Listen in to learn the latest on ART switch strategies for people living with virologically suppressed HIV. Hear from experts Chloe Orkin, MBChB, FRCP, MD, and Peter J. Ruane, MD, as they review how the recent approvals fit in the treatment landscape. Stream on the go or follow along with our expert-curated slides.
Listen in to learn the latest on ART switch strategies for people living with virologically suppressed HIV. Hear from experts Chloe Orkin, MBChB, FRCP, MD, and Peter J. Ruane, MD, as they review how the recent approvals fit in the treatment landscape of 2-drug, single-tablet regimens. Stream 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
London, United Kingdom of Great Britain and Northern Ireland
Honorary Consultant Physician
Barts Health NHS Trust
London, United Kingdom
Peter J. Ruane, MD
President
Ruane Clinical Research
Los Angeles, California
Link to program page:
https://bit.ly/3PkPoP4
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Evolving ART Switch Options Podcast
Dr. Peter Ruane (Ruane Clinical Research): Hi, good morning, everybody. It's a real pleasure to be here to review these slides set on the recent approval of islatravir-doravirine, DorIsl, as I will call it.
DHHS and EACS: Switch to 2-Drug Regimens
So, it's helpful to actually look at two other drug regimens, which we are already familiar with and have become more popular in the last few years.
Listed here is dolutegravir-rilpivirine, dolutegravir 3TC, and also the injectable cabotegravir-rilpivirine. And there are relative advantages and disadvantages and indications or usefulness of these regimens. With respect to cabotegravir-rilpivirine, the advantage of that regimen is an injectable drug given every one to two months, which can be helpful with status disclosure, the display of pills around one's place of abode, and also pill fatigue.
The other regimens have been around for a little bit longer, and it is true to say that three-drug regimens have now generally been accepted as potentially replaceable to a two-drug regimen. So what we're presenting today is another two-drug regimen just recently FDA-approved. Any of these two-drug regimens, a switch to any of these two-drug regimens typically comes with the following criteria listed here at the bottom of the slide.
Viral suppression on the current regimen for three months by DHSS or six months by EACS. No active hepatitis B infection, which we will discuss later also, I'm sure. No history of prior biological failure, which is always important, and no evidence of resistance to the regimens involved, for example, INSTIs or rilpivirine in the new regimen.
IAS-USA Guidance on Switching ART With Viral Suppression
So the guidance on switching ART with viral suppression, I'll just read it out to you. People with HIV and virological suppression may be receiving regimens that are no longer recommended due to short and long-term adverse effects, inconvenience, regimen complexity, anticipated drug-drug interactions, progressive kidney disease, etc. Switching ART to one of the recommended initial ART regimens in these circumstances is frequently the optimal strategy.
So, viral suppression is not necessarily the only goal that we go by in this day.
EACS Guidance on Switching ART With Viral Suppression
Clinicians should always review potential adverse events or tolerability issues with patients on current antiretroviral regimens. This includes ritonavir-boosted regimens.
The objectives of treatment modification should be to eliminate or improve adverse events, facilitate adequate treatment or comorbid conditions, and improve the quality of life for the patient.
DOR/ISL: A Novel 2-Drug Combination
So doravirine-islatravir, or DorIsl, is a novel two-drug combination, recently approved. Doravirine was approved in February 2018, and islatravir was just approved in combination with doravirine in April 2026.
As you know, or you may know, islatravir given at a higher dose of 0.75 mg in previous studies was associated with drops in total lymphocyte count in CD4 cells. So the newer studies all involve the dose given daily of islatravir at 0.25 mg.
DOR/ISL: Prescribing Information
This is a summary of the prescribing information, two-drug regimen, and the doses mentioned.
Virologically suppressed patients, viral loads less than 50 on the stable antiretroviral regimen, and no history of virological treatment failure, and no known doravirine resistance.
Summarizing the adverse events, in low incidence, diarrhea, dizziness, fatigue, headache, abdominal distension, these are common. I mean, these are commonly seen in all drug regimens, but in this case, in a very low instance.
And then rarely, as with NNRTIs in general, severe skin reactions have been seen, and they have been seen with doravirine. These include Stevens-Johnson syndrome, DRESS syndrome.
Contraindications for the regimen include strong CYP3A4 inducers and co-administration of 3TC or FTC, which we can talk about later if we have time.
DOR/ISL Switch Phase III Data
So, I'm going to present the Switch data. There's two studies I'm going to present, including the week 96 week data from recently presented at EASL. The FDA approval was based on the week 48 data, and there's no substantial difference between the week 48 and the week 96 week data.
Switch to DOR/ISL From BIC/FTC/TAF: Study Design
So, I'm going to start with the double-blind switch study to DorIsl. This was a randomized double-blind multicentered Phase III trial involving 513 patients. The criteria, I'll just point out the main ones. Total lymphocyte count more than 650, and the CD4 count above 50 were important criteria. No history of treatment failure or known doravirine resistance-associated mutations. And importantly, no active hepatitis B infection.
The patients were randomized and then they went to a more complicated regimen in a way. They actually went to two pills. One was active drug, and one was placebo. Post-baseline resistance testing was done for confirmed HIV RNA more than 200 copies, or just once if there was a discontinuation with an HIV RNA at more than 200 copies.
Baseline characteristics for the patients was they were on a regimen for a median time of 3.3 to 3.6 years of enrollment, although many of the patients were actually on a regimen far longer, and this may be relevant to some of the outcomes. Median age was 48 years, and approximately 21% were assigned female at birth, and 32.5% were Black ethnicity. So, it was a fairly diverse group that entered the study.
[00:09:58]
Switch to DOR/ISL From BIC/FTC/TAF: Wk 96 Virologic Outcomes (FDA Snapshot)
This is the summary of the virological outcomes by FDA snapshot analysis. This is the 96-week data. I'll take you to the middle of the slide first, showing the viral load data less than 50 copies, and also less than 200 copies. And you can see very high maintenance of viral suppression in both arms, in the continued arm, and also in the arm that was switched to DorIsl.
There were five patients who had viral loads more than 50 copies in the DorIsl arm, and two patients who had more than 50 copies at week 96 in the continued arm. And there was no virological data for some of the patients.
The rates of discontinuation. There were two patients in the DorIsl arm that were discontinued at for lack of efficacy, and three patients for reasons otherwise, with viral loads more than 50 copies. Importantly, there were no differences in CD4 total lymphocyte counts through week 96.
In a post hoc analysis, there was treatment-emergent viral resistance detected in one participant. At some point, we may be able to drill down on this patient, this individual, but it's pretty evident that this individual came into the study with a preexisting virological failure, and therefore, preexisting mutations at baseline.
Switch to DOR/ISL From BIC/FTC/TAF: Wk 96 Lipid, Insulin Resistance, and Renal Function Secondary Outcomes
This is a quick summary of the metabolic outcomes at week 96, lipid insulin resistance and renal function secondary outcomes.
I'll summarize this. There were no significant clinically relevant differences between the two arms at week 96.
Switch to DOR/ISL From BIC/FTC/TAF: Safety
Switch to DorIsl was associated in some cases with hepatitis B issues.
For individuals on DorIsl, there was no clinical hepatitis B reactivation observed. Three cases of low-level hepatitis B viremia without antigenemia or elevated transaminases, and then there were four cases of acute hepatitis B, both who are negative for hepatitis B core antibody and hepatitis B surface antibody at baseline.
There was no difference in weight change at week 96.
Okay, I'm going to pass now over to Chloe to present the O5-1 study with the switch from DorIsl from another regimen. Go ahead, Chloe.
Switch to DOR/ISL vs Continued Baseline ART Study Design
Dr. Chloe Orkin (Queen Mary University of London): Thank you so much, Peter, and I'm really happy to be here to talk about this data.
So, you've just heard about the blinded study switching to DorIsl from bictegravir, FTC and TAF. But in this study, the study design was the same in terms of who the participants could be. But in this situation, the comparison was with any standard of care, two-drug or three-drug antiretroviral regimen with also no resistance in the past and no active hepatitis B. So, they could be on whatever standard of care regimen they were on. And then I'm going to explain the study design a bit further.
So, there were two different groups. So, there's the standard of care in gray, and then on the top, there's the open label switch to doravirine-islatravir. And that is group one. And these participants had doravirine-islatravir from the first day till week 96.
And then you'll see there's another orange group. And those are the people that were able to switch to doravirine-islatravir from the standard of care at week 48. They are group two. So, they're two doravirine-islatravir groups in the week 96 analysis.
So, in terms of baseline characteristics, there's some important things to say about this population. So, the median age was 51. Around 40% were assigned female at birth. And that's great because it's much better than usual in these sorts of studies. Only 40% of the participants were White and 45% were Black.
In terms of their prior regimens, it's not written on the slide, but 64% of the participants switched from integrase inhibitors, and around 30% switched away from NNRTIs. And around 30% were on TDF at the time of their switch. Also, around 30% had core antibodies at baseline. So, I think those are some important things to say. And they've been living with HIV for about 13 years, and had been about between 3-4 years on this current regimen.
Switch to DOR/ISL vs Continued Baseline ART: Wk 48 and Wk 96 Virologic Outcomes (FDA Snapshot)
So, here are the results. And there's a bit more data here than in the slides that Peter showed, because I explained to you, we've got the different groups.
So, on the left, we're going to look at the primary endpoint and the secondary endpoint around viral load greater than 50, because that's actually the primary endpoint. So, at week 48, you can see that in the dark orange, the doravirine-islatravir group one, who had the drug for 96 weeks. At week 48, you can see that 1.4% had viral loads greater than 50 versus 1.1 in the people who had 48 weeks of doravirine-islatravir, which started at week 48. And then you can see 4.9% in the standard of care.
Then, we look at week 96. And we see that in the group who had doravirine-islatravir for 96 weeks, 1.9% had viral loads greater than 50 at week 96. And we see that some people had no data in the study window.
On the right, we're looking at viral suppression. And here, what we see in the orange groups is very high rates of virological suppression at week 48. And in those people who continue to week 96, with 92.6 of them being suppressed on doravirine-islatravir, both at less than 50 copies and less than 200 copies. So, very strong results in terms of efficacy.
Switch to DOR/ISL vs Continued Baseline ART: Participants Receiving DOR/ISL With HIV-1 RNA ≥50 copies/mL at Wk 96
So, in terms of viremia, what was presented at week 48 is that there were five participants who had a viral load greater than 50 at week 48, and there was no one with emergent resistance. So, between week 48 and week 96, what's new is that there were two participants who had viral loads greater than 50. But they didn't meet resistance testing criteria, and there was nobody who had resistance.
And then what we see in group two, in the people who started at week 48, you can see there was one person with a viral load greater than 200. And again, no drug resistance. And so, we can see that there was one person who re-suppressed on doravirine-islatravir. So, that's what happened in terms of those people with the detectable viral load at either week 48 or week 96. In this study, there was no resistance that emerged.
Switch to DOR/ISL vs Continued Baseline ART: Secondary and Safety Outcomes Through Wk 96
So, in terms of safety outcomes, what we saw in the second part of the study is that there was a lower rate of overall drug-related adverse events. Between week 48 and week 96, the rate was 1.7%. And the side effects were pretty much, you know, very much expected things like diarrhea. And there were some reports of weight increases. But remember, I told you that 30% of them had been on TDF. And there was also around 34% who were on NNRTIs. So, some of that is related to switching off weight-suppressing drugs.
There were no cases of HPV reactivation. And there were no discontinuations due to decreases in total lymphocyte or CD4 count. There were no relevant changes in lipid parameters or in insulin resistance. As I said, the majority of the participants were switched from INSTIs or NNRTIs. So, there were very few people that were switched from a PI regimen. And we didn't see any changes in lipid parameters.
There was a greater weight change with the switch to doravirine-islatravir from baseline when people were taking efavirenz or TDF. But there was almost identical weight in people who were not on weight-suppressing drugs like TDF or efavirenz. So, statistically significant increases in creatinine-based EGFR observed during the first 48 weeks after switching to doravirine-islatravir, but not observed in cystatin C-based EGFR.
Investigators’ Conclusions
So, in conclusion, looking at the first study, which Peter presented, what we can say is that we saw similar virological efficacy to continuing BF-TAF in this blinded study at week 96. And the findings are very consistent with the week 48 primary results. There was no CD4 signal or total lymphocyte signal at all throughout that study, with very similar safety and tolerability with both doravirine-islatravir and bictegravir FTC and TAF through week 96.
Then for the O5-1 study, the open-label switch, here when people switched from a standard of care treatment, which could be two drugs or three drugs, 92% maintained viral suppression through week 96. And there was no treatment-emergent resistance in this study. And similarly, total lymphocyte counts and CD4 counts remained stable. And there were favorable safety and tolerability profiles maintained through week 96 of the study.
ART Switching: Things to Keep in Mind
So, there are some things to keep in mind when we're switching treatment. Firstly, we've got to think about drug resistance.
So, it's really important when you start people on treatment to review their treatment history and try and understand whether they've ever stopped treatment, whether they've had virological failure, and also to try and look at people's genotypes so you understand what has happened in the past.
It's really important to understand people's previous intolerances and also issues around drug-drug interactions. Hepatitis B co-infection is an important issue, and understanding people's vaccination status and whether they have core antibodies and evidence of past infection, or indeed, active infection is vital, as is understanding whether someone is pregnant.
So, what could be the role of proviral DNA? Well, it's currently a research tool. It's not recommended, but sometimes in people who have very complex histories, it can sometimes provide additional information in terms of what might be there encoded in the archive. But also, equally, it can miss things that do exist. So, it's not necessarily a reliable tool.
Whenever we switch someone, close monitoring is helpful to ensure they've maintained suppression, to monitor adherence, and to identify any new adverse events.
Current ART Switch Options: Faculty Discussion
So, in terms of current switch options, I guess one of the questions that I guess we're all thinking to ourselves with this new exciting option: where does derivative miscellanea fit? Well, clearly, it fits people who are on stable antiretroviral therapy and are similar to the people that were in the studies who are virally suppressed with no history of virological failure. And I don't know, Peter, if there's anything else you wanted to say on that?
Dr. Ruane: No, I think the history of virological failure is always difficult to assess in people who are older and who have come to your clinic or rejoined your clinic in recent years, and you don't know their full history. So, I often use a cutoff in my mind as if someone who started therapy after about 2000, 2002, 2003, generally those people for sure got fully suppressive regimens. And so, the amount of resistance those patients ever developed is very small, whereas people who started treatment before that, in the '90s or the late '90s, some of those people will have archived resistance, which as you point out, may not show up in the CD4 archive.
So, I think it's relevant in assessing, in terms of the risk of assessing people for a history of significant virological failure in the past.
Dr. Orkin: Yeah, I think that's a really important point, and I think it's about thinking of errors. And this is one of the really exciting things about this regimen is it is integrase inhibitor class-sparing? So, what we know is that if the integrase inhibitor era began, and once it began, everybody was on integrase inhibitors.
So, switching people to these regimens, to this regimen, for people who've been on integrase, we know that we don't need to worry about that. And, in fact, most people had had NNRTIs in the study that I presented. So, people that had prior exposure to NNRTIs at some point. So, that's quite important.
Who are not candidates? Well, people with hepatitis B, people with resistance to doravirine, that's clearly the case.
So, in terms of outstanding questions, I guess, we always want more longevity of data, don't we? We want real-world evidence. We want, you know, lots of data for five years. I don't know if there are any other outstanding questions for you, Peter.
Dr. Ruane: Yes, I would jump in, and with respect to the hepatitis B and say, so, individuals who obviously have active hepatitis B, it's an issue. But also people who are at risk for acquiring hepatitis B through sexual activity, for example, and who are not hepatitis B immune. I think those individuals, if they're coming off a tenofovir regimen, for example, and they are not hepatitis B immune, they should be vaccinated. And if they are core antibody-positive and hepatitis B surface antibody-negative, immunizing those people further is a good idea.
Dr. Orkin: It is a good idea. And I think it's important to say that this issue is not specific to doravirine-islatravir. It's something that affects dolutegravir 3TC, which is a recommended regimen in first-line and second-line. It affects our injectable regimen, cabotegravir-rilpivirine. It affects dolutegravir-rilpivirine. And it also affects, you know, other novel combinations, because in fact, the entire pipeline is inactive when it comes to hepatitis B. No tenofovir coming in any of these future therapies in the near future.
So, this is a problem we're going to have to start to grapple with and learn to understand as a specialty.
Question and Answer Session
So, in terms of questions and answers, I'm going to pop into the Q&A and see if there are any questions. So, someone's asking about complicated regimens and saying that islatravir is really clear, any suggestion on appropriately dosing or monitoring in a group that tends to have lower clearance and more likely to accumulate islatravir. So, I think, I mean, Peter, I don't know if you want to take the first question about renal clearance while I look at the others, or would you like me to take it?
Dr. Ruane: I didn't see that question yet, so –
Dr. Orkin: Okay, so they're asking about if there's any need about renal clearance and any concerns about doravirine-islatravir and any thresholds.
Dr. Ruane: No, creatinine clearance above 30 is the cutoff.
Dr. Orkin: And I think actually there's been some data presented already at the most recent conference, I think that was CROI, looking at data going down to sort of a low-ish creatinine clearance. So I think that's really encouraging.
And I think that someone's asked about, which I might take a question on weight, no weight changes. Interesting, we're removing integrase and TAF, so no help to tell patients then anything to add. Well, I think I have to say I completely agree with you. And I think that the British HIV Association guidelines have actually specifically said that we haven't seen any improvements when switching away from integrase regimens to doravirine. And I think all of the guidelines are exceptionally clear that there is no clear evidence to suggest that you should start any particular regimen to avoid weight gain or switch to anything. Unfortunately, we are in a situation where we need to advise people to try and avoid weight gain and to manage it when it happens using alternative agents, but antiretrovirals are not the way to go.
Then there's a question for you, Peter. You said that we should immunize patients with core antibody-positive and surface antibody-negative. Do you want to just elaborate on what you were saying?
Dr. Ruane: Well, anybody who is hepatitis B, never exposed, and is at risk for incurring hepatitis B should be vaccinated. And then there are some individuals who are just core antibody-positive and they are surface antibody-negative. And we usually try to immunize those people to bring up the hepatitis B surface antibody. It can be sometimes difficult. Sometimes it requires several efforts.
But it is worth doing, I think, just for at least for minimum peace of mind. And there are some individuals in whom it's less important. So some people are in a long-term stable relationship or not actually. Their partner's hepatitis B surface is immune. It's not a big issue. But for others, I think it's relevant.
And in all of these studies, there's always going to be a few patients who develop acute hepatitis B. And I think it's going to be something to consider doing and monitoring for at the minimum. Most of the individuals in the studies who actually developed low-level hepatitis B viremia actually had no issues, but then settled back down again. But there were some acute hepatitis B infections. I think that's the matter that drew the attention and the audience at CROI.
Dr. Orkin: Yeah. So, I think there were definitely there were viremias without antigenemia. So I think there's viremias, and I think that's an important point. And I think we don't really understand what these little viremias mean necessarily. You know, when we switch to two drugs, sometimes they can be transient, and I think it's a really difficult area, and I think the tools we have, as Peter said, are around vaccination.
I just wanted to pick up on one of the other questions that's coming up in the chat and people asking about resistance. So they're asking about the M184V specifically.
And I think I'll just give an answer to that. So the M184V mutation does affect islatravir. And it's something that can result from islatravir use and also can affect islatravir. So yes, that is an important mutation.
People are asking about how common driving resistance is in clinical practice and whether we should worry about it in people who have received NNRTIs in the past. I think what I can say is that a lot of people in the study had had prior NNRTIs and did very well.
I think the question is, have they always been suppressed on their regimen? If there's never been a virological failure, and they've been having NNRTIs, that's not an issue. But if there is a virological failure, or indeed, if there's been a significant interruption while on an NNRTI, that's more of a concern. But I think, you know, I think –
Dr. Ruane: I'll just add to that, that the classic patient who failed doravirine usually just gets a K103N and that sticks with that. And the K103N hangs around a long time, even in the absence of NNRTI exposure. But those patients who, back in the '90s, failed nevirapine, for example, they often develop complex mutations. Or if they receive serial NNRTI drugs, they develop complex mutations. And a lot of those mutations will be actively resistant – some of those combinations will be actively resistant to doravirine. That's why I think nevirapine, in terms of failed regimens, the maximum period of time for that was between '96 and 2001, 2002.
And so, that's why I'm very cautious about that group of people to try and get their treatment history as best I can, or look at the archived genotype to see if I can pick up on anything. Even if you see a K103N, say, for example, dolutegravir-rilpivirine, people, you know, people consider the K103N not an issue. And in my experience, it's not an issue.
But it's always an issue as to if they have K103N, what other NNRTIs did they get exposed to in the past? And could that be relevant?
Dr. Orkin: So I think – thank you, Peter. That's a really helpful addition to the explanation. And I think I'm going to end this because we're just slightly over time.
On a positive note, which is one of the question is, is how can community pharmacists and retail play a role in promoting the switch? Well, I think one of the things I would say is absolutely important is that we do as, you know, providers need to discuss novel therapies with the people we look after. We need to tell them.
We need to review, as the guidelines have told us, we should review to make sure they're on the right drug. And also, we should inform people of new therapies, of novel therapies, because people are always asking us about, you know, novel therapies. And it's important that we keep communicating that the field is moving, that we've got new drugs, we've got new options, and keep having shared decision-making discussions with the people we look after.
Dr. Ruane: And two specific situations. I'll just jump in. People who talk to the retail pharmacist about their concern that the creatinine is drifting up, or older people who have DEXA scans showing that their DEXA scan shows a lot of osteopenia. Those are the kind of patients that will keep bringing this up. And those are the people that will consider if they're already on a tenofovir alafenamide regimen, even to consider something like this.
Dr. Orkin: Brilliant. So on that note, I am going to say thank you so much to obviously, Peter, for a fantastic discussion and presentation. And also, for attending and to claim credit, you can log on over there and print your certificate.
Thanks for joining.
Dr. Ruane: Thank you.