contraceptives can struggle with consistency and that research in the US and in sub-Saharan Africa has found that many women can forget to return for their scheduled contraceptive injection.

Trials of CAB-LA for PrEP start with four or five weeks of daily oral dosing to make sure people can tolerate the drug. But PrEP experts observe that these preliminary weeks of daily pill taking may prove challenging to people trying injected PrEP precisely because they struggle with once-a-day dosing.

We know frequent (or rare) side effects may pose safety concerns.

Safety data on long-acting CAB and RPV are accumulating from the trials to date. Through 32 weeks in the 286-person LATTE-2 trial of injected CAB/RPV for treatment, two people out of 115 (2 percent) getting their two-drug shots every eight weeks dropped out because of possible side effects (both injection-site problems), while six people out of 115 (5 percent) getting shots every four weeks stopped for possible side effects.

People living with HIV may be willing to put up with more antiretroviral side effects than people taking antiretroviral PrEP to avoid HIV infection. In the biggest CAB-LA for PrEP trial reported so far, ÉCLAIR, 106 men were assigned to the CAB group; of these, 94 completed the oral dosing phase and entered the injection phase. After four weeks of oral CAB, these men got CAB-LA every 12 weeks. Four of 94 men (4 percent) who started the shots quit the study because they couldn’t tolerate the injections. Overall, 75 men (80 percent) who started CAB shots had moderate to severe adverse events. Injection-site pain, itching or swelling accounted for the lion’s share of these problems, compared with ten men (48 percent) who received the placebo injection. ÉCLAIR concluded that the injection schedule of 800 mg of CAB-LA administered every 12 weeks was suboptimal when it came to maintaining the drug levels required for protection against HIV; the eight-weekly regimen is proposed as a solution. (Results from the HPTN 077 trial of CAB-LA among approximately 200 HIV-uninfected men and women in 8 cities in Brazil, Malawi, South Africa and the US are anticipated later this year.)

A 2016 paper that looked at all of the data from trials of CAB-LA for treatment or PrEP to date found that roughly three-quarters of participants had injection-site reactions, usually mild or moderate. Nodules popping up at injection sites can be stubborn. The same paper reported that about half of injection site nodules lasted 22 days, about one-third of an eight-week dosing interval. Outside the hand-holding discipline of clinical trials, people already squeamish about needles who nonetheless agree to a big shot in the behind every eight weeks may fast run out of patience if they find the shots painful.

Injection woes may be the most frequent problem with long-acting shots, but they may not be the most serious. The remarkable durability of injected drugs like CAB and RPV—the very trait that makes infrequent dosing possible—also poses their greatest risk. Once you stop taking antiretroviral pills, the drug is gone in a few days, and you can shut off drug exposure by removing an inserted drug delivery system like the dapivirine ring or an under-the-skin TAF implant. But once an injected drug starts soaking target cells, there’s no way to get rid of it. And that could mean there’s no way to get rid of an out-of-the-blue side effect. Taking CAB or RPV pills for several weeks could uncover side effects that warn prescribers away from injecting the drugs in a few people. But that strategy may miss a surprise reaction that comes only after a hefty loading dose gets plunged through a one-way needle. Such reactions will probably be rare but no less troubling to individuals affected.

We know the “tail” is something to track.

After a single dose of CAB-LA or RPV, the slow fade of drug from the body means drug levels eventually fall beneath a concentration that shuts down HIV—unless a person gets another shot in the prescribed time. In the ÉCLAIR trial, CAB-LA remained detectable in blood in 14 participants (17 percent) 52 weeks after the last injection. If someone taking CAB for PrEP forgets a shot long enough—or just stops—and keeps having sex, low CAB levels could permit HIV infection. And when HIV starts copying itself in the face of meager antiretroviral levels, it starts making resistant copies.

This is not a theoretical scenario. It already happened to a woman who got a single 300-mg intramuscular shot of RPV. She tested positive for HIV 84 days after the shot, and after 115 days the infecting virus carried a mutation that confers resistance to the whole nonnucleoside class. The researchers call this “a unique instance of infection with wild-type [nonmutant] HIV-1 and subsequent selection of resistant virus by persistent exposure to long-acting PrEP.” To avoid repeating this misadventure, a person taking a long-acting injectable would have to have a clear HIV prevention plan for several months after the last shot—some combination of complete condom use, behavior change or covering the slowly waning tail of the injectable with faithfully taken oral PrEP, like Truvada.

We know the trial designs are complex.

December 2016 saw the launch of HPTN 083, a 4500-person double-dummy, double-blind trial of injectable CAB-LA PrEP every eight weeks. The trial is enrolling MSM and TGW in countries in North and South America, Asia, as well as in South Africa. Researchers estimate it could take 3.5 years to complete HPTN 083 but note that the trial is “endpoint driven,” meaning that the timing depends on the frequency with which new HIV diagnoses occur in participants. HPTN 084, a parallel CAB-LA PrEP trial in women, is also a double-dummy, double-blind trial and is expected to start later this year.

Does “double-dummy double-blind” sound familiar? It might not. This and other terms are relatively new in the biomedical HIV prevention field. But times have changed. The advent of daily oral PrEP as a WHO-recommended prevention strategy has propelled changes in trials of other prevention strategies—including ARV-based and non-ARV based prevention alike. (AVAC has developed a plain language glossary of some of the commonly used terms HIV Prevention Trial Terms: An advocate’s guide.)

The designs for HPTN 083 and 084 are examples of what efficacy trials look like in the “post-placebo” era. In a placebo-controlled trial, people are randomly assigned to receive either an active agent (like oral PrEP pills) or an identical “dummy” candidate (a sugar pill or a saline injection). Both groups receive the same HIV prevention package. HIV prevention trials involving people whose primary risk is sexual exposure all provide condoms, diagnosis and treatment of sexually transmitted infections and behavior change; some also now provide referrals for voluntary medical male circumcision, PrEP and partner testing and treatment.

For now, PrEP is not part of the standard prevention package in all HIV prevention trials (e.g., vaccine studies and more). It’s being provided on referral in countries where PrEP is also part of the national policy. But this approach won’t work for trials of long-acting injectable PrEP. Trial ethics require that a trial of a new method (an injectable PrEP) be compared to existing effective methods in the same category (daily oral PrEP).

For an in-depth look at HPTN 084 trial and the “lexicon” associated with such studies, check out AVAC’s most recent issue of Px Wire.

To meet this ethical imperative and get a clear, usable answer, the trials have to ask a new kind of question: how does injectable PrEP compare to daily oral PrEP when it comes to reducing the risk of acquiring HIV?

Because of the way that statistics work, this question has to be phrased very precisely. Broadly speaking there are two questions PrEP trials can ask in the post-placebo era:

• Is this new experimental product better than a placebo or an existing product, e.g., is injectable CAB-LA better than daily TDF/FTC? A superiority trial asks this kind of question.
• Is this new experimental product equivalent to or not worse than the existing product, by a pre-specified margin? A non-inferiority trial asks this kind of question.

These weighty questions about injectable antiretroviral adherence, safety, and resistance will probably take a few years to answer because big efficacy trials have just started signing up recruits.

We know that clinical trial success is only one step—and doesn’t always translate to impact.

If injectable PrEP or treatment works in trials, there will still be lots to explore about delivery in the real world.

Most people with HIV see their provider every 4–6 months; most HIV-negative individuals who may be candidates for PrEP see their clinician much less often, if at all. That will have to change if providers intend to give people antiretroviral injections for treatment or prevention every two months. There will be many other questions too about who is willing to pay for long-acting ARVs, what types of programs these tools would belong in—and more.

As we’ve learned from many strategies—from HPV vaccine to oral PrEP—if you wait until there is evidence of efficacy to begin addressing these questions, then you’ve waited too long. AVAC is working with CHAI as part of the Gates Foundation-funded HIV Prevention Market Manager project to frame and address key questions about long-acting PrEP. At the same time, we are working with many of our partners in civil society to ensure that the trial designs are ethical, the goals well understood, and the outcomes on track to achieve the ultimate goal—a sustained end to epidemic levels of new HIV infections worldwide.

See the AVAC infographic on long-acting injectables for a nuts-and-bolts review of testing these agents for HIV treatment and prevention; see: HIV Prevention Trial Terms: An advocate’s guide for definitions of many of the terms used in this article.

Cindra is a Senior Program Manager at AVAC.

Europe is the birthplace of the smallpox vaccine and the Renaissance, among other treasures. So why can’t this continent that has brought forth such cornerstones of public health and flourishing civilization deliver oral PrEP—a mere pill a day to prevent HIV, which already exists and is being successfully implemented in several countries, including Brazil, Kenya, South Africa and the US.

To be fair, France has been rolling out daily oral PrEP (consisting of Truvada) for over a year and a handful of others—Norway, Scotland, Belgium and Portugal—recently committed to provision plans. But the majority of countries on the continent are still struggling to even start to take PrEP to scale—even though there has been a 60 percent spike in HIV incidence in the past decade.

The delay isn’t due to lack of demand or a framework for PrEP provision. The call for PrEP from civil society is loud and clear, evidenced by the do-it-yourself droves ordering PrEP over the internet, clinic hopping, pill sharing and/or smuggling PrEP drugs into countries where it’s not available via the health system.

It’s been more than a year since the European AIDS Clinical Society Guidelines recommended PrEP and Europe’s regulatory authority (EMA) approved Truvada (emtricitabine and tenofovir) for PrEP. In England, the National Health Service argued that it didn’t have the mandate to introduce PrEP programs, as HIV prevention was the responsibility of district health authorities. The English High Court ruled otherwise and clarified that NHS did indeed have the power to launch PrEP programs. Even policy makers are warming to the idea of PrEP as more data from countries where PrEP is becoming available come in, suggesting that PrEP is working as HIV prevention in real-world settings.

So what’s the hold up? Many are pointing to the drug company Gilead, the patent holder of Truvada, the only PrEP drug licensed in Europe. Recently, Gilead obtained an extension of its Truvada patent in England, where the original copyright expires this year. The pharma giant is likely to keep prices high while facing no competition from generic manufacturers until 2021. That’s almost four years in a country with 17 seroconversions a day.

As a response to Gilead’s motion to postpone its patent expiry in England, several generic producers filed a lawsuit that was kicked up to the Court of Justice of the European Union. Now any legal decision will apply to all EU member states, not only England. “If the court finds in favour of the generic companies, the cost of PrEP could be accommodated within current budgets through the savings made in treatment costs,” wrote UK clinician advocates Sheena McCormack and Marta Boffito in The Lancet.

In the meantime, some health systems have hit the pause button on piloting PrEP. England is one example where its PrEP implementation has been delayed largely due to the prohibitive costs of the branded Truvada drug. Gilead has refused to waive its patent even for pending implementation studies. A planned 10,000-participant trial was slated to have started early in the year, but recruitment is now unlikely to begin until July.

Similarly, in Italy, the Bologna Checkpoint—a community-run rapid HIV and STI testing center—was poised to begin its PrEP implementation project, but the launch was thwarted when Gilead declined to provide donated or even discounted Truvada. They were told the company would no longer support PrEP implementation pilots in Western countries. The Italians then approached Mylan, the makers of a generic form of Truvada licensed for treatment in Europe. At first the generic supplier—a plaintiff in the case against Gilead—was happy to do business with Checkpoint but then opted to wait until the lawsuit was settled in the hopes of acquiring full marketing authorization to supply the discounted drug. As of yet there is no scheduled court date for the generic companies v. Gilead.

Activist Giulio Corbelli, of the European AIDS Treatment Group, doesn’t think Gilead is cynically strategizing to block PrEP access in Europe. Rather, he says, the company simply pursues its commercial interests, creating barriers to access in the process. “They are not negotiating with the competent national authorities to identify a route for selling the drug; they are not supporting any implementation projects with their drug; and they are doing whatever they can to prevent other companies’ support of such projects,” he points out.

In addition to protecting its Truvada PrEP monopoly in Europe, Gilead has another bottom-line business incentive to slow European scale-up efforts. The company has released a low-dose version of Truvada, known as F/TAF, for treatment. Gilead has just completed recruitment for a large-scale PrEP study that will compare its new drug F/TAF with Truvada, with results due in 2020. If F/TAF proves to be as effective as Truvada in reducing HIV risk, Gilead can bring this new formulation of the drug to the European market—right in time to replace an extended expiration of the Truvada patent in 2021.

The PrEP in Europe Initiative (PEI) sent Gilead an open letter asking the company to surrender its Truvada Supplementary Protection Certificate (patent extension). However, it’s not likely the company will cave based on its previous intransigence around its shamefully priced hepatitis C drugs. Short of a Gilead walk-back, activists are encouraging health ministries to advocate for an expedited court case to finally rule on the patent extension so generic companies could hopefully get the green light to provide an affordable form of Truvada as PrEP. Or there might just be an uprising, another historic feat Europeans are known for.