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 Hoffman, 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 Hoffman here with my friend and colleague Eileen Scully to talk HIV cases. What case do you have for us today, Eileen?

Dr. Eileen Scully:
Well, hi, Chris. It’s great to be here with you.

Our case today is inspired by a recent clinic experience that I’ve been having. There was a beloved provider who had many patients in our shared practice who is transitioning to a smaller role and eventually retiring. This has left me in the position of inheriting patients from their practice. And I have to say, this has always been both a humbling experience and one that has taught me so much.

It’s humbling from the perspective of walking into a situation where a patient has had a relationship, sometimes for 15 years, 20 years, and to try to fill those shoes can feel quite intimidating. But also, it’s hard to rebuild that kind of deep knowledge of someone’s health. When you’ve been with a patient and walked through hospitalizations and life events, the loss of parents or siblings or children or partners, and been through all of those experiences with them, it gives you this ease in thinking about their management that is not there when you start fresh, especially when you have someone who’s come from a relationship where they had that, it does sometimes feel like a, really beautiful opportunity and also a tall order.

Chris, have you had that experience recently? Does that bring up anything for you?

Chris:
Yeah, for sure. You mentioned the beloved, which always is very intimidating to take over somebody’s care and participate in their care after they’ve had a long relationship with another provider who’s really a great provider. I have been in that situation in the past and sometimes still pick up patients from long-term, well-respected, excellent providers and try to fill their shoes while also using my approach. But also, it’s always exciting to meet a new patient and see what I can contribute to their care journey.

Eileen:
Yeah, exactly. I feel that way about my own long-term patients. Sometimes you wish someone else would take a deep look at their chart and make sure you haven’t missed something along the way. So it’s also a good opportunity to take fresh eyes and also for the patient to try some things that they might not have tried.

Let’s start with a hypothetical case. I mashed up a few recent patients. We’ll talk about a 62-year-old gentleman with a history of HIV that was diagnosed in the 1980s and lost many friends early in the epidemic and does have some survivor guilt.

He was on a variety of regimens early on, engaged in care right away, but he did not achieve full viral suppression several times during that treatment course. He had the addition of a single medication that was newly available on top of a previously failing regimen because that’s what we did in those days. That was the best that we had available.

He has a history of pneumocystis pneumonia and ocular CMV in the distant past, but more recently has had viral suppression and a restored CD4 count in the range of about 400 to 500 cells for the last 10 to 12 years. His current regimen is darunavir/ritonavir plus etravirine plus raltegravir. All of those components are taken twice a day.

He has an additional history of hypertension, some impaired glucose tolerance or pre-diabetes, and gout, and is on a few medications for those things.

So on transfer to you, you start to build this relationship and talk about many things with respect to his health, but he is actually interested in whether or not he could reduce his pill burden. Although he does at the same time feel very strongly about this regimen as it was the combination that finally brought him to stable viral suppression. And as he says to you, it saved him.

So Chris, how do you approach changing a regimen in this type of a situation?

Chris:
Very common scenario, at least in my practice, with, in fact, this specific regimen. As you mentioned, this was the lifesaver in 2007 or 2008, sometimes called the TRIO regimen for these 3 agents: darunavir, etravirine and raltegravir. Lifesaver for lots of patients.

I’ve recently, in the last year or two, switched some people off of it. As you mentioned, the new provider is both an opportunity to review things and sometimes a new start for a patient. I’m very cautious about rocking the boat in a way that may not lead to a good patient-provider relationship. That is, if there are initial problems, side effects, drug-drug interactions that were not anticipated because of a poor review of the rest of his medications, that can really get things off on the wrong foot.

I expect he has a lot of HIV drug resistance, given that he’s been on multiple regimens that we may or may not know the full treatment history. You mentioned he’s been on perhaps monotherapy, maybe with zidovudine; probably dual therapy, possibly with zidovudine and lamivudine or D4T or DDI; then probably early protease inhibitors like indinavir.

It sounds like he’s maintained an undetectable viral load while he’s been on the TRIO regimen, which suggests that he has no resistance to the raltegravir or the integrase transfer class overall, which gives him great opportunities for potential switches.

I’m going to take a step back and think about change at all. Some of the things that go through my mind—is there a reason for change, which typically is failure, side effects, or regimen complexity, tolerability. He’s already highlighted that he’s taking a lot of pills twice a day. So we have a reason for change given the complexity of this regimen.

The next thing is to think about treatment history, which you nicely spelled out. And as I said, probably a high level of resistance to a lot of the older agents, especially in the NNRTI class and NRTI class. And finally, it would be nice if we have some HIV drug resistance testing, although to some degree, the resistance mutations he’ll have are predictable, but still valuable to review, especially in regard to INSTI resistance.

Eileen:
I love that rubric, and I’ll also highlight that what’s not on that list of things you think about is provider preference. Sometimes we look at regimens, and we’re just, well, they could be on something different. But if the patient’s not interested in that, if there’s not a meaningful advantage in some domain, there’s a pretty good argument for staying with what’s working.

That said, I do think in this case, there is a bit of regimen complexity, and there’s a couple features of these medications themselves that might make us want to think about changing. I love also the way you introduced what we probably don’t have to worry about, which is that he’s been fully suppressed for the duration of his exposure to the INSTI class with raltegravir. There’s no reason to suspect you would have any resistance to that particular class. So that’s one thing we can immediately put into the column of what we know about him, likely, as we think about alternative agents.

And now I’ll also give you that in this case, hypothetical though it may be, we will imagine that we actually have very detailed treatment records, and they’re exactly as you had imagined them, sequential addition of nucleosides and nucleotides when they became available, and then some of the NNRTI class followed by protease inhibitors of the earlier generation, and then ultimately switching to the regimen that he’s on.

There were no other unexpected exposures, and we do actually have genotyping data from shortly before he started on this particular regimen. That genotyping data was on the drug pressure of his prior regimen, so considered to be relatively reliable. I’ll give you those mutations in the reverse transcriptase gene: we have the M184V, which confers resistance to 3TC. We have two of the thymidine-associated mutations, or TAMs--M41L and T210Y, which are in the TAM2 pathway, which confers higher level resistance to tenofovir than the other pathway. Those were likely selected by first-generation nucs like D4T and AZT. Then there’s K103N and Y181C, both selected by non-nucleoside reverse transcriptase inhibitors,

and both generally do not have major impacts on viral replication capacity, so those do tend to persist in circulating virus. That’s where we are with those two classes.

For the protease inhibitor gene, we have one mutation, an I54V, and then what’s really more probably appropriately identified as a polymorphism, which is the L63P.

PI resistance is one of the things that can be a little bit… I would say that when we talk to the fellows about it, they don’t necessarily need to commit all of these to memory because it’s just much easier to go and look at it. The 54 position is of concern for darunavir, and many of them are not, but this particular mutation, the 54V, is not one of the ones that’s considered a primary darunavir resistance mutation. So it’s in the position that can sometimes impact darunavir, but it is not a mutation that is known to impact darunavir.

With that as a background, I thought maybe we could dive in a little bit to talking about these different agents that are in his regimen currently. Chris, you mentioned etravirine (or etravirine), which is a tomato-tomahto situation. Do you want to comment a little bit on how we decide whether or not you can use etravirine? It’s a little bit different than for the other nucs.

Chris:
With the etravirine (or etravirine) there, there is likely susceptibility, even though the K103N and Y181C are present. We typically calculate a score for susceptibility or plug these into the Stanford HIV Drug Resistance Database to assess for susceptibility. There should be some amount of susceptibility here in Stanford. I believe it would be intermediate resistance given the Y181C and then probably a bit higher level resistance to some of the other agents like the efavirenz, nevirapine, and rilpivirine.

I wanted to follow up and comment on what you said about the darunavir and the mutation there in the I54V. The interpretation of resistance has changed in terms of when to use twice-daily dosing. You’re highlighting here that with current algorithm interpretation, we would still likely consider single day dosing appropriate for this individual.

Overall, we want to move away from many of these agents in this regimen and certainly have the opportunity to do that.

Eileen:
Chris, you’re bringing up a great point about darunavir, and this is one of the things when we talk to the fellows about why it is that darunavir has really remained almost the last protease inhibitor still standing. This is because darunavir is known as an agent with a high barrier to resistance and very low levels of cross-resistance in settings where an individual had already developed significant protease inhibitor resistance. That’s not an accident.

The development of darunavir was actually done by screening several thousand clinical isolates from patients who had protease inhibitor resistance. So by definition, this was a drug that was selected to work even if you’d failed earlier generations of protease inhibitors. It has unique binding characteristics. It’s less likely to be displaced from the protease by single mutations. And in vitro selection of resistance took longer than most other available most other available antiretroviral agents, which is why we call it a higher barrier drug. It has less cross-resistance to almost any PIs, with one exception, which is fosamprenavir and amprenavir-based regimens, which can select resistance that follows a similar pathway to darunavir that was developed shortly before darunavir so it was not included in that library for selection.

One other random note about darunavir is to remember that it does have a sulfa moiety that should be considered in patients with a true sulfa allergy. Although it’s more like the sulfa that’s associated with Lasix than the sulfa that’s associated with Bactrim, it’s less likely to be allergenic than some other agents.

So this is how darunavir has stayed king of protease inhibitors for the modern era. Great characteristics as a drug itself, good performance against isolates from people with long experience with other protease inhibitors in the past.

Now, one of the things that you highlighted was the dosing of darunavir. As we mentioned, this regimen, the TRIO regimen saved many people. And in part, it was because they were sort of trialed on these agents that were the best available, and also all of them being used with the assumption that there might be some resistance.

For darunavir, there were a couple of trials that looked at people who already had mutations that were associated with resistance to protease inhibitors, some of which were also associated with resistance to darunavir itself. They found that with sequential addition of more of these mutations, you then had a dropping probability of successive suppression. When you had people with more than one primary darunavir resistance mutation, the recommendation for dosing is twice-a-day. The dosing for that is 600 milligrams of darunavir and 100 milligrams of ritonavir taken morning and at night. This is in contrast to the once-daily dosing, which is 800 milligrams of darunavir plus 100 milligrams of either ritonavir or a cobicistat booster, and that’s taken once-a-day.

In the early time when we were using this medication in a salvage regimen for people who had failed many other things, oftentimes, we used twice-a-day dosing if there was any protease inhibitor resistance at all. As time has gone on, we feel more confident that this is not necessary unless there are truly darunavir resistance mutations. And in a case like this, many people would feel very comfortable not using the twice-a-day dosing, but using only once a day.

So going back to our goals here… we have someone who’s coming in on 3 drugs twice a day. As I try to make a move on one of them, let’s for example, say I’m even just going to change from twice-a-day darunavir to once-a- day--does that really meaningfully impact our patient’s regimen complexity? It does, but one of the questions is, is there any way we can get to all once-a-day?

There are good studies from the cardiovascular literature showing that combination pills lead to better hypertension control and also even more strong evidence for the fact that once-a-day dosing is better than multi-dose regimens. Chris, do you frequently drop from twice-a-day darunavir to once-a-day in your practice?

Chris:
I do sometimes for a variety of reasons. As you highlighted, this is state-of-the-art antiretroviral therapy circa 2007, and we have both new regimens and even more importantly, new evidence of what works. Back in 2007, 3 active or at least partially active agents were considered essential. That was because of both RCTs and observational studies demonstrating higher levels of treatment failure when there were 2 or fewer active agents.

Things have changed since then because of new agents that have very high barriers to resistance and also very high potency. This has been highlighted in a couple of studies mostly in low- and middle-income countries at using an INSTI plus NRTI background compared to sometimes other regimens in patients who already had treatment failure. In the participants with treatment failure, there was a wide distribution of NRTI resistance, including resistance to both of the NRTIs that somebody was continued on. And yet, individuals who are on dolutegravir, for example, the rates of virologic suppression were excellent.

So compared to 2007, now we have data using more modern agents that we can actually have success despite the fact of resistance. So I would say for him, it would be nice just to move away from the darunavir altogether, as well as some of the other agents. The etravirine or etravirine has a lot of drug-drug interactions that can make it a little more complex and lead to accidental errors in dosing because of that if those are not well assessed. And also, while raltegravir is very well-tolerated, the fact that it’s twice-a-day dosing is one downside, but to me the bigger downside is just that it’s less potent and has a lower barrier to resistance than the newer second generation INSTIs.

Eileen:
All great points, Chris. I’ll highlight one little fact about the etravirine that people should keep in mind. As we use it less frequently, can fall out of our general knowledge. Etravirine among the drug-drug interactions it has are with dolutegravir. So if we were to, for example, say, let’s drop the raltegravir and substitute in dolutegravir once a day, more potent, great option, that would work in this triple regimen. But it does not work if there’s not also a protease inhibitor with the etravirine. Otherwise, etravirine induces metabolism of dolutegravir, you get lower than optimal levels of drug. So keep in mind, dolutegravir, etravirine, you also have to have a protease inhibitor in the mix. And it just highlights also that as we create novel combinations of these new agents, you can also check those directly in Liverpool.[Liverpool HIV Drug Interactions Checker]. Don’t only be looking at the other concomitant medications, look within your regimen when you’re making novel combinations of drugs.

But I agree with your points about etravirine. It was also favored at some point because it can be dissolved and taken orally as a slurry, which for some people was an important option at times when there were problems getting large pills down. But other than that, there’s very few reasons for why you would select it. And as both an inducer and an inhibitor of the cytochrome P450 system, it can have pretty pleiotropic and unpredictable drug-drug interactions. So I agree with you. That’s one I would love to drop.

In terms of the darunavir/ritonavir, I agree that it is a drug we’d like to move away from, and we could probably find other things that would be good for him.

That also raises another point, which is when someone newly achieves viral suppression, that’s a little bit different than someone who’s been suppressed for a decade. When I say that’s different, I don’t think we have great clinical evidence to say that that’s really different, but we do know from basic science studies that the reservoir does generally get smaller over time, in particular with respect to the replication-competent reservoir. Over time, just through natural attrition of the cells that are there, you tend to have a lower and lower amount of HIV with sustained viral suppression. This likely makes it a little bit less likely that you’ll have viral rebound immediately, or maybe just reduces the probability that whatever does rebound will have drug resistance. But I do think a little bit differently about someone who’s been fully suppressed for 10 years as opposed to someone who’s been fully suppressed for 10 weeks in terms of how likely they are to tolerate a switch. And that’s why we think about switch versus initiation studies a bit differently also.

So in this case, I agree with you. I’d love to try to reduce his medications. I do sometimes get into the conversation and then find that the person feels quite insecure about changing the regimen. That’s where I try to be flexible and to ask them what their priorities are and how we could adjust it. One option that you can start with for an instance like this would be to do substitutions. So here we can take the darunavir/ritonavir and reduce it to once-daily dosing. We can take the etravirine and swap in doravirine, which has very little penalty related to the 2 mutations that are present, the K103N and Y181C, and that’s once-a-day, irrespective of food, so a substantial advantage, and then add dolutegravir. And then that way we’ve got our three regimen pillars identical to the ones that we previously had with some modernization to higher barrier agents and those with fewer interactions.

Over time, if that works, then maybe we consolidate down a little further. I did have one patient who recently came to me who was on one of these complex regimens, including a twice-a-day dosing of darunavir, had a long history, had had treatment failure. He was very attached to his regimen.

I did introduce the idea of changing, but I was a little unsure if it was the right thing to do. As you said earlier, you don’t always want to rock the boat if things are working well. He opened the door wide for me by telling me that he actually only takes 1 of the twice-a-day doses of his medications. And that is also a question to ask people with a very open-ended approach. You know, “Do you have any trouble with your medications, and specifically, do you ever miss the second dose?” And with him, he said, “Actually, I almost never take it.”

So there, I completely removed my problem of figuring out whether or not it would be okay. He’d already done it essentially. And by actually changing to once-a-day dosing, we were actually just getting him more medication. So what do you think of my substitution plan, Chris?

Chris:
That would work great. Reduces the pills, reduces it to once-a-day, and provides more modern agents. as you said, it’s completely a discussion with a patient. Sometimes I have gone the substitution route like you outlined. Sometimes I’ve gone for a single tablet like Biktarvy. Either way in patients like this, typically I suggest that they check their viral load more frequently than perhaps the guidelines would suggest, not so much because I think there’s going to be any treatment failure, but because often they are very fixated on viral load and that will just give them peace of mind if they check it every 4 weeks for the next 6 months and see that it is undetectable during that whole period.

Eileen:
Got it. I always have people come in in the range of 2 to 4 weeks after a change of regimen. And if they come in on the earlier side, then I’ll do a second measurement just to make sure that we made our transition with no evidence of virologic failure. I also agree, might have them come in a little bit more frequently in the first 6 months if they’re feeling concerned about it.

One other thing to note is that low level viremia can arise in the setting of a switch and while we sometimes will attribute it to the change in regimen, we should be mindful of the fact that over time, the reservoir changes, and there are often blips even in the absence of a change in regimen, so to not necessarily overinterpret those if they are apparent immediately after a medication switch. Sometimes that’s just due to expansion of a particular clone of T cells that happens to carry a little bit of virus that’s more likely to show up in a little bit of a viral blip. And by blip, I’m talking about numbers that are less than 200 definitely, but most frequently less than 100 copies per mil.

Chris:
Yeah, great point. A trap that I probably have fallen into every time it’s happened. And a lot of anxiety for myself and for the patient as well.

Eileen:
For this patient, we’ll try to get him to once-a-day first, and actually, we’ll go from a total of, so it was 2 pills for the darunavir/ritonavir in the morning, 2 at night, and then 2 of the etravirine. So now we’re up to 6 and then 2 of the raltegravir. So 8 total pills down to 3, because we can have darunavir/cobicistat as a co-formulated option, doravirine and dolutegravir individually as pills.

Chris:
Yeah, and that can be a great reduction in burden, even among patients who say they have no problem with the heavy pill burden and have been doing it for the last 10 years and it doesn’t affect their lifestyle at all. I don’t think I’ve had a single patient where I’ve made a change who has not come back and said, I’m actually really happy that I’m not taking so many pills any longer.

Eileen:
Yeah, I agree. The one other thing to look at, though, is just make sure you review other medications to see if there are any other meds that their levels might have been impacted by etravirine that would then need to be adjusted because of the absence of the medication.

Chris:
Good point.

Eileen:
Thanks for talking through that case with me. I will continue to absorb my new patients and the joy of hearing their long stories of HIV and the challenge of figuring out how to move forward.

Chris:
Yeah, good luck. Always every new patient is a is a new fun story to get to know and personality to get to know.
Thanks so much, Eileen, for this discussion. Thanks to the listeners.

Announcer:
Thanks for listening to Viremic. If you enjoyed the show, please subscribe wherever you listen to podcasts. We’ll be back in a couple of weeks with a new case to discuss.

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.