Spotlight Center on HIV Prevention Today


Long-Acting Injectable Antiretrovirals for PrEP: Will the Tail Wag the Drug?

June 7, 2017

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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 (ÉCLAIR) 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 shots 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.

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This article was provided by AVAC: Global Advocacy for HIV Prevention. Visit AVAC's website to find out more about their activities and publications.

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