Listen now as experts, Chloe Orkin, MBChB, FRCP, MD, and Jihad Slim, MD, explore the potential clinical implications of new data on novel options for optimizing HIV therapy, especially for treatment-experienced people with challenges using currently available regimens, high pill burdens, and reduced adherence. Listen on the go or follow along with our expert-curated slides.
Listen now as experts, Chloe Orkin, MBChB, FRCP, MD, and Jihad Slim, MD, explore the potential clinical implications of new data on novel options for optimizing HIV therapy, especially for treatment-experienced people with challenges using currently available regimens, high pill burdens, and reduced adherence. Listen on the go or follow along with our expert-curated slides. Topics covered include:
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Presenters:
Chloe Orkin, MBChB, FRCP, MD
Professor of Infection and Inequities
Dean for Healthcare Transformation
Faculty of Medicine and Dentistry
Queen Mary University of London
Honorary Consultant Physician
Barts Health NHS Trust
London, United Kingdom
Jihad Slim, MD
Assistant Professor of Medicine
New York Medical College
Valhalla, New York
Chief of Infectious Disease
Saint Michael’s Medical Center
Newark, New Jersey
Link to program page:
https://bit.ly/4u31NGv
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Optimizing ART
Dr. Chloe Orkin (Queen Mary University of London): Thank you so much. So I'm looking really forward to, together with my wonderful colleague, Dr. Slim, talking about optimizing treatment and telling you all about new and exciting things that are just on the horizon.
Complex ART Regimens
So complex treatments. We know that the gold standard for treatment is a single-tablet and that people living with HIV who are treatment experienced often are not able to attain this level of simplicity due to issues around comorbidities, drug resistance, tolerability issues. And, you know, this could mean that they have limited treatment options. And this can lead to pill burden. It can lead to difficulties with adherence, you know, really affecting people's quality of life. And really one of the big concerns is drug-drug interactions because they're at a risk of higher liability of drug interactions.
So there's a real unmet clinical need for drugs with novel mechanisms, new combinations, new agents and a focus on tolerability. And achieving the dream of less is more that we have with so many other people living with HIV. This population has been effectively left behind.
Options for Simplifying ART
So we have all these options for simplifying treatment. We can use a three-drug simple treatment like bictegravir, FTC and TAF, or two-drug simple treatment like dolutegravir/3TC. We even have injectable options for those people who are virally suppressed.
And for people who have multi-drug resistance and virological failure, there's the option of optimizing using lenacapavir as an injectable option together with an optimized backbone.
DHHS and EACS: Switch to 2-Drug Regimens
And so, if we think about what guidelines tell us. Guidelines identify that there are certain two-drug switch regimens, which are preferred, based on clinical trial data and a more evidence based. Chief amongst these are dolutegravir/3TC, which is also recommended as an initial – initial regimen for most people.
Dolutegravir/rilpivirine, which is just for people who are switching. And then cabotegravir/rilpivirine as a two-monthly injectable agent, which may improve quality of life and really help people, particularly people who have stigma concerns. But to have these regimens, you need to be virally suppressed, except for dolutegravir/3TC, which you can have as a treatment-naive regimen.
But in the case of suppression, you need to be suppressed for at least three to six months without hepatitis B, no history of virological failure and no evidence of resistance to the drugs in the regimen.
BIC/LEN: A Novel 2-Drug Combination
So what does BIC/LEN potentially bring to the table? So this is a novel two-drug regimen with the option to really simplify treatment. And what I'm going to show you is some data from the ARTISTRY-1 study, which was a very, very particular population of people with exactly the type of complex virus that I was telling you about in the background.
So to remind you, bictegravir is an INSTI, an integrase inhibitor, and it's oral, but they have very high barrier to resistance. And then we've got lenacapavir, which is a capsid inhibitor, our first capsid inhibitor, which can be either oral or injectable. And there's no documented de novo resistance before exposure because it's a new class.
BIC/LEN Phase III Data
So here are some phase III data. It's very exciting. These data were presented at CROI and they're published in The Lancet if you're interested in reading more.
ARTISTRY-1 Switch to BIC/LEN From Complex ART: Study Design
So ARTISTRY-1 study was looking at switching people from complex treatments. So these people had to been undetectable for six months and having GFR of greater than 15. So very, very low GFRs were allowed in. No resistance to BIC. No prior treatment with LEN and no HPV.
So it was an open-label study, where half the participants carried on in their complex regimen, and half of them were switched to BIC/LEN. And then they were offered an OLE – an open-label extension. And the primary endpoint was viral load greater than 50 at week 48 using an FDA snapshot analysis.
Now, what do I mean by complex antiretroviral regimen? So what I mean is a twice-daily regimen, a regimen using more than two different agents, a regimen where you also have to use an injection are some examples of a complex regimen.
ARTISTRY-1 Switch to BIC/LEN From Complex ART: Baseline Characteristics
So I'm going to focus now on this population because it is exceptionally novel population. So this is the oldest group of people that have ever been studied in a registrational trial of an HIV agent. The median age for this population was 60 years old, okay, which is really remarkable. 77% were on a PI-containing antiretroviral regimen. Okay? And most of this was boosted PIs.
The most common regimens were PI plus an INSTI in 30% or a PI/INSTI plus an NRTI in 24%.
This population also had multiple comorbidities. So 50% had two or more of the comorbidities listed on the slide of dyslipidemia, hypertension, hyperglycemia, or chronic kidney disease. Okay. It's very, very high. And between – you know, all of them had at least one comorbidity. And more than half had two additional medications that they were taking as well as their HIV treatment. And you can see there were some people with low GFRs.
ARTISTRY-1 Switch to BIC/LEN From Complex ART: Baseline Disease Characteristics
So in terms of other baseline characteristics, a very, very important figure to pull out is this median duration of prior HIV treatment. This population had been taking HIV treatment for a median of 28 years. Now we can all visualize these people who they are. These are the people that took three-drug – you know, they took pills three times a day. They took hand pills of pills. You know, they've really been through it, these people.
And in this population, you can see that 40% were still taking twice-daily regimens. And there was someone in the study who was taking 11 pills a day. So the reason for the complex regimen, 80% had a history of resistance. So this is important.
And in terms of the resistance, you can see that there was resistance across multiple classes. Okay. So we really can get a good picture of who these people are and what their needs are, and that they've been really effectively left behind by a drug development so far.
ARTISTRY-1 Switch to BIC/LEN From Complex ART: HIV Outcomes at 48 Wk
So here are the outcomes, the headline findings. Look at the outcome at week 48, BIC/LEN in orange, complex ART in blue. You can see that there was non-inferior to – BIC/LEN was non-inferior to maintaining these very complex regimens.
There were three people in the BIC/LEN arm with a viral load greater than 50, all resuppressed. All had low level viremia with no need to change their regimen. Very importantly, there was no treatment-emergent resistance detected in either study arm. So you can see that BIC/LEN was non-inferior to maintaining the complex regimen with no emergent resistance, and the CD4 count remained stable. It was all good in terms of that.
ARTISTRY-1 Switch to BIC/LEN From Complex ART: Safety
Now, if we're going to look at safety and tolerability, whenever you switch a regimen in an open-label study, you expect to see more side effects. But in terms of serious side effects, there were no signals in terms of more serious adverse events, grade 3 events at all.
There were five deaths, none of which were considered to be related to the study drug, and some of them related to cancer or sudden events. Remember this population were older and had a lot of comorbidities.
In terms of the milder sort of factors and more common adverse events. You can see they were very common things like upper respiratory tract infection and headache. But in terms of AEs that led to discontinuation, you can see what the AEs were that led to discontinuation on the slide. And in the complex regimen, there was also a discontinuation due to pulmonary embolism. And actually, in fact, there was a drug interaction in that particular person involving an anticoagulant and a PI.
ARTISTRY-1 Switch to BIC/LEN From Complex ART: Fasting Lipids and Patient-Reported Outcomes
So let's think about other factors. When I told you these people had a lot of cardiovascular comorbidities. So what happened to their lipids in the study? So people who were switched away from their PI-containing regimen or their complex regimen to BIC/LEN had an improvement in their lipids. And this is likely driven by taking away the boosted PI, which causes lipid concerns. So you can see significant improvements in their lipids.
You can also see, unsurprisingly, very significant improvements in patient-reported treatment satisfaction through the study. There was a big increase in treatment satisfaction as measured by the HIV treatment satisfaction questionnaire with BIC/LEN versus no change with the complex antiretroviral regimen.
So in summary, non-inferior with improved lipids, improved treatment satisfaction and CD4 count remaining the same.
Key Takeaways: ARTISTRY-1
So you can see, as I've said, maintaining similar rates of suppression, regimens much simplified, well-tolerated. And as I've said, improved lipids and no treatment-emergent resistance with non-inferior viral control.
And with that, I'm going to hand over to my wonderful colleague.
ARTISTRY-2 Switch to BIC/LEN From BIC/FTC/TAF: Study Design
Dr. Jihad Slim (Saint Michael’s Medical Center): Thank you so much, Chloe. You did a great job. You improved their score by more than double. So hope I could do the same here.
ARTISTRY-1 was a very important study for people who needed it badly. So ARTISTRY-2 was more of a study to try to increase the use of BIC/LEN, increase the more choices of two-drug regimens that we could switch to for those who needs it. Right? So it is a totally different concept. So we're changing gears now. We're talking about a multicenter, double-blinded, active-controlled, randomized phase III trials. Right?
So in this study, they took basically patients who were doing well on – I'm going to call it B/F/TAF, right? People who are stable on their B/F/TAF regimen for six months or more were undetectable, had a GFR more than 30 milliliter per minute, obviously because they are on B/F/TAF, had no resistance to neither TAF nor bictegravir and couldn't have chronic hepatitis B either, were randomized two-to-one to either switch to BIC/LEN or to stay on B/F/TAF.
And so but because there was a placebo there, so everybody that was on one pill, on a single tablet, one pill once a day, now they have to take two pills a day for the next 48 weeks. So it's making it a little bit harder for the patients to participate. Yet there was great participation and you'll see the results in a second.
This is 383 patients were switched to BIC/LEN, 191 continued on their B/F/TAF. And obviously you have to give the loading dose for lenacapavir in the beginning of the study for the first two days. You have to give them.
And the primary end point was again, a 48 weeks primary endpoint for proportion of people with virus load more than 50 copies per ml at week 48. At the end of 48 weeks, everyone was offered to participate in the open-label extension study, where they would go on BIC/LEN for – we'll find out for how long. We don't know yet, but at least a year or probably more than that.
Some important secondary endpoint again. But these are the usuals that we look at in those kind of switch studies, where the proportion of people with virus load more than 50 copies per ml at week 48, and the CD4 change, as well as the safety at week 48.
ARTISTRY-2 Switch to BIC/LEN From BIC/FTC/TAF: Baseline Characteristics
Let's review the baseline characteristics. So their baseline characteristics are, they're slight – they're younger than people that were in ARTISTRY-1, right? The median age was around 50 years old.
And females, White, Black, Asian and Hispanics were all well represented. They had very good CD4 count, but they still had a good amount of comorbidities. Dyslipidemia was present in more than 40%, hypertension in close to 35%. And the people with at least two or more comorbidities were around 30% in each arm.
ARTISTRY-2 Switch to BIC/LEN From BIC/FTC/TAF: Outcomes at 48 Wk
Now, the results which you peeked at earlier. You probably could guess that at the primary endpoint at week 48, it met non-inferiority. There were five people in the BIC/LEN and two in the B/F/TAF that had a virus load more than 50 copies per ml at week 48. Remember, this was a two-to-one randomization, so it really met non-inferiority. And you could see the confidence interval with the non-inferiority margin in the confidence interval plot on the right-hand side.
And the people who met criteria for resistance that they were able to do resistance testing for, there were four people, two in each arm. And one of them had – from the BIC/LEN arm at week 36 developed R263K, which is an integrase substitution. And there was no resistance to lenacapavir in this person.
And this person was prior – who had a prior exposure to raltegravir and dolutegravir in the past.
As far as the other secondary endpoint that we were talking about, the virus load less than 50 copies per ml. You could see again, 93% had – in the BIC/LEN, 93.5% had virus load less than 50 copies per ml and 90.6% in the B/F/TAF. Non-inferiority was met. The CD4 cell count, weight, and BMI remained stable in both arms throughout the trial.
ARTISTRY-2 Switch to BIC/LEN From BIC/FTC/TAF: Safety
Now the safety was the other secondary endpoint. And you could see in the slide that there was no serious treatment-related adverse events reported, same as we saw in ARTISTRY-1. There was only one grade 3 treatment-related rhabdomyolysis in BIC/LEN. So again, very rare events. And the most common events that were seen in at least 5% or more of people in the BIC/LEN arm were diarrhea, nasopharyngitis, upper respiratory tract infection, headache and nausea, which again were similar in both arms.
And these are people who were already on B/F/TAF, right? So for at least six months and tolerating it well. You could see that there was no major events. No new side effect was seen.
I think the – what you want to look at also the treatment discontinuation was related to drugs was 1.6%. So again, talking to the safety and tolerability of those drugs.
Key Takeaways: ARTISTRY-2
So in conclusion, the ARTISTRY-2 really showed that switching to BIC/LEN was non-inferior than continuing B/F/TAF in maintaining virological suppression at week 48. BIC/LEN was well tolerated with no serious treatment-related adverse events reported. Discontinuations due to adverse events were infrequent. The CD4 cell count, weight, and BMI remained stable in both arms throughout the trial. And treatment-emergent resistance developed in one participant.
ART Switching: Things to Keep in Mind
So now that you've seen both ARTISTRY-1 and 2, I think it's important to talk about switching the DHHS – according to our guidelines, you really need to pay attention when you're going to switch patients by reviewing their antiretroviral therapy history to see if they had virological failures and to review all their previous resistance testing, because resistance does not go away once it happens.
You want to review their history for also safety for drug intolerance in the past. And so not to use the same ones. And the really important one is drug-drug interaction in our patients that are, again, getting older and are on multiple other regimens. Important to look at comorbidities mainly hepatitis B coinfection.
And when it comes to resistance testing, we really like the genotypic testing much better than the archived DNA – than the proviral DNA. The proviral DNA is currently not really recommended to make decisions on, even though sometimes we use it in some difficult cases.
What is really important though, anytime you switch a patient to a new regimen, it's so important to keep a close eye on them especially in the first three months. So I usually try to see the patients within the first month, try to do blood work early on as well to make sure that they're tolerating the drugs well and that they're not failing the regimen. That so important.
Taking a look at what to come in the next – in this year and few years down the road, really, phase II and III drugs. We have doravirine/islatravir coming up. Then we – that's another potential daily regimen for – again was studied at switch with the B/F/TAF.
We have the weekly oral regimen of islatravir/lenacapavir, again studied as well against B/F/TAF. We have islatravir with ulonivirine as also a weekly regimen oral. We have the long-acting regimens, injectables, and oral lenacapavir once a year as a PrEP or other. We have a new capsid inhibitors. We have more INSTI coming and INSTI capsid inhibitor combinations. We have the bNAbs.
So a lot of interesting drugs with either new mechanism of action or an improvement on what we currently have. And again, going with the more long-acting to try to include everybody. I mean, the whole goal here is to get everybody with HIV on whatever works for them that has – that is safe and keep them undetectable so that they could stay in treatment is going to be so important for the future in order to end the epidemic.
I think, with this, I'm going to turn it back to you, Chloe. Right? Or…
Q&A
Dr. Orkin: So one of the questions, Jihad, was for your – actually directed at you around the ARTISTRY-2 study is, why was TAF resistance an exclusion criterion if patients were already on B/F/TAF and they were suppressed? Why would TAF resistance matter? So that's the question that someone has asked you.
Dr. Slim: Yeah, I think it's a good point. I don't know that we can tell how long if you do have K65R and you happen to be suppressed on B/F/TAF, it's still a relatively maybe weak regimen that could potentially fail. So why take that chance? Right?
I think trying to keep the study as pure as possible, I think it would be better to not include K65R. But you could see that they didn't include M184V though for FTC because B/F/TAF is approved to be given in people who are virologically suppressed with M184V but it is not approved. It's not FDA-approved to give it for people with K65R. That to me, the main reason why that was entered. What do you think, Chloe?
Dr. Orkin: Yeah. No, I totally agree with you. And I think also, you know, if you want to study a drug, you have to study it in its optimal form with the person who's fully sensitive to the drug. So I think that makes perfect sense. Yeah.
Dr. Slim: And then you asked me a very – they're very critical about – about what's FDA approved or not. So if you're not FDA-approved for it, you really shouldn't include them in the trial.
Dr. Orkin: Exactly. Because obviously you're not comparing like with like. So and then there's another question around why increase – why is the dose of BIC 75 milligrams in BIC/LEN and 50 milligrams in B/F/TAF? And I guess, you know, I mean, I'm happy to – I mean, I think they're trying to make sure that they have an optimal drug level for a two-drug regimen in this – in this particularly – they knew that they were making a drug that would, you know, was going to be – anybody can take BIC/LEN. Obviously, it's not only people on complex regimens, but because people on complex regimens can benefit from this regimen, you know, it's an optimal exposure. So that's the reasons. Yeah.
Dr. Slim: My understanding too is that the way it's formulated, the bioavailability of the 75 milligram is really the same as the bioavailability that's in the B/F/TAF.
Dr. Orkin: Exactly.
Dr. Slim: We get the same.
Dr. Orkin: Exactly the same amount of dose. And it's not due to a drug interaction or a boosting effect of TAF or LEN. It's just – it's a bio – but yeah, exactly. So then there's a question – someone's asked, is BIC/LEN available now? No, it isn't. I think the filing to regulatory bodies has been made. And I think, you know, hopefully we'll hear soon, but it's not available now.