One of the most widely anticipated studies whose results were presented at the International AIDS Society Conference on HIV Science, held in Mexico City last week, was the DISCOVER Trial, which looked at whether emtricitabine/tenofovir alafenamide (F/TAF, Descovy) was noninferior to emtricitabine/tenofovir disoproxil fumarate (F/TDF, Truvada) for HIV prevention. In the session where the research was presented, the audience only raised a few questions that provided a broader context for the study. TheBodyPro sat down with one of those voices to discuss those thoughts in further detail. That person was Joseph Eron, M.D., professor of medicine at the University of North Carolina School of Medicine, as well as chief of the Division of Infectious Diseases with the University of North Carolina Medical Center.
Terri Wilder: Tuesday, July 23, there was a presentation by Christoph D. Spinner, M.D., on the DISCOVER study for PrEP. The presentation was entitled "DISCOVER study for HIV pre-exposure prophylaxis (PrEP): F/TAF has a more rapid onset and longer sustained duration of HIV protection compared with F/TDF." Can you tell us a little bit about the highlights of the presentation?
Joseph Eron: Sure. This was a presentation of the DISCOVER study, which you mentioned, which was a large, randomized trial of mostly MSM [men who have sex with men] [and] a very small number of transgender women -- 2,600 men in each arm -- that compared Descovy with Truvada. Truvada is, of course, the approved single tablet for prevention. And Descovy, a very similar drug, but has TAF, which has some advantages -- which really was what this presentation was about.
They didn't show us any new transmission data. This was the same data we saw at the CROI [Conference on Retroviruses and Opportunistic Infections] meeting a few months ago, showing that there were fewer transmissions in the Descovy arm, compared to the Truvada arm, though the number of transmissions overall was very small -- 22 total; 7 in one arm and 15 in the other arm. And, in fact, probably five of them occurred at the time of entry into the study. So there probably were only about 17, total, that actually occurred on the study.
One criticism of the study was, well, are these really high-risk men? And I think they showed us pretty convincing data that these were very high-risk men, and that the risk was balanced between the two arms. Because one reason you could have a difference would be that, for some reason, the men on the Truvada arm were at greater risk, so there were more infections.
With a study that large, that would be really unusual, to have an imbalance in randomization. But they showed that there was very high risk.
The issue is they did it on mostly white men. So part of risk is about behavior, but also about who you're having sex with. So if you're in a population that has a lower prevalence, even if you're very risky it's going to be a little less likely. And so some of the studies that are in development now or ongoing have tried to enroll more young men and more MSM.
But then, the gist of the presentation was if you looked at drug exposure, how much of the tenofovir diphosphate was in the cells -- which is where that drug works, the active drug -- there were consistently higher levels, with the TAF arm, the Descovy arm, than there were with the TDF arm. And I think that, while what they showed was true, I do think their title is a little misleading. Because they actually didn't show that infections occurred early with the Truvada arm, which is implied by [saying] its onset is faster; and they actually didn't show that any of the infections occurred at the end of the study or at the period between visits.
So they basically just showed pharmacokinetics. So I think the title of the study was a little bit misleading. I asked the question because, actually, there was only one person on the entire study who [acquired HIV] at the time where drug monitoring -- they can measure tenofovir diphosphate in red blood cells, so they can do these dried blood spots measures, which gives you kind of an average over time -- only one man in the entire study actually [acquired HIV] when it looked like he had adequate concentrations. All the other men were infected, were essentially infected, when there weren't adequate concentrations of the drug. So I think they kind of overstated their case a little bit, because there was no evidence that people on Truvada who had measurable drug were actually at risk.
I think it was an important presentation. I think it's convincing that Descovy is active; it is a prevention medication. Whether it's better than Truvada? My conclusion would be that they're pretty close to the same. That would be my conclusion. But [the researchers'] conclusion is different. It is, I think, marginally better, and the pharmacokinetics would suggest, maybe in a bigger population or people that aren't as good at taking pills, it could be better. I'll give them that. I think it could be better. I don't think they proved it was better.
TW: So, Gilead submitted a supplemental new drug application to the U.S. FDA [Food and Drug Administration] in early April, for once-daily Descovy for PrEP, with a target FDA action date anticipated within six months. So, in anticipation that this will probably happen, what do you think providers and patients need to consider once Descovy gets FDA approved?
JE: That's a great question. And I think the most conservative approach would be that first of all, I would only use it in men, because it's only been studied in men. And I would even be a little hesitant about transgender women, because the proportion in this study with transgender women was quite low, which is different than, for example, the iPrEx study, the original study.
But for men that have some additional risk of renal dysfunction -- if they're older, if they already have an abnormal creatinine, if there's some reason why you wouldn't want to expose them to tenofovir DF -- what's in Viread; what's in Truvada -- I think that's exactly the right person that should get Descovy.
On the other hand, if they cost the same -- and I think Descovy probably is a little bit better tolerated -- I think it's safer for bones. And they didn't show this yet in the DISCOVER study. They could show us more bone data, for example, especially in the younger men who might still be forming bone. If you have a normal creatinine, I think both are very, very safe options.
And if it's an issue of access or cost, I would have no problem continuing to use Truvada -- none whatsoever -- except in someone whose creatinine clearance has fallen below 60 or 50. So that's kind of my take. I'm not 100% sure the FDA will -- this will fly through, because the noninferiority margin was a little bit different than has been recommended in other studies. But I agree with your conclusion. I think it will be approved.
TW: In our morning plenary session July 24, one of the opening presenters posed the question, does TAF promote weight increase? And there was a greater increase in weight for the, obviously, [HIV-negative] transgender women at risk for HIV infection receiving PrEP with TAF/FTC, versus TDF/FTC, after 96 weeks of follow-up.
JE: Yeah. I think it's possible. I think exactly what's happening with TAF and weight gain is not completely clear. In a supplemental slide from DISCOVER, they did show that there was about a kilogram difference -- I think it might have been 1.1 kg; I can't quite remember the slide -- between the men who were randomized to the Descovy. And it was a randomized, blinded study, so that's like two pounds, two and a half pounds, maybe, if it's 1.1.
And they made the point, which I think was quite valid, that in another prevention study with injectable cabotegravir and placebo -- this wasn't in high-risk people; it was in lower-risk people over about a year and a half, 66 weeks -- there was a gain of a kilogram. We all tend to gain weight over time.
JE: So I think what's a little different is there may be an interaction between dolutegravir (Tivicay) and TAF, or bictegravir and TAF -- which is separate from the prevention discussion. I don't think there's very much weight gain with TAF, but there's some. I think it's a little bit more than TDF.
One argument is that TDF actually decreases appetite, because it makes people feel a little bloated and a little bit nauseous. So it may be that it's not actually, TAF causes weight gain -- it's that TDF prevents weight gain -- I think is possible. I'm not an expert in this, though.
TW: Descovy and Truvada both have boxed warnings in their U.S. product labels, regarding the risk of acute exacerbation of hepatitis B. Is that something [to worry about]?
JE: Yeah. I think we have to be super careful about screening men who want to be on PrEP for hepatitis B. I think that's a standard screen. That doesn't mean a man with hepatitis B couldn't be on either one of the two medicines, if they were at high risk for HIV infection. So, they're HIV negative but they have active hepatitis B. It's just that those men would be -- or women, for Truvada -- at very high risk if they kept going on and off. It's actually when you come off that's the problem.
And so I would have a very, very specific conversation with an individual who was at risk for HIV [and] had active hepatitis B (not antibody, but antigen) about, "I can see why you want to be on this. I understand. But you're different. You need to take this very seriously. And if you do want to come off at some point, then we're really going to have to monitor you carefully."
TW: In terms of Descovy, any other potential side effects that people might want to keep in mind?
JE: I think it's pretty well tolerated. I think that in general it has less side effects than Truvada. So I don't think that there's anything else. I think it could have slight renal risk; but it's much, much lower than Truvada. We almost never see Fanconi syndrome with Descovy. There's a warning about lactic acidosis, but we almost never see that anymore. You know, all the nucleosides have that warning. We almost never see it. I can't remember the last time I saw a lactic acidosis case. No. It's quite a safe drug, I think.
TW: What happens if people stop taking Descovy, in terms of concentration? Is it more forgiving than Truvada?
JE: Yeah. This is a great question. You might think two things. One: what they showed in the DISCOVER presentation was that there are higher levels for longer.
So the implication, I think, was that if people miss doses or go off therapy, they may have some protection that extends a little bit longer with TAF-contained Descovy versus Truvada.
One of the things that Trip Gulick asked, and I think is really important, is there are differences between rectal concentrations, when you take Truvada versus TAF -- versus Descovy. And Truvada, because it actually is either excreted or not completely absorbed in the gastrointestinal tract, I'd say it has higher rectal concentrations.
So I think some of the assumptions that Dr. Spinner and his colleagues made about the direct relationship between PBMC [peripheral blood mononuclear cell] concentrations and protection might not be exactly right. That's what Trip was after. Because they only measured blood concentrations, which -- we know TAF gets about six times higher -- which they showed. They've shown it a million times. They showed it again.
Do we actually know that the rectal concentrations -- which we think are probably important; we don't know for sure -- probably they're not six times higher with Truvada versus TAF. So that's a really important question and I think is a slight flaw in the logic of Dr. Spinner's presentation.
The other thing is that people forget, you know, there's this concern about the tail for cabotegravir. Because it will have a very long tail. But, you know, either Truvada or Descovy has some tail. There is a period of time when the tenofovir diphosphate concentration is below the active level. You know, maybe it's a week or 10 days; we don't know exactly how long. So there is a tail there, too. It's much shorter; probably not a big deal.
We do see resistance with Truvada PrEP, but it's usually in people who actually contract HIV when they don't have much Truvada on board -- either when they first start or they're intermittently adherent -- and then they take the Truvada. Not many people. There are few case reports of people that take Truvada very assiduously who have become [HIV positive]. But they are really case reports. They're pretty uncommon.
So I'm not worried about the TAF or the TDF tail. I do think that if rectal concentrations with Descovy are actually as good or better than TDF, then probably there's a longer protection, just as you said.
TW: What about cisgender women? I don't remember him saying anything in his presentation [about cisgender women]. Maybe I just didn't catch it.
JE: I do know, because I asked someone from the company. They are actually now doing studies in cisgender women with Descovy. So we will get the answer. Again, I think there are differences in concentrations between TDF/FTC and TAF/FTC in vaginal and cervical biopsies. That's work from Angela Kashuba's group at UNC. So I think I would not make assumptions.
It will be interesting. I assume the FDA will only approve this for men who have sex with men. It will be really interesting. But that's my assumption. I think we need to see the data in women. And that's hard, because outside of Southern Africa it's really hard to find high-risk women -- I mean, there are clearly women at risk -- but the really high-risk women where you have to have an incidence of 3%, 4%, 5% per year to study. So that's a real challenge.
There's a nice paper by Dr. Adimora that actually kind of tries to address this challenge, and how do we understand whether these drugs are good for women? It's really a difficult question.
TW: Yeah. But important that we not let a challenge keep us from it.
JE: No, no. And I certainly am -- you know, the sponsor of Descovy and Truvada take this very seriously. And I didn't know there were two studies enrolling with Descovy in women. I didn't ask where they are. It may be available on clinicaltrials.gov. I don't know where they're doing it, whether it's in Africa or the U.S., or in other places. But anyway, it's critical that we not stop.