The era of new drug development for orally administered, once-daily HIV medications ain't over yet.
Following the drug-pipeline heyday of the 2000s and early 2010s, the past few years have seen the flow of promising new once-daily HIV antiretrovirals slow to a trickle, even as excitement has gushed forth for next-generation forms of HIV treatment: long-acting antiretrovirals, immune-based therapies, gene editing and a revived search for a cure.
Yet, here at CROI 2017 in Seattle, it feels a bit as if what's old is new again: The conference featured a major set of presentations on antiretroviral drugs and strategies in development, including bictegravir (a new integrase inhibitor), doravirine (a new NNRTI), an experimental class of drugs known as capsid inhibitors and a "maintenance" approach to therapy that involves switching people with HIV from successful regimens to equally successful regimens consisting of fewer drugs.
During the conference, I spoke with Paul Sax, M.D., a professor of medicine at Harvard Medical School, the clinical director of the HIV Program and Division of Infectious Diseases at Brigham and Women's Hospital and the author of a blog on NEJM's Journal Watch, entitled HIV and ID Observations. He presented Phase 2 study results on bictegravir at CROI 2017, and he is a co-author of the doravirine study whose results were presented shortly afterward. I asked him about the clinical importance of both drugs -- and about what else is on the near horizon when it comes to antiretroviral therapies for HIV.
Myles Helfand: What do you see as bictegravir's potential role within the HIV treatment armamentarium?
Paul Sax, M.D.: Now, this is all assuming that everything goes well with the Phase 3 [studies]. Then you could envision this as being a regimen that you could basically start without even needing any blood tests. You just start bictegravir, TAF [tenofovir alafenamide] and FTC [emtricitabine, Emtriva].
MH: What's the difference between this and dolutegravir, which bictegravir was compared with in its Phase 2 study?
PS: I would argue that for both of those regimens, you could start without any blood tests. Basically, a person comes in, newly diagnosed. You want to start them? Go right ahead. Resistance testing: not necessary. Getting their baseline labs back: Almost nothing is going to be exclusionary for newly diagnosed patients to start either TAF/FTC with dolutegravir or TAF/FTC with bictegravir. The advantage of the latter is that it's gonna be a single pill [per day].
MH: In addition to bictegravir, there's also doravirine, whose study results were presented in the same abstract session in which you presented the bictegravir results. Let's talk briefly about doravirine and what sets that apart.
PS: Doravirine appears to have some of the advantages of other non-efavirenz NNRTIs in that it has less CNS [central nervous system] toxicity. It's once a day, very metabolically friendly; those are good things.
The problem with doravirine is that we are moving away from using non-nukes as initial therapy. In the study that was presented [at CROI 2017] and I'm a co-author on, the comparator arm is darunavir [Prezista]. Darunavir is not the state-of-the-art comparator.
MH: We've been moving away from NNRTIs in treatment, but isn't that partly because efavirenz [Sustiva, Stocrin] is associated with CNS problems, there really aren't any other viable NNRTI alternatives and integrase inhibitors have been on the rise?
PS: I agree with you that it's not the non-nukes intrinsically; it's not the mechanism. It is that the non-nukes we have all have flaws. Efavirenz, as you mentioned: CNS issues. Rilpivirine [Edurant]: not too potent. Nevirapine [Viramune]: say no more. Etravirine [Intelence]: cumbersome formulation. None of them is really perfect. Doravirine seems as if it's an improvement on those existing NNRTIs.
MH: Is it likely to bring sexy back for NNRTIs?
PS: [laughs] It could easily be an NNRTI option that has advantages over those others.
MH: One of the things that makes this study intriguing is that, when we think about CROI over the last few years, we've seen a reduction in the amount of research on antiretrovirals in development. But this year, we have some high-profile drugs.
PS: It's exciting! It's nice.
MH: The question has been, what is gonna set a new antiretroviral apart that would give it a prayer of making it through clinical trials and getting approved as a new drug, when we have so much already that works so well?
PS: Well, approval is not contingent on being superior to existing strategies. The FDA [the U.S. Food and Drug Administration] does not base its approvals on whether something is transformative. It gives more accelerated approvals to things that are transformative. But FDA approval is not based on the [need] that you have to be so different from what's out there, and better.
MH: To what extent do you feel the research at this conference is part of a renaissance for antiretroviral development?
PS: I actually think it's nice. We saw doravirine; bictegravir; this capsid inhibitor that looks extremely interesting; EFdA, which is a long-acting nucleoside that's being developed; and then, hidden away in the poster hall is another non-nuke, [elsulfavirine], with a 20 mg dose, that has an eight-day half life. There does seem to be some interest in new drugs, which is nice.
MH: When you think about the conversations you're going to have with your patients coming out of this conference, and their questions about --
PS: Yeah, they're gonna say: "What's new at the conference?" And I'm gonna say that bictegravir is new, doravirine's new, some of the long-acting preparations, the dolutegravir/rilpivirine [switch study] data. These are advances in the field. They may not be the kind of thing that completely changes the world the way raltegravir [Isentress] did when it was released in 2007, but they're still improvements.
MH: What's next? Let's look at the near future: What are we looking at that might change the conversations you have with your patients about what meds to take, what meds to switch, what to do with their health?
PS: The Phase 3 bictegravir program is fully enrolled, so that means we could conceivably see the results later this year --
MH: Which could super-conceivably mean an FDA submission for approval by sometime next year?
PS: I think 2018 is a reasonable speculation.
MH: If all goes well.
PS: If all goes -- [laughs] totally, an important caveat. In addition to the dolutegravir/rilpivirine two-drug maintenance strategy, there's a dolutegravir/lamivudine two-drug maintenance strategy as well. And there's a single-arm study here [on dolutegravir/lamivudine maintenance] which has a great name called LAMIDOL. [laughs] That is a great name; it sounds like some kind of skin ointment. Where these go -- with more data and fully powered studies -- two-drug strategies will be interesting.
In a related strategy, the cabotegravir/rilpivirine injectable is the lead. But ultimately, where are we going with injectables? Probably somewhere else, because it's cumbersome to give that regimen. I'm looking forward to seeing what Charlie Flexner says about it in the last session tomorrow afternoon [on Thursday, Feb. 16]. Will you be there?
MH: Yes, I will be there.
PS: It's got a great name: Modern ART. [laughs]
MH: [pauses] I feel like that one's been used before.
This transcript has been lightly edited for clarity.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
Follow Myles on Twitter: @MylesatTheBody.