Activity Transcript

Eric S. Daar, MD: Hello. I'm Dr Eric Daar. I'm a professor of medicine at the David Geffen School of Medicine at UCLA and chief of the division of HIV medicine at Harbor UCLA Medical Center in Los Angeles, California. Welcome to this Medscape program, titled Optimized Background Therapy: Giving Heavily Treatment-Experienced People Living with HIV the Best Chance for Success.

I'm very pleased to be joined today by Dr Mary McKellar, who's an associate professor in the division of infectious diseases at Duke University in Durham, North Carolina. Welcome, Mary.

Mehri McKellar, MD: Thank you very much, Eric. It's a pleasure to be here.

Dr Daar: Fantastic. Over the next 30 minutes, we're going to be discussing various aspects of optimized background therapy (OBT) and its importance in individualized treatment for heavily treatment-experienced people living with HIV. But first, let's start off by defining the key part of optimized therapy, and that is the optimized background. Mary, do you want to go ahead and get us started in discussing this?

Dr McKellar: So, let me tell... talk about optimized background therapy. And, when a new drug is actually added to a failing HIV regimen, the other drugs in the regimen are known as the background therapy. But they also may need to be changed. And the changes that we make to patients antiretrovirals really depend on their resistant test results and their treatment history. And this is a common discussion with students in my clinic, is it's very important to go back through prior resistant test results, and its accumulative effect. You need to collect them all and review them basically.

And so, the OBT gives, really, a chance for this new HIV regimen, whether you're using a new drug or a new drug or an experimental, it gives it the best chance of succeeding. There are a couple of drugs, too, that we should bring up that have higher barriers to resistance than others. And so, the drugs that are known to have higher barriers to resistance, which are helpful in the OBT, include: boosted PIs, dolutegravir and bictegravir -- ie, the second-generation integrase inhibitors. Drugs with lower barriers to resistance include the non-nucleoside reverse transcriptase inhibitors (NNRTIs) raltegravir, elvitegravir, emtricitabine, and lamivudine. And so, those are important things to consider when you put together your OBT, your optimized background therapy.

Another thing, as I mentioned already, it's very important, is to look back at these drug resistance tests and, you know, there's a couple of different types of drug resistance tests, and we can go through them as well. And it's the timing is also important, too. But before I get into timing, I want to mention that usually you can only perform these drug resistance tests when the viral load is greater than 200 copies. Every once in a while, you'll get some results where it's less than 200, but for the most part, it's greater than 200 and greater than 500 copies/mL. As I mentioned, it's really important to go back through all the prior resistance tests an- and their treatment history, which is a real bear at times because it's often not collected with times and dates and whatnot, and this drug resistance is accumulative. There are some score systems used. I don't actually use it so much, but there's a genotypic sensitivity score and a phenotypic sensitive score that might be helpful for providers.

So, among the different types of resistance testing, and many of you already know this, but there is the genotype testing, and that's usually what we use for first-line or even second-line ART failure. And then there's phenotype testing, and that's typically used when it's a little bit more complex and you worry about complicated drug resistance patterns. And then there's the ARCHITECT or- archival test, which is relatively new. We're still trying to figure out how to interpret all the results. But we use that test when a person has low viral loads or even undetectable virals in that it analyzes the proviral DNA that may provide more information on the drug resistance. However, I actually find it really only helpful if you can find something. If you don't find anything, it's not entirely clear if that means the person doesn't have resistance.

And so, there are a couple of resources that I use, and I'm sure others use, too, but the big one is Stanford University Drug Resistance Database. I think it's just a great tool for interpreting these resistance tests. There's so much there, actually, probably investigate only the tip of the iceberg. There are other tools, too, out there. I think the International Antiviral Society, IAS, has one as well, which can be useful.

Timing is also really important when you're looking at resistance. Preferably, you order these tests when the person's still on the regimen, or shortly thereafter, within 4 weeks. This might be slightly different for person who are long-acting antiretrovirals, where the medications is still on board for an extended period of time, and then you can order possibly a resistance test at a later time. But the timing is important because if you wait too long, you might end up getting a wild type variant, which makes it confusing.

So, the first case I'm going to go through is actually not a wildly failing case, but it's a very common case that we see in clinic in a person who has failed before, and you need to kind of figure out what you can do to improve things. So, this is a 60-year-old man who's had HIV for a long period of time. Currently, his viral load is 50 copies per mil, and his CD4 count is about 350. He does have past resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and NNRTIs in that he has a K65R, which is relatively rare, an M184V, and a K103N. He's been on tenofovir, emtricitabine, and efavirenz before, perhaps something else, too. He's not quite sure, and he's currently on tenofovir alafenamide, emtricitabine, darunavir, and it's boosted with cobicistat. And so, he's been suppressed on his current regimen with the boosted darunavir. But he's running into some issues in that he has other comorbidities that are starting to become a bigger issue than his HIV, in that he's hypertension; he's hyperlipidemia, and he was just diagnosed with atrial fibrillation and has been started on anticoagulation, which is causing problems with his current regimen.

And so, the question that you asked yourself, is there a simpler regimen, a cleaner regimen, that he can use without all of these drug-drug interactions and comorbidities even though he has significant resistance from times past?

So one of the studies, actually, that gives us some data to support why we can make a switch and simplify this gentleman's regimen, is, well, the first study was the EARNEST study, and this was a study basically looking at second-line therapy after failing 2 NRTIs plus an NNRTI, and so it's a concept of recycling inactive NNRTIs with a boosted protease inhibitor (PI), or an integrase inhibitor. And so, this is actually a very important study in Africa because that's where they use a whole lot of first-line therapy with efavirenz and nevirapine and patients can develop high-level resistance to the NRTIs. So then, again, they wanted to see if we could use these NRTIs in a second-line ART. So, these, these were patients who were failing regiments, and they were assigned to 1 of 3 regimens, one being boosted ritonavir with 2 or 3 NRTIs, or boosted lopinavir with raltegravir or boosted lopinavir with 12 weeks of raltegravir followed by a maintenance monotherapy with a boosted PI.

And actually, what they saw at 96 weeks, the proportion of patients who had less than 400 copes was the same in both the NRTI group as well as the raltegravir group, and much lower in the monotherapy group and the adverse events were similar among the groups. So, this gave some evidence that we can actually use these NRTIs in our second ART regimen. And I believe that a number of these patients, too, had, like 90% or greater had mutations to the NRTIs going into the study. So, that was very reassuring.

Eric, I think you were gonna mention some other studies as well.

Dr Daar: Yeah. Thanks. Thanks, Mary. This is a terrific. So, EARNEST was really interesting because not only did it turn out that they did well with the boosted PI, a high-barrier drug with the nukes, but as you mentioned, when they looked back after the fact, because they didn't have real-time resistance data, they found out that a substantial number of these people had high-level resistance to all of the nucleosides included in the new regimen, and it was the first really well-designed study, and there were several others like it that showed that a high-barrier drug like a boosted PI can be extremely effective even with nucleosides that are only partially active. And we know that the partially active nukes were contributing because they did better than the monotherapy group.

And, and you think about it, your patient, kind of ended up being treated the same way. Your patient had high-level nuke resistance, ended up on a boosted PI with nukes, and has done really well, except now, there are issues about their comorbidity and there's always issues about potential toxicity in drug-drug interactions with the boosted PI.

But this was a groundbreaking study, but the follow-up question was that if a high-barrier boosted PI can work with partially active nukes, what about a high-barrier integrase like second-generation integrase inhibitors, dolutegravir and bictegravir? So, there are several studies that have now given us new insight into this.

Now, in your case, we're looking at making a switch. These were all studies of virologic failure. The actual amount of data switching people from a boosted PI with underlying nuke resistance to second-generation integrase-inhibitor with underlying nuke resistance is relatively limited. However, I think a general principle has been in the field that if a regimen will get somebody suppressed who's viremic, it is very likely to be able to keep somebody suppressed who's on a suppressive regimen. So, extrapolating from these failure studies to a switch strategy like your patient is being considered for, is a very reasonable thing to do.

So, the first study trying to address this was the DAWNING. And the DAWNING study went into it with the idea that we're all a little nervous about using an integrase-inhibitor without at least one other fully active drug. So, that's the way the study was designed. These were people failing that first-line nuke non-nuke based regimen, have real-time resistance based in data available, and to be eligible, they had to be on a new regimen that it included at least one other fully active drug with either dolutegravir or ritonavir-boosted lopinavir. And what they found in this study was, again, with these high-barrier drugs, with at least one other active nuke, that it was highly effective with very high rates of virologic suppression.

So, of course then, that naturally led to the next question, and that is, "Okay. Well, that worked. Can we get away with a high-barrier integrase like we do with a high-barrier boosted PI in people who don't have one fully active nuke?" So, the NADIA study, which was recently published, addressed that specific question. It took individuals who were failing a first-line regimen with nukes and non-nukes, and randomly assigned them to receive either dolutegravir or darunavir ritonavir, 1 of our 2 high-barrier drugs, with nucleosides. And they found very high rates of virologic suppression in both groups on the order of 90% at 48 weeks, which is pretty amazing in a highly resistant population.

And then they looked after the fact at the level of resistance within the nucleoside class, and they found that the majority of them had significant nuke resistance. In fact, probably more than 50% had just what your patient had: K65R and 184V, which would confer resistance to both tenofovir and to FTC or 3TC, and despite that, again, dolutegravir without any fully active nukes, just partially active nukes, had very high rates of virologic suppression, showing us that you really can get away with using a high-barrier integrase with partially active nukes.

Now, an important caveat from this study was that amongst the small number of people who did experience virologic failure, some of those in the dolutegravir group did fail with dolutegravir resistance. Again, small numbers, but there was some resistance, nine total individuals. In contrast, the boosted PI does appear to have a somewhat higher barrier to resistance without anyone failing with boosted PI based resistance. But again, this is all in the backdrop off of 90% virologic suppression.

And then, a follow-up study called VISEND was very similarly designed. First-line failure, tenofovir 3TC non-nukes, and randomly assigned to receive tenofovir with nucleosides. And it turned out that about two-thirds of the people at the time of randomization had high-level nucleoside resistance with the K65R and 184V, and despite that, we saw on the order of 80% virologic suppression, reaffirming the data that were seen in NADIA, and the fact that we really can use a high-barrier INSTI like we can a high-barrier boosted PI with so-called recycled nukes or partially active nukes, without any of them being fully active.

Dr McKellar: Yeah. Thank you. That was really helpful, and provides some reassurance, hopefully, to, to everyone. And so, in terms of the polling question,

just to review the case again for my patient who harbors resistance to NRTIs and NNRTIs, which of the following regimen would be most appropriate? Would you continue with what he's on, which is tenofovir alafenamide, FTC, darunavir, cobicistat? Would you actually switch him to TAF + FTC with twice daily dolutegravir because you're a little anxious? Would you switch him to TAF FTC with bictegravir, single-tablet regimen? Or, would you use that single-tablet regimen, TAF FTC bictegravir, but add on some fostemsavir as well? So we'll see what our listeners have to say about that. What would you do, Eric, actually? While we're waiting.

Dr Daar: Yeah. So, you know what? It's a great question. It's really a relevant question for your patient. The first thing is I do think this, there's a good reason to be considering a switch in your patient. Obviously, we'd only wanna do that if we can maintain virologic suppression in doing so. But with his comorbid conditions and as our patients get older, having them on boosted PIs and dealing with drug-drug interactions and metabolic derangement, it's ideal if we can get them off of it if it's possible. And I think what we've learned from studies like DAWNING and NADIA and VISEND, we can use a high-barrier integrase.

So, option 2 is the... Well, option 1 is reasonable, but it does not allow us to get rid of the boosted PI. Option 2 is using twice daily dolutegravir, which we'd only use in someone who has some underlying integrase resistance, and that's not true in this case. And option 4 is using the 2 nukes plus bictegravir and another drug, fostemsavir, which based on the data from these trials, is probably more than is necessary. So, I think 1, A, is a reasonable option, but comes with the downside of the boosted PI in this particular case. But I think that we now have enough to support a consideration of TAF FTC bictegravir.

Now, admittedly, all the studies I showed you were with dolutegravir, but I think most of us believe the barrier to resistance for dolutegravir and bictegravir are probably quite similar. So, I probably would use option 3, after having a reasonable discussion with the patient so they're fully aware of what the potential risks are associated with resistance, albeit quite small.

Dr McKellar: Yeah. And I agree with you. And I think that's what we ended up doing in clinic, and we're hoping he's doing just fine.

Well, I think that's provides a lot of information here, in that patient who were on a fully active boosted PI or second-generation integrase inhibitor, can have these recycled NRTIs used as a good strategy.

And so, moving on, let's go to your case.

Dr Daar: Thank you. This is a 62-year-old man diagnosed way back in 1994. Had CD4 count at that time of 32 and a viral load of over 450,000, and had an extensive treatment history like so many people we treated back then, and had a virologic rebound on dual nucleosides followed by nukes with non-nukes, and then with non-boosted PIs, including indinavir and then nelfinavir, followed by a first-generation integrase-inhibitor, raltegravir. So, the person really was experienced to most of the key classes, and then during the course of treatment, had documented pan-resistance to nukes, non-nukes, and boosted PIs with some intermediate resistance to darunavir and intermediate resistance to dolutegravir with the N155H, which is commonly selected for in people failing a first-generation integrase like raltegravir-based regimen.

And then the most recent regimen the patient was on, the patient was persistently viremic in 1000 to 2000 copies per mil range, and they were on TAF FTC, dolutegravir, in this case BID because of the underlying resistance, and darunavir ritonavir BID, again, because of the underlying resistance to darunavir. So, we have a patient who has high-level nuke non-nuke PI and some integrase resistance, who's now failing a regimen that includes nukes and twice a day integrase and darunavir ritonavir.

So, anytime we're confronted with a person with virologic failure it's really important to try to understand why it happened. And certainly, a lot of the explanation for that in patient I just described was the result of inadequate therapy. It was nobody's fault. This patient was treated before we had great regimens, and sequentially collected more and more resistance to different classes. But we also need to make sure that it's not driven by other factors, even in a highly experienced patient. Like, are they adhering to their therapy? Are they tolerating it? Is there a dosing or a pill burden issue that's creating challenges for them?

And then, when we think about what the next regimen is, we have to do exactly what Mary talked about, and that is we need to go through a detailed review of all of the previous resistance data, recognizing that anything selected for in the past is likely to still be there, as well as looking at contemporary data on resistance. And Mary already talked a little bit about the different options, and, you know, certainly genotypic testing is by far and away the most commonly-used strategy, and it's probably adequate for most individuals with suspected or documented underlying resistance. In the phenotypic tests, the main role for that is perhaps in people who have really complicated resistance patterns, such as the patient that we're talking about here, where it might provide some additional information.

And then the other test that's worth mentioning in a highly treatment-experienced patient is the tropism test because when we're thinking about new drugs and new classes, one of them is a CCR5 antagonist, maraviroc. This has not been used in this patient before. It might be an option. But we know that it's only active in people who do not have virus present in their blood that utilizes the CXCR4 co-receptor. So, what we're looking for in tropism is somebody who's referred to as R5 only, where the virus detectable in their plasma only uses CCR5. And if that's true, we have very good evidence showing that maraviroc can be an effective agent. So, it would be a new, fully active drug for a patient like this.

Unfortunately, a large proportion of people, especially those who've had advanced disease in the past, will have virus that uses CXCR4, and this isn't always going to be an option in some of these cases. So, it does require us thinking about other new drugs and new classes.

And that leads us to the question of how many of those drugs do we need? Mary walked us through a case, and we went through some of the data showing that if you have a high-barrier drug, like a boosted PI or second-generation integrase, it turns out you don't need much in that optimized background regimen to have success. But we know from previous data that in a setting where you don't have a fully active boosted PI, like our patient, and you don't have a fully active second-generation integrase, like our patient, that you do need more drugs to markedly increase the chance of success.

And one early study that demonstrated this really nicely was the BENCHMRK study. So, this was a study of highly treatment-experienced patients back in an era where they had usually experienced resistance to nukes, non-nukes, and often to PIs, and suddenly a new drug and a new class, raltegravir, came along. So, they designed a phase 3 trial where they randomized these people to optimize background regimen based on what drugs were available, even though they had resistance to many of them, plus or minus raltegravir. Alternatively, they received placebo, and it showed... There was a significantly greater virologic response in the raltegravir group. Not surprising.

But the question is, what would have been a predictor of not just a better virologic response, but achieving our goal of undetectable levels of virus? And they basically broke the data down based on that phenotypic and genotypic susceptibility score that Mary talked about. And what they found was that if you had, counting raltegravir as a fully active drug in anyone who received it, if you only had 1 fully active drug, you had a reasonable but not real high chance of achieving undetectable. If you had 2 fully active drugs, you got up into the 60+ percent range, and if you had 3, you got into the mid-70s. So, what this and other studies conducted in a similar population showed us, that if you don't have that boosted PI or the second-generation integrase is fully active, the best chance of success is to put together a regimen that includes at least 2 and preferably 3 fully-active drugs, often used along with a host of other partially-active drugs.

So, we need to know what the resistance testing in the past has showed, know what resistance they're likely to have based on their treatment history, and their current resistance data, to get a sense as to how many of the previous drugs in existing classes are likely to be fully active. We know in our patient the answer to that is none. They have nuke, non-nuke, PI, and INSTI-based resistance, at least partial resistance. So, if we're going to come up with 2 and preferably 3 fully active drugs, we need to be looking at new options. And fortunately, we have such options, and that 3 drugs over the last several years, 1 even in the last year, have been developed specifically for this patient population. These are new drugs and new classes and are anticipated to be fully active in any patient who's not been on them in the past.

And they include fostemsavir, an oral extended-interval dosing (EID) drug that binds to GP120, ibalizumab, a monoclonal antibody that works at post-attachment and it binds to CD4 and prevents entry, and then the most recent of the drugs, lenacapavir, a long-acting drug given subcutaneously every 6 months, and this can be used as a new drug and a new class. All 3 of these drugs are currently only FDA-approved for these highly treatment-experienced patients who need new options. And this is the fostemsavir phase 3 trial, this was the BRIGHT trial that showed optimized background regimen with or without fostemsavir, showing best virologic response in those who received initially add fostemsavir added, and then very high virologic responses when they were followed over time on optimized background and fostemsavir, virologic suppression rates in the 60% range. Not 100%, not 90, but 60. But for this population, it's pretty good, and fostemsavir's really contributing.

Ibalizumab also did a phase 3 trial. These were very small studies, where they took people with multi-drug resistant virus and they gave them ibalizumab to make sure that it had some intrinsic potency, and it did, at reducing the viral load and then gave it to them with optimized background regimen and showed reasonably high rates of virologic suppression, again in the 50% to 60% range. So, not a home run, but definitely a major advance for people who need new options.

And then finally, lenacapavir. This is the CAPELLA study, and we just recently had published the 52-week data. This, again, highly treatment-experienced patients, multi-class resistance who were given lenacapavir to demonstrate that it had intrinsic potency and then received lenacapavir every 6 months after an oral lead-in just to make sure it's tolerated, every 6 months along with that optimized bas- background regimen, based on what drugs were available for that individual. And in this case, again, tiny numbers, but these were the phase 3 data. They saw 80% to 90% virologic suppression, which is extraordinary in a group of people at a high-level resistance. And when they broke it down based on how many active drugs were in the regimen along with lenacapavir, they found that even if there were no other active drugs, about two-thirds got suppressed, although admittedly tiny numbers. If they had 1 active drug or 2 or more active drugs along with lenacapavir, they saw suppression rates of 80% to 85%. So again, another really good option for people who not that long ago really had very few options to consider.

So with that background, let me ask you this polling question.

For a patient with pan-resistance and no fully active agent in the nuke, non-nuke, PI, INSTI class, like our patient, which regimen would you use along with partially active drugs from these classes? So, you'd continue some background regimen with partially active drugs, and which of the below would you then add? Lenacapavir alone? B, lenacapavir plus fostemsavir plus ibalizumab? C, lenacapavir plus fostemsavir? D, fostemsavir and ibalizumab? Or fostemsavir alone? Go ahead and vote.

Mary, let me ask you. What do you think you would do in this particular situation?

Dr McKellar: Unfortunately, we don't see this very often, and as you mentioned, it's mostly are older patients who were on less potent regimens, and then we also see it with, you know, younger persons with congenital infections. So, for me, we've really struggled to have ibalizumab, to operate it successfully. So, I try to avoid ibalizumab. But at the same time, you've told me that I've no other active agents or fully active agents in the OBT. I'm assuming we're going to continue BID, darunavir, cobicistat; we're gonna continue 3TC or FTC, plus or minus tenofovir, and we may continue the integrase inhibitor, correct? The BID?

Dr Daar: I think, I think you're exactly right. When we think about partially active drugs, we likely continue to use the nukes and the PI and the integrase-inhibitor unless current resistance data suggested that there was high-level resistance to the PIs or the INSTIs or both. And then we'd be looking to add new drugs and new classes as fully active drugs to that background.

Dr McKellar: Well, in that case, I think I'm going to need more than just having one because these 3 drugs, although we're very excited about them, I don't think they have high resistance barriers. So, I want to preserve them to the best of my ability. So, I think I'm going to go with letter C, which is lenacapavir and fostemsavir, trying to avoid the ibalizumab logistics. And I don't think we need all 3 drugs, but that could be another option, I imagine.

Dr Daar: I completely agree with you. I mean, these are challenging, you're absolutely right. It's a really important point that when we go down this path, we need to realize that most of the evidence suggests none of these have real high barriers. So, if we don't do it right, we do risk selecting for resistance to these newer drugs, and that'll be problematic for the future. And we also realize that we don't have a lot of options left after this, so we do want to get it right, and we need to balance as many active drugs as we can along with the feasibility. So, I tend to agree with you. If it was easy to give ibalizumab, I'd probably be tempted to give all 3, but since it's not, I think I'd feel pretty comfortable, based on the existing data, to use 2 new fully active drugs along with my partially active background regimen.

Dr McKellar: I agree.

Dr Daar: So, in thinking about how to go down this path, I think we sort of alluded to already ease and mode of administration's important. Patients still are going to have to be able to manage the complexity of these difficult regimens: frequency of administration; cost can sometimes be an issue. I can assure you all of these drugs are extremely expensive. And then, do the drugs have high barrier to resistance, and how careful do we need to be? And I think we've already talked about very careful with these newer drugs. And then the issue of when to use recycled drugs.

The regimen selection now potentially is going to impact what happens in the future, so there is a lot of pressure to get this right. We know that if we choose the wrong regimen, if they don't get fully suppressed, resistance will emerge. And when we think about what's next, now that we're basking in the glory of 3 relatively new drugs and new classes to work with, there's not a lot. There's islatravir, which is in development and will provide potentially another active or partially active drug for these highly resistant people. This is a nucleoside reverse transcriptase translocation inhibitor that remains active against any viruses in resistance; and then we have broadly neutralizing monoclonal antibodies as another new class in development. But again, pretty much in the very early stages. So, we do need to be thinking about what the future holds, but be careful in the interim.

So, in conclusion, there are important things to consider when a patient's experiencing confirmed virologic failure or has experienced virologic failure in the past. We do need to prioritize using regimens and assuring good adherence and making sure the medications are well-tolerated as possible because there's few things associated with poor adherence more than an intolerable medication. In taking the medications appropriately, we need to assess for resistance present on the current regimen as well as do that very careful review of previous resistance data and treatment history in order to fully determine what are likely to be fully vs partially active drugs for inclusion in the next regimen. And finally, in these very unusual but highly treatment-experienced challenging patients, it's often important to include a new regimen that includes combinations of new drugs and novel classes.

And with that, I thank our audience for joining us, and Mary, I thank you so much for joining me for this important discussion.

Dr McKellar: Thank you very much, Eric. I appreciate it.

Dr Daar: And thank you all for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.