Doctors and advocates discuss treatment and prevention breakthroughs on the horizon

People living with HIV can live long, healthy lives with current antiretroviral therapy (ART). By taking just one pill a day, HIV has become for many a chronic, manageable condition. However, even with these lifesaving medications, a pill a day can lead to pill fatigue and serve as a daily reminder of HIV.

On the prevention front, our options have never been better. We currently have daily oral PrEP (pre-exposure prophylaxis), condoms, and U=U (undetectable equals untransmittable). But what if we could make HIV prevention even more accessible and easier to take? We spoke with a few providers and experts to see what’s currently on the horizon for HIV treatment and prevention.


Perhaps the most exciting option and the closest to becoming available to people living with HIV, long-acting injectables are seen as the future of HIV treatment and prevention. For many living with HIV, not having to take pills every day would be liberating. Imagine going to the doctor’s office once every month or two for an injection. No more daily pills. That may soon be a reality.

There are currently two Phase 3 studies in progress evaluating the safety, efficacy, and tolerability of switching from a pill regimen to long-acting cabotegravir (an integrase inhibitor) plus long-acting rilpivirine (a non-nuke).

Jared Baeten, MD, PhD

Professor and vice chair of the Department of Global Health, University of Washington, Seattle

“The things that are furthest in testing are long-acting injectables, both for treatment and for prevention,” said Jared Baeten, MD, PhD, professor at the University of Washington’s Department of Global Health. “It’s the same product—cabotegravir is being tested for both. To speak from more of a prevention point first, it offers another option for potentially effective HIV prevention. Of course, it’s still in testing, but what everyone needs are more choices so they can choose what’s going to work for them.”

How close are we to having long-acting injectables on the market?

Both Phase 3 studies recently reported non-inferiority results, showing that the two-drug long-acting injectable regimen did not perform worse than a standard oral three-drug regimen. The next step would be submitting these drugs to the U.S. Food and Drug Administration (FDA) for approval.

W. David Hardy, MD

Adjunct Professor of Medicine, Johns Hopkins University School of Medicine, Division of Infectious Diseases

“Both trials hit that non-inferiority margin, which is really important because it means that they will probably be FDA approvable,” said W. David Hardy, MD, Adjunct Professor of Medicine at Johns Hopkins University School of Medicine in the Division of Infectious Diseases.

Updated results of these two studies are anticipated at the CROI conference in March. If the data are good and the drugs are submitted to the FDA for approval, we could have long-acting injectables on the market very soon.

“For many, many years while the studies were being slowly recruited, it was always talked about ‘into the future, into the future,’ but now the future is pretty close,” said Hardy. “I think the good news is that the reality of patients being able to access injectable antiretrovirals outside of the clinical trials is going to be probably within the next year or so, by the end of 2019 I would say.”

But is it for everyone? Will patients really choose an injection over pills?

Thanes Vanig, MD

HIV provider, Phoenix

“I think it depends on the patient,” said Thanes Vanig, MD, a longtime HIV provider based in Phoenix.

“A few years ago when I talked to patients, they were excited. But now when I talk to them again—I think you have to differentiate between people who have been on HIV medications for like 20–25 years—they are actually excited. I think they have pill fatigue. They don’t want to take pills anymore. I think for younger generations, one pill is just so easy to take. Most of my patients are MSM [men who have sex with men] [and working professionals]. If they travel a lot, it might be a hassle for them to come in for an injection.”

Daniel Lee, MD

Clinical Professor of Medicine, University of California at San Diego, Owen Clinic

“It probably is not going to be an option for everyone,” said Daniel Lee, MD, Clinical Professor of Medicine at U.C. San Diego’s Owen Clinic. “I think there are certain challenges certainly with the injectable. First of all, the downsides with injectable medications may include possible side effects—if it’s a longer-acting medication, then theoretically the side effects last the length of however long the injection is.”

There’s also a lead-in phase before patients can start the injectable regimen. “In terms of even getting people on the long-acting,” said Lee, “my understanding is that the plan is to first put people on the same medication, but in oral form to make sure that they tolerate it. This lead-in period will probably last a month or several weeks before they get switched over to the long-acting injection, just to document that there’s tolerability and that there are no side effects. These can be barriers to people who aren’t even adherent during the initial oral phase.”

While the idea of receiving injectable treatment once every one or two months sounds like it would be easy, there could be issues for some. The cabotegravir/rilpivirine long-acting injectable would actually be two large injections, and there might be issues with storage since the medications come in big boxes which may need to be refrigerated, according to Vanig.

“Actually, when I tell patients it’s not one shot—that it’s actually two large injections—they’re like, ‘Oh my god.’ It reminds them of Bicillin for syphilis,” said Vanig.

And what about long-acting injectable PrEP for prevention?

“The analogy I make is to contraceptives,” said Baeten. “A woman seeking contraception can walk into her doctor’s office and would be presented with a number of options—there’s a pill she can take every day, or a shot she can take every few months, or maybe an implant that will last for a long time. Each option has its pluses and minuses, and side effects. Some people don’t want something that’s inside them for a long time, while other people won’t mind. Each person has to decide for themselves which pluses and minuses will make the most sense for them,” he explained.

Will injectables solve adherence issues?

“The other side of the coin is that even if a person is on a longer-acting medication, how adherent are they going to be?” Lee asked. “All of a sudden they’re just getting an injection every now and then—will that lead to more non-adherence? I think these are questions that we don’t know the answers to. The nice thing about seeing people so regularly, whether it’s every several months or so, is that we can infer that things are okay. I wonder if the longer-acting medications will affect people’s adherence. Will they forget that they have HIV? That may lead to other issues down the line.”

“But ultimately I think it’s a great option for a lot of people who have pill fatigue. I think that’s kind of huge for people who have been HIV positive a long time,” he added.

“Just because it’s a shot doesn’t mean that adherence problems are solved. That’s really important,” said Baeten. “To be effective long-term, either as treatment or prevention, means getting that shot, and getting it again and again. That means either the shot has to be patient-friendly, or the location where they get the shot—the clinic, the pharmacy—has to be patient-friendly, too. Otherwise, you’re not going to solve some of the really big adherence challenges, which are getting back to a clinic, wanting to go back and getting a refill.”

Making injectable therapy patient-friendly is exactly what Hardy has in mind. “What could be set up—as national pharmacy chains have done in the U.S., like CVS or Walgreens—is that as long as someone has a prescription in the pharmacy, they could actually go to whatever pharmacy around the country to get their injection,” said Hardy. Being able to get an injection at any pharmacy in the country may not immediately solve adherence issues, but could make adherence much easier.

“I think one of the lessons we’ve learned in HIV therapy since 1996 is that adherence is everything. If you don’t take the meds, you don’t become undetectable,” said Hardy. “Having worked in a center here in D.C. where most of our patients are undetectable, but about 20 percent are not, that 20 percent is a real challenge. If the responsibility for prescribing, obtaining, and injecting the medication is put on the health care practitioner and taken away from the patient, that would probably work a hell of a lot better.”

Hardy further explained, “Because [for] health care practitioners, that’s their business, that’s what they’re trained to do. Patients in many situations are not trained to take pills. Many people don’t like taking pills. People don’t like remembering taking pills every day. If all you had to do was show up at a clinic, or even a pharmacy, once every two months, walk into a private room, drop your pants, get two shots, walk out, that would make being HIV positive a whole different story. I think that that could really revolutionize the way therapy is given.”

Are injectables something that patients could eventually administer themselves at home?

“Well that’s certainly the hope,” said Lee. “I trust that our pharmaceutical companies will be working on a formulation that can be administered by patients on their own. I think that’s the next Holy Grail, developing an injectable medication that can be of lower volume to inject and can be something that may be self-administered. It takes time to develop that type of formulation, but I think it’s certainly feasible. We seem to continue to move forward, so I have good hope”.

“The [current] volume of the injections are either 2 mLs or 3 mLs. One mL is about a teaspoon, so the 2 mL is quite a bit of substance, so trying to inject that much into one’s own buttock can be problematic,” explained Hardy. “Although people have done intramuscular injections on an ongoing basis before, for example, back in the bad old days when we had to use a lot of testosterone to keep people from wasting, a lot of men injected their own testosterone at home, or had a friend do it. This could be done at home, but I think it’s going to have to be something that’s going to have to be very carefully managed.”

What about the forgiveness window in between when one shot runs out and you need the next one?

“It’s not known yet—neither for treatment nor prevention, because the drugs are still in research studies to figure it out,” said Baeten. “Defining that is going to be critical. You need to know what your forgiveness window is going to be. That takes time to figure out, and will be figured out.”

This may include going back to daily pills if a patient can’t get to the clinic for their next shot.

Long-acting injectables do appear very promising for HIV treatment and prevention. As Baeten points out, just having additional options would be welcome.

Not only would long-acting injectables be a new option that could address pill fatigue, they could also help reduce stigma because people living with HIV would not have to carry around pill bottles and could discreetly get their shots once every two months.


Implantables with long-acting HIV medications are another emerging option for treatment and prevention. Although the research is not nearly as far along as long-acting injectables, implantables could offer another long-acting option for people who don’t want to take pills every day.

“There’s some really cool research being done on implants of various types using different medications and slightly different ways of making the implants,” said Baeten. “There are implants that are put in and removed. There are implants that people are working on that might be dissolvable. These are all very, very early studies right now—most are before human studies—but they all suggest that this could be workable. So, that makes me really excited. There’s a segment of people out there for whom an implant would be just the ticket.”

However, with implantables, especially if they cannot be removed or are difficult to remove, side effects could be a worry.

“We have implantables for things like testosterone. For HIV, it does become a challenge in terms of possible side effects. I think with any kind of implant, it probably would be similar to the injectable in the sense that there may need to be a trial period with the medications involved before you implant it, to make sure that there are no tolerability issues,” said Lee.

What would an implantable look like in practice?

Like long-acting injectables, long-acting implantables could greatly reduce stigma and further normalize living with HIV.

Lee points to current testosterone implants as an example. The implant would go right under the skin, maybe in the buttocks. The implant looks like a little matchstick and is designed for slow release.

“But the issue with an implant is that you have to remove it, to be replaced by the next implant,” said Lee. “What I don’t know with implantable agents is how many would need to be inserted, and if you take the implant out, my guess is that you can’t just put the new one in the same location. You probably need that area to heal, so you would need to put it in, let’s say, the other buttock. The chance of scarring or infection might be a little higher. But implants can also be removed if there are side effects, so I think that makes implants perhaps a little better than injectable agents.”

Another wrinkle for implantables is who would do the implanting. It’s not exactly something patients could do at home themselves. Lee notes that either a surgeon or specialist could place the implant, or HIV providers would need training to do so.

Like long-acting injectables, long-acting implantables could greatly reduce stigma and further normalize living with HIV.


Next we have a vaginal ring for HIV prevention. Results from the HOPE study showed that when a ring was used most of or all the time, HIV risk reduction was at least 56%. “The dapivirine ring is a PrEP agent, so it’s PrEP that happens to be delivered in a topical way,” explains Baeten. “It’s delivered in the mucosa rather than being delivered in a shot. It’s not an implant because it’s easily taken in and out, so it doesn’t live permanently inside the body. It acts as a microbicide because its major action is right at the site, that mucosal site. It prevents HIV in the same way these other things prevent HIV, by blocking the virus right at the beginning where it would infect somebody.”

“The only PrEP products that have shown that they can reduce HIV so far are the Truvada [emtricitabine/tenofovir disoproxil fumarate] pill and the dapivirine ring. Everything else is in the testing phase. The first out of the barn was the pill, then the dapivirine ring. The dapivirine ring has shown that it does work; it reduces HIV. Right now, it’s in the process of being evaluated by regulatory authorities, to validate that the data are right and that the product is effective so it can become part of the armamentarium,” said Baeten.

Why is the dapivirine ring exciting?

“I’m super excited about all of these options for PrEP and I am particularly excited about the ring because I think it fills a prevention need that hasn’t been filled yet. It is private, it’s easy to use; it’s also easy to stop. It’s incredibly, incredibly safe. And incredibly safe is really important, particularly for women. The ring releases a lot of drug in the vagina where the HIV would come into contact—but it releases only a very small amount of drug into the body. Because of that, it is incredibly safe,” said Baeten.

The ring could also be safe if a woman were to become pregnant. “Many women think about drug exposure to an infant. The dapivirine ring could be a great option for a woman who wants something private that she can control,” said Baeten.


“Vaccines are the great hope of HIV, of course,” said Baeten. “There are some really interesting vaccines being tested right now that everyone has their fingers crossed for, because they will point the way to what might become an effective HIV vaccine. The science going into vaccines is top notch; if there’s potential to develop an HIV vaccine, the things being developed right now have done all the right things to where we hope to find something that reduces HIV.”

What would an effective vaccine look like?

“A lot of people who work on vaccines have come to realize that developing a vaccine is going to be really hard, and if a vaccine is found, it’s not going to be a perfect 100% protective vaccine. I think everybody would be thrilled if they found a vaccine that reduced HIV risk by 50%. That is going to require really reframing and rethinking how we see a vaccine. Because when most people think of a vaccine, they imagine it working 99–100%. Something that works 50% is different—especially something that works 50% that might also require three, four, five shots to get up to fully working—which is what all the HIV vaccines being tested now require,” said Baeten.

One candidate that is in Phase 2b research is the Ad26 vaccine. The study, called APPROACH, shows a lot of promise in human participants. Another vaccine candidate currently in an efficacy study is a modification of the ALVAC vaccine. This was the first vaccine candidate to show moderate efficacy back in the landmark RV144 study in 2009.

Mitchell Warren

Executive Director, AVAC

“Results are still three to four years away for both, and the path to licensure is not entirely clear, but it is quite promising to have these two approaches in simultaneous late-stage trials,” said Mitchell Warren, executive director of AVAC, a global HIV prevention advocacy and policy network. “In addition, there are a number of next-generation candidates in earlier stages of development.”

Could a vaccine lead to a cure?

“I do think the cure will be in the form of a vaccine, in terms of getting the immune system involved in taking care of the virus itself,” said Lee. “I don’t think that it’s going to be a medication because obviously with pills and with medications, you can’t get the medication to reach everywhere. We always end up with toxicity as a result. The immune system is the only thing that can get everywhere. So, I think that the cure is going to have to come from a vaccine of some sort.”


Perhaps the area of prevention science that has evolved the quickest is in broadly neutralizing antibodies (bNabs). “While we have a few vaccine candidates and a few antiretrovirals for prevention, we have dozens of newly discovered antibodies,” said Warren.

“The VRC01 antibody is currently in large efficacy trials—using an infusion every two months. While infusion is not a viable public health strategy, the trials are proof of concept to see if the antibody can reduce the risk of transmission. If it can, the field is primed to focus on three priority next steps—how to manufacture antibodies so they can be injected, not infused; how to increase durability so the injections could move to every six or 12 months, as opposed to every two months; and which antibodies to combine, as it is now increasingly clear that we would need two to three antibodies, just as antiretroviral therapy requires a combination,” Warren explained.

What about antibodies for treatment?

We do have one monoclonal antibody already approved for HIV treatment. Trogarzo (ibalizumab) is a new medication for people who are highly resistant to current antiretroviral therapy.

It’s a great new option for patients who need salvage therapy,” said Lee. “However, Trogarzo needs to be administered every two weeks via intravenous infusion. At the same time, patients would still need to take pills every day.

 “I just wrote my first prescription a few days ago. It’s relatively new in terms of I haven’t had that experience yet. Some of the challenges are that it requires an infusion and space to do the infusion, so we are in the process of trying to figure out if a nurse can go out to the patient, but then there are also issues of [insurance] coverage.”

Infusion requires a registered nurse to administer, which means having enough training to do the procedure. Infusion also requires dedicated space for an IV to be inserted and run for at least 30 minutes. This can be an issue, especially in smaller clinics or clinics with a lack of space.

“However, the studies do suggest that Trogarzo is quite good for people who need it, and we have a few people in our clinic that do require it—for whom many if not all of the currently available HIV medications have failed,” said Lee. “And while it’s not meant for monotherapy [it’s used in combination with other active or partially active agents], the results look very good. So, I think we feel that it will actually get people to be better controlled and for some people it can certainly get them to be undetectable. But I’m looking forward to having a bit more experience with it.”

Could future antibodies be a first-line option? Would people want to do infusions instead of taking pills?

“That’s an interesting question,” said Lee. “I think that for first-line treatment, it may be a bit early just because it requires an infusion. I’m not sure we’re quite there yet. There are additional costs that come with infusions that make it more complicated in terms of getting the guidelines to recommend an infusion up front. I think the only way that that changes is if these monoclonal antibodies somehow can change the course of HIV infection by doing it early up front.”


Another option that may be useful is a rectal PrEP douche, which could be used as an on-demand product. For those who may already use an anal douche for cleansing before sex, one that also contains a PrEP agent could also help protect against HIV.

“Right ahead of sex, either a few hours or a few moments before, because sex isn’t always planned and some people don’t want to think about a prevention option otherwise. They don’t want to think about it every day or they don’t want to make clinic appointments, but they want something that’s right there when they need it,” said Baeten.

Research for this is still at a very early stage, but could offer yet another option.

Similarly, another option could be a PrEP that’s inserted anally or vaginally to immediately release HIV meds.

“That is the next frontier as well. And there’s some really good science that’s just moving into people that’s testing those options as well. And I think that also fills a big need,” said Baeten.


Perhaps a hidden-in-plain-sight option of the future that’s already here are two-drug regimens. Three-drug regimens have been the gold standard of HIV treatment for decades now. And for the past decade, a single-tablet regimen containing three drugs has been the norm. But could two drugs be better than three?

Juluca (dolutegravir/rilpivirine) is a two-drug HIV regimen approved for maintenance therapy. That means that once a person has achieved an undetectable viral load using a three-drug regimen, they can switch to Juluca. The idea is that if you can maintain an undetectable viral load with a two-drug regimen, you could theoretically reduce the cost of drugs and maybe reduce potential toxicities.

Dolutegravir/lamivudine (DTG/3TC) is another two-drug regimen that’s being studied for HIV treatment. In two Phase 3 studies, DTG/3TC was found to be non-inferior to a standard three-drug regimen. The single-tablet, two-drug regimen was submitted to the FDA for approval in October 2018.

The aforementioned cabotegravir/rilpivirine injectable regimen will also be a two-drug regimen, so perhaps two-drug regimens will be the new norm in the future.


As you can see, there are many new emerging options for HIV treatment and prevention. Some are a lot closer to being approved than others, but all have potential to provide more options for everybody. For many, long-acting injectable therapy may be the welcome change they’ve been waiting for. For others, a long-acting implantable may be more appealing. And for others still, taking pills may continue to be what works best for them. Until there’s a cure or vaccine, we continue to fight HIV in as many ways as possible.

Warren Tong is a freelance health and science journalist, with an extensive background writing about HIV and hepatitis C.