Segment Description:oseph Eron, MD; Paul Sax, MD; W. David Hardy, MD; Eric S. Daar, MD; Ian Frank, MD, consider the use of dolutegravir with lamivudine and boosted protease inhibitors for women who are pregnant.
Joseph Eron, MD: Yeah, so I agree, and I think we’ve kind of touched on the safety and efficacy. And these drugs are very safe with a barrier to resistance, and the pill burden is small. So I think we should get to this: who falls outside most patients. And I think we might as well address that—women who are thinking about becoming pregnant or are pregnant. So who wants to—David, are you going to start?
W. David Hardy, MD: I think that we know the 1 thing the guidelines did several years ago is that they no longer just had a single box, a single recommendation for first-line therapy. And they qualified it by saying, “for most patients.” And then they went into great detail in other parts of the guidelines and with new and different tables, where the patients were being discussed. Such as those who have comorbidities like renal problems and could not take even TAF [tenofovir alafenamide], for example, and needed perhaps a non-nuke regimen.
For women of child-bearing potential, women who want to have children, 2 of them are recommended. Well, all but 1 of the recommended regimens for everyone could be used in women: the raltegravir. Bictegravir and dolutegravir are not going to be recommended at this point, especially not the dolutegravir at this point in time as more data are accumulated around the study.
But I think you know it’s really trying to, again, get back to the individualization of therapy and breaking things down and say, you know, for most patients as we have talked about, the integrase inhibitor regimen with 2 nukes, especially with a TAF [tenofovir alafenamide] component. It works really well for most patients. You know you would have to say probably in 75%, 80%, 85% of patients who we see, and even that idea about having to use a boosted PI [protease inhibitor]—you know that’s gone, that’s gone away as well.
So you know what I struggle with, many times, is trying to find those patients, besides women of childbearing potential, or you know even for a patient with hepatitis B or hepatitis C, the first-line regimens are still oftentimes the best ones.
Joseph Eron, MD: So Eric, let’s say you have a woman. She comes in, and she says that she wants to have a family and wants to start soon. She realizes she has to suppress first, but she doesn’t want to wait too long. What are you going to give her, and why?
Eric S. Daar, MD: You know, the challenge is that it used to be when we had this discussion is that people would go immediately to the pregnancy guidelines and say that these are the drugs approved in pregnancy. And a lot of the reason why these drugs are recommended in pregnancy was because we had some experience, but mostly we had the PK [pharmacokinetic] data…
Joseph Eron, MD: Right.
Eric S. Daar, MD: Telling us that we were OK in that trimester—second, third trimester—when there’s the increased volume and distribution. The way I always looked at it was well as long as I’m following her: If she gets pregnant, I’ll worry about that later. I don’t really care what I start her on.
Joseph Eron, MD: Right, sure.
Eric S. Daar, MD: Even efavirenz has sort of fallen off the list as a concern for teratogenicity.
Joseph Eron, MD: Right.
Eric S. Daar, MD: And then came the Botswana cohort that was trying to look more carefully at the relationship with dolutegravir as it was being rolled out. So they were following women prospectively during their pregnancy and there was the signal report about a year ago—of 4 cases, I think. Four cases of neural tube defects, which translated into about a 7- to 10-fold increased risk over other antiretrovirals that are being used. And sort of then what you’d expect in an HIV-negative group, it got a lot of attention and raised concerns appropriately. So now all the guidelines, you know, jumped on the fact that dolutegravir is an issue and particularly where it showed up was in women who were exposed at the time of conception.
Joseph Eron, MD: Right, that’s the key point.
W. David Hardy, MD: That’s a key point.
Eric S. Daar, MD: Not the first trimester. In general, not beyond the first trimester.
Joseph Eron, MD: But it was very safe.
Eric S. Daar, MD: At the time of conception—which makes sense for neural tube defects, so you can’t dismiss it, because most of that happens in the first 6 weeks or so. So it created a problem. It used to be the only time we had to worry about these drugs in pregnancy was for our subset of patients who were pregnant. Now we have to worry about it for all our women of childbearing potential who aren’t reliably using contraception.
Paul Sax, MD: Boy, it’s a tricky one because here we’ve been praising the dolutegravir-based regimens. And one could easily say probably the same thing about bictegravir, for which we have no data but very similar drugs. And you don’t want to deprive women of the best possible therapies, and it ends up being a difficult trade-off. Numerically, it’s a trade-off that is not easily answerable because the benefits to a woman of going on the best regimen may exceed the risks of the neural tube defects, which are really right now a big unknown.
Eric S. Daar, MD: It is. I mean, it is conceivable the signal will go away with more follow-up. I think there’s going to be additional analysis next month.
Joseph Eron, MD: Sure, and it’s going to be very soon, actually. It may be happening right now, literally.
Eric S. Daar, MD: I think when they originally reported it, they said the end of March 2019.
W. David Hardy, MD: March 2019.
Paul Sax, MD: Yeah, this is the last follow-up.
Eric S. Daar, MD: So then we have no data with bictegravir, and then we have raltegravir, which is at least still on 1 of the lists. And when we think about why it might be there, you could argue for women of childbearing potential, because it is 1 of the drugs approved in pregnancy. But it’s not because we know there’s a lot of documented experience for exposures at the time of conception, right? The registry has all sorts of limitations. And even when it breaks it down in the first trimester, you can’t really specifically say how many of them were at the time of conception. So the data are really thin.
Joseph Eron, MD: Though I guess there is probably enough raltegravir that has been distributed over the last 13 years.
Paul Sax, MD: Maybe.
Joseph Eron, MD: Maybe.
Paul Sax, MD: It’s very hard because there’s been nothing like this prospective data collection…
Eric S. Daar, MD: Systematically looking at it...
Joseph Eron, MD: No, no. I get it. I get it.
Paul Sax, MD: One thing I will say is that boost of protease inhibitors in pregnancy is still widely used, but we haven’t been so enthusiastic. I think part of it has to do with just the GI [gastrointestinal] tolerability, which has always been an issue. Part of it has to be you dose darunavir twice daily -- It’s really kind of difficult. And then also my colleagues who study this think that it is associated with premature birth, and that’s really not a good side effect during pregnancy. One thing I confess, we’re using raltegravir still for the women you described, Eric, and then we’re very comfortable using dolutegravir late in pregnancy.
Joseph Eron, MD: And I think the other thing that is important to know is we used to say that if a woman was on a stable regimen that they were tolerating, don’t mess with it, even if it’s a drug [for which] we don’t have necessarily data. But cobicistat now is 1 that is out.
Paul Sax, MD: Out.
Joseph Eron, MD: So if a woman who’s on a stable cobicistat-containing therapy and becomes pregnant, you should change that therapy.
Paul Sax, MD: PK concerns.
Joseph Eron, MD: Because there are PK concerns.