Viremic – Cases in HIV

Announcer:
Welcome to Viremic–Cases in HIV, a podcast that explores quandaries in adult HIV clinical care. In each episode, Drs. Eileen Scully and Christopher Hoffmann, HIV specialists at Johns Hopkins, discuss a case, review challenges in the plan of care, and highlight evidence and guidelines that inform clinical decision-making. Now, here are your hosts, Eileen and Chris.

Dr. Christopher Hoffmann:
Welcome to Viremic. I’m Chris Hoffmann and I’m here with my friend and colleague Eileen Scully. Hi Eileen.

Dr. Eileen Scully:
Hi Chris, it’s great to be here, and I’ll say it’s extra great because as I understand it, you have a case for us to talk about today.

Chris:
I do have a case, Eileen. Something that has been bothering me and something I’ve been confronting more recently is viremia among my patients on Cabenuva.

Unlike some of my patients on oral medications, where basically if they have great adherence, I’m pretty much assured of viral load suppression, I’ve had a few patients on Cabenuva who have developed viremia despite what seems like excellent injection adherence.

I’m presenting a composite of a couple of patients, but I’ll call it my patient who started Cabenuva soon after it was FDA-approved approximately 3 years ago and had been doing great until his most recent blood work. At that blood work, the viral load was elevated, and this is the first time in over a decade of any antiretroviral therapy that he had an elevated viral load, and it was around 1,300.

Certainly not the first time I’ve had to address the issue of viremia with Cabenuva. Each time there’s a new challenge, a new wrinkle. The important thing is that this patient and other patients have not missed any injections. So it doesn’t seem to be an adherence issue, which seems counterintuitive given the robust data and nature of current preferred oral regimens that have such great virologic suppression when adherence is excellent.

I thought we could pause here, Eileen, and you could help walk me and the listeners through this case and considerations—the data on Cabenuva and how Cabenuva is administered and the options for frequency of administration.

Eileen:
Chris, this is a great case for us to think about and an increasingly prevalent problem, as many of us have a growing population taking cabotegravir/rilpivirine injectable therapy, or Cabenuva, for their antiretroviral regimen.

Before I start talking about Cabenuva, I just do want to do a little bit of definitional ground-setting, specifically around the viral load level.

In the composite case you’re talking about, the viral load was 1,300 copies/mL. I would characterize that as true viremia, as you did. One of the things when we’re talking about viremia is to be really precise about what level it is that we’re talking about, because many of us have grown accustomed to the fact that there will be frequent detectable, but less than a certain threshold copies, even in our patients on oral antiretroviral therapy.

The threshold for when you start to get concerned is one of the things I think we should focus on. For oral therapy in general, there are several studies that suggest that a viral load between 50 and 199 copies/mL doesn’t have a major impact on the risk for subsequent virologic failure, although it may have a slight increase in risk associated with it.

Viral loads greater than 200, a little bit more mixed, but there are some studies that suggest that having a viral load greater than 200 copies but less than 1,000 may also be associated with an increased risk of virologic failure. But in general, viral loads of 45 copies or 38 copies, that’s not something that I get very concerned about, in particular with oral therapy.

I would point out that this is an area where we don’t yet have the same level of certainty with injectable therapy. And that’s one of the questions I think will have to be sorted out over the next several years as we get more real-world clinical experience with understanding how to use Cabenuva.

Chris, I’ll pause there. Do you agree with how I’m describing those stratifications of viremia? Of course, acknowledging that your case is something different.

Chris:
I think that is a great framework, starting with how high the viral load is. All clinical guidelines use the cutoff of less than 200 or greater than 200 as a starting point for defining virologic failure, with virologic failure generally defined as 2 consecutive viral loads greater than 200. And that’s certainly the level where I start to have real concern about treatment failure and potential development of antiretroviral resistance.

Eileen:
Chris, as you say, using that definition actually takes us really nicely into the next part of what we were going to talk about, which is the initial trials of how cabotegravir/rilpivirine came to be approved and the definition of virologic failure in those trials, which, in general was exactly as you say, viral load greater than 200 on 2 consecutive measurements to confirm virologic failure.

In this case, we’re definitely greater than 200, so let’s start to talk about the data. We don’t have our second confirmatory here, but I think most of the people who are listening who care for people with HIV, nobody ignores a viral load of 1,300 copies.

In the past, just as you say, if this happened, if you then called the patient and talked to them, they may mention, “Yeah, I traveled and I didn’t have my ART for a couple of weeks,” and that was right before this, and with a renewed attention to adherence, this kind of viremia may resolve.

But in the setting of injectable therapy, we’re in a different ballgame. You know that they have received the medication, and so we have a different question to ask. So to your initial point, what is cabotegravir/rilpivirine and how did we come to use it?

Cabotegravir is an integrase strand transfer inhibitor; rilpivirine is a non-nucleoside reverse transcriptase inhibitor. Rilpivirine is available as part of oral combination regimens and cabotegravir is available as an oral lead-in but isn’t generally used as an oral agent on its own.

In terms of how these drugs compare to other agents, cabotegravir is generally thought to have a high-ish barrier to resistance, although slightly lower than dolutegravir or bictegravir. Rilpivirine is, as an oral agent, a little bit more susceptible to the development of resistance in part because it has some significant absorption requirements. Oral rilpivirine requires a 450-calorie meal and the absence of any acid suppression to get good drug levels. For that reason, it’s a little bit more susceptible to variations in how patients take it and doesn’t have a super high barrier to resistance as a drug itself, but in general can be highly efficacious.

These two drugs are co-administered, each as an intramuscular injection, and have been studied in a couple of pivotal trials, which led to its approval—ATLAS and ATLAS-2M.

ATLAS was an open-label antiretroviral therapy switch study. This enrolled individuals who had viral loads less than 50 copies/mL, and it was a non-inferiority trial comparing either continuation of your oral regimen or switch. It had about 300 people per group and was demonstrated to be non-inferior. There was about 1% withdrawal for adverse effects, which was, in general, injection site reactions, which decreased over the course of the trial. Many of the participants preferred injectable therapy, which is not surprising since they enrolled in a trial where they knew that was a possibility.

ATLAS 2M extended those findings. This was an open label cabotegravir/rilpivirine, at every 1-month administration or every 2 months administration. This again demonstrated non-inferiority. There were 8 failures in the 8-week arm of about 500 participants per arm and 2 in the 4-week arm. Among those who failed, they did identify some baseline non-nucleoside reverse transcriptase inhibitor resistance in retrospective testing in 5 out of the 8 individuals who failed. Those two trials show what happens when you take an individual on therapy with no history of treatment failure to any of the components or known resistance at baseline and switch them to cabotegravir/rilpivirine, either dosed every 1 month or every 2 months.

In the FLAIR trial, we saw the enrollment of antiretroviral-naive individuals who were initially suppressed on a regimen of dolutegravir/abacavir/3TC, and then, after achieving viral suppression, they were randomized to either continue on that regimen or to switch to cabotegravir/rilpivirine in the Q4 week dosing with two papers, one at week 48, which showed non-inferiority to the oral regimen and one at 96 week follow-up that confirmed these results showing that the regimen had good durability and remained non-inferior.

To summarize what we’ve discussed so far, that’s how we came to have approval to use cabotegravir/rilpivirine in the setting of existing viral suppression. But one of the things that did come out is that there is a rate of virologic failure. And as you mentioned, with oral agents with 100% adherence, we really don’t see that. That suggests off the bat that there’s something a little bit different happening with cabotegravir/rilpivirine and more things to understand there.

Chris:
Eileen, thanks for that great review. I wanted to emphasize that despite documentation of the intramuscular injections of the cabotegravir/rilpivirine in each of these studies, we saw less than 100% virologic suppression. Initially, that was a little surprising because we had documented adherence to excellent antiretroviral agents that were provided intramuscularly. Now it’s the reality that we have to deal with using these agents. So, to start with, I think cabotegravir/rilpivirine, despite the possibility of virologic failure, are excellent agents, and for many of my patients and patients around the world, have enabled good adherence and managed to achieve virologic suppression in ways that oral agents sometimes were unable to do because of adherence or other barriers. In addition, patients like this one who had excellent adherence on oral agents have just had an improvement in quality of life using the injectable and not having to take daily antiretrovirals and be reminded about his underlying HIV condition.

Eileen:
All of those points are getting to the heart of what we’re trying to do, which is not necessarily to decide what we would prefer, but to offer the different modalities that we have available and find the one that works for each patient. Some people don’t like needles and would never want an injectable option. Other people hear the message that they could be potentially on every 2 months dosing of an injectable therapy, and they would only have to think about their HIV 6 times a year, and that sounds like liberation.

So exactly as you say, Chris, being flexible about how we think about these options is a key part of rolling out new therapeutic possibilities. You highlight this important question, and as you say, initially it’s surprising, and then it becomes, “Okay, this is how this works.”

In my discussions with patients about the potential switch to injectable therapy with cabotegravir/rilpivirine, I always state upfront that to our best knowledge, if you take your oral therapy every day, you will not have viral failure. That does not happen when you’re taking your oral regimen to which we know you are susceptible. However, with cabotegravir/rilpivirine injections, we do know that even with on-time injections of full adherence, there is a very low but present rate of virologic failure. I typically quote that as between 1 and 2%, which is consistent with the results from these trials, some of which were about 1.6% and has also been remarkably consistent with the real-world cohort experience. It seems about 1% of the time people have virologic failure despite on-time injections. How do you counsel your patients?

Chris:
I do the same. The first thing that I noticed when cabotegravir/rilpivirine was first available, I had some patients who thought maybe it was going to be more effective because it was delivered via injection rather than oral absorption. With the data that we have from the clinical trials and the real-world experience, I explained to patients that it’s an excellent option, but just like with any therapy, we have to do close monitoring, and there’s a chance of failure. If failure occurs, then they may no longer be able to use injectable antiretroviral therapy and may have to return to oral therapy, but we can manage that. And they’ll be able to resuppress on a regimen that is oral therapy or some yet to be developed novel injectable regimen.

Eileen:
The one other thing I’d add is the risk tolerance of the individual and their concerns about return of viremia. For example, a reproductive age young woman talking about the potential for virologic rebound in the context of a pregnancy, for example, is a slightly different conversation than talking about it with someone who would never worry about that or for whom virologic failure would be an event that then you change back to your oral therapy without much consideration. So, if people are very concerned about transmission to partners or have other considerations, I think that’s an important part of the discussion too.

Chris:
Great points, especially with the potential for pregnancy and increased risk of maternal-to-fetal transmission. With episodes of viremia during pregnancy, it’s important to counsel about that possibility, even if it’s unlikely. And whether a woman who’s planning on pregnancy would want to switch to an oral regimen certainly could be a discussion.

Usually, we can say if you remain fully adherent to your regimens, you will qualify for U=U and maintain a viral load less than 200. But as we’ve seen in this case, there is viremia, which does increase the possibility of transmission.

When I saw this viral load, my first response was to panic because this patient had had a long-term virologic suppression, really was comfortable with the injectables, and had been fully adherent. After taking a breath,

I took the approach that you described—thinking about how high it is, and with a viral load greater than 200, certainly failure is a possibility.

Then the next step is to confirm that with repeat viral load testing as soon as possible. Then, just as I do with individuals who are on oral therapy, where I see if they missed some doses either because of travel, insurance, or other issues, I went back to the electronic medical record to see that each injection was fully documented for both agents, which it was for each injection. Each one was also on time within the window that is permissible for Cabenuva.

You also mentioned that while cabotegravir has a relatively high barrier to resistance, it is lower than bictegravir or dolutegravir. In clinical trials, we certainly have seen cabotegravir resistance developing among patients with viremia, so I wanted to move pretty quickly and get my patient on the phone and get them into the lab, both to repeat viral load testing to see if he actually met the definition of failure, or if this was a spurious lab result, and also to assess for INSTI drug resistance. Then I talked to him about any supplements or other medications he may have started that potentially could have a drug-drug interaction, as well as any intercurrent illnesses around the time that he had the viral load testing, as simply having an acute viral illness can cause at least a blip in viral load. I didn’t identify any.

Eileen, just wanted to see if you can tell us a little bit about the data on factors that have been identified to be associated with viremia on Cabenuva.

Eileen:
Great question. In the trial setting, there were a couple of things that were generally associated with the identification of virologic failure. But before I list those things, I’ll mention that it required that you had 2 of them.

So, proviral rilpivirine-resistance-associated mutations—this is using a proviral genotype that was done retrospectively in the trial to see if there was evidence of an archived resistance mutation that would have impacted real pivoting. That was one factor.

A BMI of greater than or equal to 30—that was ultimately thought to be related to whether or not the medication depot is successfully delivered to its intramuscular target, so there are recommendations about using longer needles for individuals who have high BMIs. That was one of the other factors.

In the early analyses, there were also associations with specific subtypes of HIV, specifically A1 and A6, that were associated with a risk of virologic failure.

Then from the later analysis of every 2 months versus every1 month, there did seem to be a higher rate of treatment virologic failure in the every-2-month-dosing arm, but that was predominantly within the first one year of administration of the medication.

In general, those factors are thought to be, when linked together, associated with a potential increase in risk of treatment failure.

Going back to our earlier point, checking for proviral resistance-associated mutations might be one step that we would take. Although, I guess you could say that if you didn’t have the other risk factors, then because we need two, it wouldn’t necessarily be a recommendation.

I don’t know how many of us, as we sit there with an unclear treatment history, will decide in either way, but to summarize, there are a few things associated with a risk of failure, but nothing that’s a smoking gun or clearly identifies a patient who will not have success with this regimen. To that point, there’s a nice paper in Clinical Infectious Disease in July of 2024 (we can link to it in the show notes) where they go over a series of 5 cases of Cabenuva treatment failure. This is from a European group where the only approved use of Cabenuva is every 2 months. So that is one baseline factor. There’s an optional oral lead-in, which was also used by some of the patients and not others in this case report. In this anecdotal report, they go through the cases and show that there’s an absence of any of these predictive risk factors. In one case, there was a delay of the injection, but there was some attempt to bridge.

The frightening part for me was that there was not a smoking gun in any of these cases in terms of identifying the reason why this person experienced virologic failure, so I have not adjusted the counseling that I give. My interpretation of that is if you are sitting across from someone who has a A1 subtype virus, a very high BMI, failure on an NNRTI regimen in the past and then you check and maybe there’s a possible rilpivirine-associated mutation, then maybe that, and they will only do it if they could do it every 2 months, that seems like a case where you would say, “I’m not sure this is the right option for you.” But absent that sort of perfect storm of all the risk factors, I generally counsel people equivalently to say that everyone has a risk of failure because I’m not sure that these while they may be somewhat predictive, they’re not exclusive.

Chris:
Those are all good points. For my specific patient, early on in my use of Cabenuva, I was not doing archive proviral DNA resistance testing. I don’t know if he had archived NNRTI resistance mutations. He had never had any treatment failure on an NNRTI and unfortunately did not have any pre-treatment resistance testing. So, I don’t know if there was any transmitted NNRTI resistance, which certainly is a possibility, especially having started therapy and being diagnosed 10 or 15 years ago when NNRTIs were more commonly used and the prevalence of NNRTI resistance was higher and transmitted resistance was a bit higher than it may be now.

I was using every 2-month dosing. I tend to do that because patients prefer coming in every 2 months versus every month. Although there were no other risk factors, that is, his BMI was in the normal range, certainly less than 30, subtype was not A6 or A1. I was a little surprised that he had done so well for about 3 years and then had this episode of viremia. Is there any additional insight into timing a failure from any of the studies that we have?

Eileen:
From the registrational trials, we’ll get pretty limited information because most of them go out to around 96 weeks. From the case series in CID, the time to failure ranges from just 3 months out to 13 months. But again, probably somewhat limited by the amount of time that this medication has been approved.

It sounds like your composite patient is one of the early adopters, so he’ll be among those who give us the first indication of whether or not if you get through an initial window, this is less likely to occur, or if it’s an ongoing risk of about 1% and at what frequency that occurs over time, which I think will be really helpful to know.

My initial impression from the data of the 8 weeks versus 4 weeks was that if you got through the first year on 8 weeks, you probably were going to be okay, which your patient would suggest might not be true if we looked in larger groups.

What we’re dancing around here is that we don’t actually know why this happens. In the CID paper, most of the individuals had one drug level that was below their quartile 1 cutoff of population-estimated exposures to drug, suggesting that they have low exposure to a drug at some point. These weren’t monitored in a perfect pharmacokinetic way but were just spot measures that were done in the setting of having an unexpected treatment failure. That suggests there might be something about the drug getting from the injected depot into the bloodstream. This is where we’re going to have to understand more. Is this related to injection technique and whether or not it gets to where it’s supposed to go? Is this related to differences in inter-individual variabilities in drug metabolism? So, you put it perfectly in the muscle, but my enzyme chews it up faster. How frequent are such variations in the population in general? Or is this some other unrelated factor where, maybe the drug is not penetrating to all the sites where we believe that HIV reservoirs exist in the same way that oral therapy is? I’m not aware of any data to suggest that’s true, but it is impressive that there’s this difference in the risk of treatment failure based on the modality of receipt of the therapeutic, at least it appears to be for cabotegravir/rilpivirine.

So, I wouldn’t have done anything different for this patient. I agree with you. Early on, we did not have this data about rilpivirine proviral mutations being potentially a predictive factor. There was an absence of other risk factors that were associated. And I’ll also mention that the every 4 weeks versus every 8 week dosing is sometimes dependent on the clinician decision, but also there are other factors like insurance coverage and how much and how frequently the injections will be covered. For all of our European colleagues, they are required to do Q8 dosing because that’s the labeling for the medication.

So, circling back to your initial response of panic, I fully co-signed that. I always tell patients that’s our job—to get really nervous about things and to let them know when they need to be nervous. Your urgency and having the patient come in for a repeat is very warranted because in the studies with cabotegravir for PrEP, for example, we know that earlier identification of viremia may be useful in preventing the development and emergence of resistance. So, getting the person back in to have them retested right away would also have been my first priority. And then also to have the confidence that we have multiple possible regimens and this person will achieve viral suppression again, even if this does not mean that we can continue to use an injectable regimen.

So, what did you do? I guess I can’t ask you what you did to a composite patient, but if we’re confronted with this, let’s say he has a repeat viral load checked and it remains elevated, not exponentially increasing, but maybe in the 2000 range.

Chris:
So, when again going to a framework of now confirmed viremia, my goal is to get the viral load suppressed again as soon as possible. And we know we can do that in an oral regimen. We do not know if going to monthly injection would achieve that. So, I would not go to that.

The other possibility could be to add lenacapavir every 6 months, although that is not guideline-recommended or standard of care, and certainly I’d want to confirm that he had no cabotegravir drug resistance mutations. So, the starting point for me is getting the confirmation of persistent viremia and making the diagnosis of virologic failure, along with getting HIV drug resistance testing for integrase, as well as in NRTIs and NRTIs, and then initiate him on a regimen that I’m pretty sure is going to work while I’m waiting for the resistance test results.

For him that could certainly be a PI-based regimen. I wanted to comment that, although I’ve had this panic and perhaps added headache of addressing this issue and working through it with this patient, in my view, this is a great product and is the appropriate choice for a lot of patients with the considerations that you’ve brought up—that they realize that there is this small but real chance of virologic failure.

The only difference in my management of patients when I’m considering Cabenuva now is to get that proviral DNA resistance testing beforehand to see if there are any rilpivirine-associated resistance mutations. If there are, then I generally recommend against using Cabenuva.

Anything else to add, Eileen?

Eileen:
Your point that this is an excellent regimen and a life-changing option for patients is one that we should make here because all things have risks and benefits. For some people, this is truly transformative in terms of their relief from the stigma of daily medications or the just burden of it. So, I agree with you—this is a really excellent option for a lot of individuals. We have to present it within the appropriate context and also make sure that we know how to respond when there is something unexpected. More frequent viral load monitoring than you would do in your oral therapy patients is one feature that may come up. And then responding to it appropriately within a timeframe that makes sense if you suspect that there’s been virologic failure so that you can maximize the options that people will have on the other side of a potential biologic failure are the things that I would do to manage that. But overall, I agree, and I hope that we understand more about who is most at risk for this outcome so that in the future our counseling will be even more specific and a little bit more effective.

Chris:
Thanks for this good discussion. Like always, I learned a lot from you today, Eileen. And thanks to all of our listeners tuning into today’s podcast.

Announcer:
Thanks for listening to Viremic. If you enjoyed the show, please subscribe wherever you listen to podcasts. We are taking a break for the holidays — and we’ll back with new Cases in HIV starting in January.

Viremic is sponsored by the Clinical Guidelines Program, a collaborative effort of the New York State Department of Health AIDS Institute and the Johns Hopkins University Division of Infectious Diseases.

Visit the program’s website at HIVguidelines.org.

The podcast is produced and edited by Mary Beth Hansen and Brian Hatcher with appreciated assistance from Jesse Cicotte and Laura Lebrun Hatcher.

Viremic’s case discussions are presented for informational purposes only and are not offered as medical or clinical practice advice for patients or clinicians. Any mention of specific medications or commercially available products is a description of use, not an endorsement.