Second-Line Dolutegravir for HIV Favorable to Other Boosted PIs

Second-line treatment with dolutegravir and recycled nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir and lamivudine was superior to protease inhibitor (PI)-based treatment using a new nucleoside backbone, according to a study presented at the virtual Conference on Retroviruses and Opportunistic Infections (CROI).

MedPage Today brought together three expert leaders in their field -- moderator Monica Gandhi, MD, MPH, of the University of California San Francisco, Carlos del Rio, MD, of Emory University in Atlanta, and Renee Heffron, PhD, MPH, of the University of Washington in Seattle -- for a virtual roundtable discussion on the VISEND study. This is the third of four exclusive episodes.

Following is a transcript of their remarks:

Gandhi: Let's shift over a little bit to some other topics. I think that second-line ART [antiretroviral therapy] was important here only because we are getting into more mature epidemics. And so we do have times where we are turning to second-line therapy for resource-limited settings. And so these studies, I think, got quite a bit of attention because they are about second-line therapy in mainly resource-limited settings.

I mean, if we say that dolutegravir is really our first line for first line, but also in a way first line for second line, the VISEND study was really looking for second-line therapy if patients or participants had failed nevirapine or efavirenz, what they would go on next, which we all know in the WHO guidelines is essentially dolutegravir.

And the VISEND study was just to look at dolutegravir versus atazanavir/lopinavir boosted. And then there was another attempt at a comparison in the VISEND study, which was to compare 3TC [lamivudine]/TDF [tenofovir disoproxil fumarate], which is one option versus F/TAF [emtricitabine and tenofovir alafenamide] -- so, FTC [emtricitabine]/TAF. And essentially it showed what you might think -- dolutegravir looked good, and it was noninferior to -- well, let's just stick to the comparing it to the PI.

It was essentially actually superior to both PI atazanavir/lopinavir. Didn't mean that they didn't work well. But the design of the trial was that the backbone, if you were in a boosted PI was 3TC/zidovudine. So, it gave the boosted PI arms a little bit of a disadvantage. So you compare it to those boosted PIs with an old NRTI regimen, dolutegravir did better.

And then the other comparison was dolutegravir combined with 3TC/TDF or combined with F/TAF. And they're basically the same. So you can have your choice really about those two backbone agents, but just like in the advanced study, there was a look at weight and there's something about dolutegravir/TAF and women that look like we have higher weight gain in women with dolutegravir TAF/FTC.

And I don't know if Renee or Carlos, you want to comment on this. But we saw greater weight gain in women with that combination of dolutegravir-F/TAF. There's great implications in the pregnancy literature as well. So any comments on what you thought VISEND showed us?

Heffron: Well, I think I can just say that as this unfolds and we get more data and more clarity and precision about what the weight gain might look like, that will definitely be a part of people's choices and what they're considering when and if they have a choice to switch regimens or to stay on what they've got. At the same time, controlling HIV viremia is incredibly important and a priority. And so that will have to be a part of the decision too.

del Rio: Yeah, but to me the other interesting finding is that, at least initially when the weight gain issue came up, I thought, "oh, it's all because of the dolutegravir or the INSTI [integrase strand transfer inhibitor]." But now, the studies and others have shown that it's not necessarily dolutegravir. It's dolutegravir in combination with TAF/FTC. And, in fact, in the group of participants that received dolutegravir with TDF/3TC, we saw weight gain but it wasn't no different than in those seen in people that got lopinavir/ritonavir or atazanavir/ritonavir. So there is something with that combination with TAF. And I think something that, from a mechanistic standpoint, we need to understand better, and we need really some basic science in weight gain to help us understand exactly what's going on.

Gandhi: Yeah. I mean, I think this reminds me of all these questions coming out. Is it TDF and efavirenz that leads to weight loss? And maybe we can talk about one other study at CROI that came out around that in terms of pregnancy outcomes. But is it efavirenz and TDF that leads to weight loss, or is it dolutegravir and TAF that leads to weight gain, or is it the relative aspects of both? And I think that we started out in 2018 CROI having weight gain be almost one of the biggest things that we were talking about. And, we're now here in 2022, and we're still trying to sort out what it is. But there's something specifically related to women, I think with that combination of dolutegravir/TAF.

And that does remind me, because I don't know, Renee, if you reviewed the data that was presented right before CROI on the IMPAACT 2010 study and weight gain in infants -- this was essentially efavirenz compared to dolutegravir. And as we expected, there is something about infants having lower weight gain if mothers were on efavirenz than if they were on dolutegravir. So there is this aspect of weight in efavirenz and dolutegravir that keeps on coming up -- more related to weight loss with efavirenz, I think.

Heffron: That sounds like very interesting and important results to unpack. I haven't had a chance to look at it.

Gandhi: Yeah. It was just a little more on IMPAACT 2010, which of course was published in The Lancet. And we all know the primary results of dolutegravir versus efavirenz, but also TAF/FTC versus TDF/3TC. And it looks like dolutegravir plus TAF/FTC had great outcomes, and especially for the neonates, but there is this aspect of weight loss that's lower gestational weight with efavirenz. So, it just kind of reinforces that.

Watch episode one of this discussion: Long-Acting Prevention and Treatment of HIV: CROI 2022 Part 1

Watch episode two of this discussion: Long-Acting Prevention and Treatment of HIV: CROI 2022 Part 2

Watch episode four of this discussion: Third 'Cured' HIV Patient Headlines CROI 2022

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