HIV: Single-Tablet Combination Therapy and Patient Weight
Interpretations of data supporting the use of single-tablet darunavir/cobicistat/emtricitabine/tenofovir alafenamide as treatment for patients with HIV and its effects on patient weight.
Grace McComsey, MD, FIDSA: Todd, we talked about darunavir, COBI [cobicistat], TAF [tenofovir alafenamide] FDC [fixed-dose combination], a newer, single pill that has a lot of advantages. What do you think about it in the setting of this hot topic of weight gain? Does it have an advantage over other drugs like integrase inhibitors?
Todd Brown, MD, PhD: There is potentially some advantage, although the data aren’t quite there yet. The integrase vs the boosted PI [protease inhibitor]. Most of the comparisons, integrase inhibitors are very effective drugs and generally well tolerated, but there is this association with increased weight gain, either with people initiating antiretroviral therapy or people switching onto integrase inhibitors from other regimens. It turns out that the comparator regimens are important. Whether people are switching, what they’re switching from to an integrase inhibitor, or in trials that have compared integrase inhibitors to other regimens, what the comparison regimen is. The biggest differences are when integrase inhibitors are compared to efavirenz. And this brings up the question of whether the integrase inhibitors have an effect, per se. Or does efavirenz have some appetite suppressant effect? Or is it a combination of the two? My personal bias is that it’s probably a combination of the two. But trying to understand the comparison between protease inhibitors that are well tolerated, like boosted darunavir, and integrase inhibitors is a critical step going forward.
Grace McComsey, MD, FIDSA: You think the potential advantage of boosted darunavir vs an integrase is that it’s not an integrase inhibitor, right? I mean it’s not as positive on avoiding weight gain as efavirenz, but also efavirenz has its issues, right?
Todd Brown, MD, PhD: That’s right.
Grace McComsey, MD, FIDSA: This potentially provides a non-CNS [central nervous system] toxicity drug with potential benefit of weight gain. But you’re right. Today that remains to be seen.
Todd Brown, MD, PhD: One of the challenges; I alluded to the idea of drug-drug interactions. That is a challenge with boosted darunavir-containing regimens. Again, it’s manageable but something that you need to think about. As patients’ care becomes more complicated and they see more subspecialists with varying degrees of familiarity with HIV treatment, you might start to see or see more drug-drug interactions that pop up with other medications.
Grace McComsey, MD, FIDSA: Absolutely.
Tavell Kindall, PhD, DNP, APRN, FNP: Can I add, patients won’t necessarily tell these other subspecialists they’re seeing that they’re on antiretroviral therapy with a cobicistat-enhanced regimen. And they’re prescribing against them, and then all of a sudden, all these drug interactions and things start showing up. And everybody’s trying to figure out what’s going on. That’s always a point too.
Osama Hamdy, MD, PhD: I would like also to draw attention to the interaction of 2 groups of medications that are common in treatment of diabetes, DPP-4 inhibitors and SGLT2 inhibitors. If it was ritonavir you have to increase canagliflozin if they are used in those patients. Dapagliflozin is fine. But also, DPP-4 inhibitors, because of the cytochrome P450 inhibition, you need in those patients to reduce the dose of DPP-4 inhibitors. This also must be considered in the treatment.
Grace McComsey, MD, FIDSA: Tavell is right. You must tell other specialists about all your drugs. Don’t omit the fact that you have HIV. Sometimes they still feel bad about it, and they’re worried about stigma, but that is important for sure.
John Koethe, MD: Grace, one other thing that will be coming out soon, and what caught the attention of the field in terms of the cobicistat, boosted darunavir with TAF [tenofovir alafenamide] as a potential drug for switch or for prevention of weight gain, was really 2 things. The first was in the AMBER trial, that the weight gain that they saw in the boosted darunavir with TAF arm was about 1.5 kg at 48 weeks, which was considerably lower than what was seen in some of the large observational cohorts for the emtricitabine arm, which granted, that’s observational data and a little harder to interpret. But it’s also lower than the approximately 3 kg that were reported in some of the pooled clinical trials data published in Clinical Infectious Diseases in 2020 for the newer generation integrase inhibitors. That may have set the stage. Then the other thing that brings up this question, which I’ll get in a moment to the clinical trial that’s been started, but additionally, looking at weight gain among individuals on integrase inhibitors, there is this population of people who gain a very large amount of weight, anywhere from 10% of their pretreatment body weight to even over 15%.
They probably represent a very susceptible group to weight gain. Weight gain of that degree can also engender a lot of future metabolic complications, development of diabetes that we’ve seen from the DAD cohort and other similar longitudinal data. There’s a need to investigate that population. That’s what the DEFINE trial, that’s one of the switch studies that’s going on in the field. But this is one that’s taking individuals who are already overweight or obese, who have had greater than 10% weight gain on an integrase inhibitor plus TAF [tenofovir alafenamide], and then switching them to this darunavir plus TAF [tenofovir alafenamide] combination pill to see what the effects are on weight gain and metabolic function. One key thing there is to keep in mind that this is a data-free field to an extent right now. But this DEFINE trial with the boosted darunavir and then the other trials looking at switching off of integrase inhibitors to different regimens and the effect on weight and metabolism will be coming out in the next few years. We’ll probably be able to answer some of these questions a little better.
Grace McComsey, MD, FIDSA: Good. We’ll have more data when people ask, “What do you do? Should I switch my regimens?” It’s good to have data. We need it desperately.
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Transcript Edited for Clarity
