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 and I’m here with my friend and colleague, Eileen Scully. Eileen, what HIV case do you have for us today?

Dr. Eileen Scully:
Hi, Chris. Today, I have the kind of situation where you’re caring for someone, but you don’t necessarily know their entire HIV history. So our hypothetical for today is a 56-year-old woman currently on a regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide, coformulated as a single pill, who presents for a routine appointment.

She has multiple medical comorbidities, and recently there’s been discussion between you and some of her subspecialty providers about whether there’s a simplified option for her HIV treatment. Two specific features that have been raised are the drug interactions with her cobicistat booster and a potential need for a direct acting oral anticoagulant, or DOAC, and evolving renal function.

Chris, what are your first steps in approaching this type of question if this patient were to wander into your office hours today?

Chris:
I’m going to take a step back, Eileen, and begin with the question of the DOAC and possible drug-drug interactions. When we see the possibility of anticoagulation, certainly the prospect of drug-drug interactions immediately pops into our minds. Probably we should always be thinking about that with any new medication or sometimes even medication somebody’s been on for a while—that a potential drug-drug interaction has been overlooked.

I’m just going to mention some of the resources I use in terms of looking at drug-drug interactions: One is online interaction checkers such as the Liverpool [HIV] Drug Interaction Checker, which I have on my cell phone as an app, but it’s also online, and there’s some other online checkers. I also find just looking at tables can be helpful and the guidelines produced by the New York State AIDS Institute have great tables for a variety of different classes of medications and interactions with antiretrovirals. Give me a moment as I pull those up just to go through some of the things that are listed right there in that table. And why I’m starting with the table rather than looking at a single anticoagulant is that this lists all currently FDA licensed anticoagulants and goes through interactions with currently used HIV medications.

First, in terms of classes of drugs of NRTIs, dolutegravir, bictegravir, cabotegravir, raltegravir, rilpivirine, and doravirine there are no significant interactions expected with any of the classes of anticoagulants. Now, if we move on to elvitegravir which is boosted with cobicistat there are a number of interactions, including with warfarin, rivaroxaban, dabigatran, apixaban, and other DOACs. But really the question here is with her Symtuza, which has the boosted darunavir; there are interactions with warfarin decreasing or sometimes actually increasing exposure. And then certainly to the DOACs, rivaroxaban, dabigatran and apixaban. Generally the feeling is to avoid concomitant use of a DOAC along with a boosted protease inhibitor.

That, initially when DOACs became available, was pretty much in almost all situations, the recommendation. That has softened a little bit. In the FDA inserts for a number of the DOACs, there are guidelines or guidance for co-administering with a boosted protease inhibitor. For example, apixaban—the dose can be reduced if a standard dose of 5 mg twice daily is being used, cutting that in half to 2.5 mg twice daily is a potential option. If they’re already down to 2.5 mg twice daily, then according to the FDA insert, concomitant use should be avoided. Similar recommendations are provided for dabigatran and edoxaban. However, reading the fine print in either the FDA inserts or information on the hivguidelines.org website or the Liverpool [HIV] Drug Interaction Checker is that there’s not really a lot of clinical data in co-administration, and there can be some form of kinetic variability.

So getting back to our case here with the possible DOAC… I really try to avoid using a DOAC along with cobicistat or ritonavir boosting to simplify what’s going on, number one, and number two, to avoid another provider accidentally increasing the dose of apixaban to the standard dose, for example, or another error that could lead to overcoagulation and potential bleeding.

Eileen:
Chris, I agree with you, and you’ve highlighted one of the major advances of our therapeutic landscape, which is that, back in the earlier eras, a lot of HIV management was around figuring out drug-drug interactions and ensuring that other well-meaning providers didn’t inadvertently cause steroid excess or trigger other significant interactions with our HIV regimens. But as you mentioned there at the top, a lot of the current first-line agents have no interactions even with the DOACs, which are commonly used for many different indications.

Now, in the past, when anticoagulation was managed much more frequently with warfarin, while there is an interaction there, it’s just an interaction of dosing. you can get to a steady state and maintain that; just will be likely a little bit different than it would be if you weren’t on the booster.

But with the DOACs, we don’t have great measures of their anticoagulant efficacy, so as you mentioned, my practice is similar in that I try to avoid use of a booster together with DOACs, although there is some limited data for safety and when needed, that can be relied on. In general, it’s preferable in my mind as in yours to try to avoid those interactions and just have a cleaner pathway to knowing that we’re therapeutic on both classes of medication, both the antiretrovirals and anticoagulants.

I’ll also co-sign on your resources. I love Liverpool and like to click down and see the strength of data for any interactions that are suggested, which also helps me to modulate whether or not I’ll say, “Oh no, not usable drug interaction” or, “Okay, this is manageable.” This is based on data, this is not based on data, meaning clinical data as opposed to inferred modeling data. And tables are great because one of the things that happens when we try to prescribe a medication is you choose a medication, then you find it has an interaction, so you need an alternative. You also need an alternative that will work for your patient’s particular insurance, so a table with lots of options can be a really great tool for organizing how to approach these types of drug interactions questions.

What other kinds of questions do you want to ask or what other things do you want to know in order to figure out what our options would be if we were going to choose a new regimen?

Chris:
First, in terms of switching regimens either for side effects or for potential drug-drug interactions, there are some recommendations and guidelines from the New York State AIDS Institute, which go through a lot of considerations.

Some of the basic considerations I have when looking at any regimen are basically about 7 different questions:

One, Is there a reason to change? And some of those could be treatment failure, that is a viral load persistently >200, is the regimen complex and a simpler regimen is an option? Is the patient experiencing side effects or potential long-term toxicity? And then in this case, are there drug-drug interactions that we want to minimize or avoid?

The second thing is really what is the treatment history? That will really help in determining what is available for this patient from all the various antiretroviral agents that are currently approved.

Then the third is what laboratory tests are available, including any kind of resistance testing.

Perhaps related to that is history of CD4 count and viral load testing, especially those identifying a nadir CD4 count and a maximum viral load. This mostly comes into consideration when thinking about an NNRTI like rilpivirine but is just a useful thing to always keep in one’s mind.

The next thing is comorbidities. You mentioned this patient has an evolving kidney function (mysterious terminology, but certainly not uncommon in the world of HIV care), and considering what any of our drugs could have on either interpreting kidney function labs or affecting long-term prognosis of declining kidney function.

Then the sixth thing is what drug-drug interactions to consider.

And finally, but definitely not least important, are patient preferences, what they’re best able to manage, and what their medication-taking patterns have been in the past and currently are in terms of missed doses or periods of non-suppression.

What I’d like to know now is what has her treatment history been, both in terms of meds and her success with those different meds?

Eileen:
Let’s get back to a few more features of this case. She acquired HIV in her mid-30s, so a long time ago now, more than 20 years, and started treatment back before the availability of many modern regimens. She has a history of multiple treatment combinations in the past and only came into your care a few years ago. And despite our electronic medical records, we don’t have access to great information from her care prior to being in your clinic.

She remembers the name of several drugs that she was on through those years. She includes Combivir which is an AZT/3TC combination; Sustiva, which is efavirenz; and Reyataz, the brand name for atazanavir. And she knows she had what she describes as a period of, quote, “trouble” at some point when not all of the medications were what she describes as working for her. She can’t specifically remember which medications she was taking at the times of her trouble.

She’s currently fully suppressed on darunavir/cobicistat/FTC/TAF and has been suppressed for a good long while.

Chris, with her verbal history, you know, we’re going to look into the chart to add things into the conversation—a couple of the things that we would want to pull out would be genotypes, and as you already mentioned, viral loads. I tend to also try to look at prescription records if those are available, even if clinic notes are not.

Are there other things that you would look at?

Chris:
That’s certainly the starting point. You’re way better than I am in terms of delving into the prescription records. Often I stop with that verbal history. However, the more information on what people were on in the past, the better for sure.

We’re at another of these 7 questions that I go through, and that’s the resistance testing results, if they’re available. Often if they were done in another health system or some years ago, they may have never been provided electronically and may be lost from our access. But either asking the patient sometimes or delving through the records, whatever is available.

CD4 and viral load history, certainly helpful, especially as I mentioned for an NRTI consideration.

That’s really what I would be focused on at this point in working through what we can consider for agents for her to switch to.

Eileen:
Well, I do love looking at records. I don’t know whether that means that I missed my calling as either a detective or a librarian, but I just love going through old things and finding little bits of information.

For this case, we’ll imagine that with our deep dive, we find a few scattered records, including a genotype that was done in between 2 prescription records for efavirenz plus FTC and TDF, and starting atazanavir/ritonavir with FTC/TDF.

On review of the virologic data, while she was on the efavirenz-based regimen, she had suppressed viral loads until a few detectable viral loads in the range of 3,000 to 4,000 copies and one up at 50,000 copies/mL. At that point, she re-engages in care after about a 6-month hiatus from visits and has a genotype done.

Just to reset this—she’s in between her efavirenz/F/TDF and the start of atazanavir/ritonavir/FTC/TDF. She’s been not seen for about 6 months, had a low-level viremia—not low-level, had a mid-level viremia in the 3,000 to 4,000 range—and then a viral load of 50,000, at which time she has a genotype. The results of that genotype are notable for a K103N, and she was then started on the atazanavir/ritonavir/FTC/TAF, and achieved full viral suppression.

Chris, I’m going to ask you to comment. What’s your interpretation of this genotype and, what features are you thinking about in the context of our treatment history?

Chris:
This is a lot of great information, and I wish I was so lucky to always have this amount of information when I’m considering regimen switches for my patients.

Number 1 is that she was on a failing efavirenz-based regimen for some period of time. As you mentioned, she had several viral loads that were in this mid-level of 3,000 to 4,000 copies, suggesting some amount of viral suppression, but not enough to fully suppress and just enough to lead to resistance, which we saw on her genotyping. And I’ll get to that in just a moment.

Then we have this viral load of 50,000, which seems to be completely off of treatment, which is helpful to understand what her set point may be or may have been, which is helpful because it’s less than the 100,000 cut off for using an agent like rilpivirine.

It’s great that she re-engaged with care and sounds like she, based on the records, may have been doing okay on the boosted atazanavir. Now if we get to the genotypic resistance testing with the K103N, that causes high level resistance to efavirenz which she was on at the time or prior to the resistance testing, but during a period of partially suppressed viremia.

This mutation can appear within weeks of no longer having suppressed viremia and is especially common due to the extended tail of efavirenz. Tail is something we talk about these days more in terms of long-acting injectable antiretroviral agents, but just as a reminder, efavirenz has a very long half-life, depends a little bit on the metabolism status of the individual taking the efavirenz, but often around 2 to 3 weeks of basically monotherapy with efavirenz. If somebody was on efavirenz, TDF and FTC during that time, the chance that resistance will develop is extremely high. So no surprise that our patient here has high level resistance to efavirenz with the K103N.

In terms of the rest of the interpretation of this genotype, just because we don’t see other mutations doesn’t mean that they’re not there. She has some risk for having the M184V because she was on lamivudine or emtricitabine during the time of failure on the efavirenz.

Finally, she’s also at some risk for the K65R for resistance to tenofovir or TAF. However, this takes longer to emerge, and it’s my guess that she probably wasn’t on a failing efavirenz/TDF/FTC regimen long enough for K65R. That’s how I would interpret the genotypic resistance tests. We know that she has archived K103N. She may or may not have the M184V and probably doesn’t have the K65R.

Eileen:
Thank you for that detailed discussion. the points that you made there are exactly those that I always use in considering a genotype—what was the drug exposure at the time of the genotype? Here there was none. She had stopped her treatment in between the efavirenz and the atazanavir. So no pressure to maintain a mutation.

Back when we used efavirenz as the backbone of most regimens, that was the rationale behind initial genotypes because there’s a relatively high rate of transmission of that mutation when present in the donor, which means that recipient individuals would be resistant to efavirenz-based treatment. So I agree. We know what we had on the circulation. We know that efavirenz is out.

We think there’s a possibility she had some other background mutation, but it wasn’t present at high levels, in part because of the timing of our testing. We also know that once she started the atazanavir/ritonavir and FTC/TDF, she achieved viral suppression again, which is great. She, again, continued on that for a while.

She had a kidney stone, and those who trained in the era when atazanavir was used more frequently will know that one of the idiosyncratic side effects of atazanavir is actually crystallization in the urine and atazanavir-induced stones. It wasn’t clear that that’s what she had actually or whether she had more standard kidney stones, but she was switched to a darunavir-based regimen at that time and has continued on that, first as separate pills, but now in the combined regimen, maintaining her viral suppression.

As you mentioned, she wasn’t on the failing efavirenz-based regimen for very long. We don’t have a lot of details about how she responded to earlier generation therapeutics. She did mention being on AZT and 3TC in the past, but again, those didn’t show up on her prevalent genotype, although most of those resistance-associated mutations would be selected against.

Now we have, as you’ve laid out for us, a mandate to try to find a simpler regimen. We have some resistance known about that will restrict us a little bit in what agents we could choose, and we have some unknowns about other potential resistance associations.

I’ll mention that if you have documentation of viral suppression continuously, it doesn’t matter really what regimens you’ve been on before. You can feel confident that there has not been selection of resistance. If they have a baseline genotype, full viral suppression, and you can document that over time. Even in the absence of any additional genotypic data, you can feel confident that they haven’t selected resistance. What we know about resistance is that that does not usually happen in the absence of virologic failure.

Now let’s talk about potential alternative therapeutic options, keeping front of mind our concerns about eliminating boosters and this question, how did you describe it? It’s [an] interesting description of evolving renal function.

What I was trying to evoke with that description is those patients, as they get a little bit older, have decreasing muscle mass, and you start to be a little concerned that smaller changes in their creatinine might represent more significant changes in their GFR. When you’re monitoring their renal function over time, you really just want to take off the table the possibility of your antiretrovirals causing renal damage or masking renal damage by having a bump in the creatinine through inhibition of secretion. You’re just trying to clear the decks and let the renal function be separate and not a concern as you consider their antiretroviral therapy.

A bit of a tall ask, but actually we do have a lot of tools that allow that these days. what are you going to suggest, Chris?

Chris:
First, the updated information you’ve provided is really very positive for her future success. That is, long-term past viral suppression is somewhat predictive of future success on current regimen or new regimen. Her long-term suppression both on boosted atazanavir combined with FTC and TDF, and more recently with boosted darunavir combined with FTC and TAF, doesn’t really add a whole lot of information in terms of her underlying HIV drug resistance, except that we can pretty much assume that she does not have resistance to protease inhibitors.

But getting to questions about a new regimen, a couple things to comment on in terms of the kidney function. One is the regimen she’s on right now is relatively safe in terms of kidney disease or causing a worsening in GFR. The cobicistat component can cause a physiologic increase in creatinine. if we stop that, as I think we should, given her need for a DOAC, that may actually lead to a slight improvement in her creatinine or a slight decrease in her creatinine and improvement in her calculated GFR.

So we have now 2 main medical considerations for selecting a new regimen. One is to avoid a drug-drug interaction with the DOAC, and the other is to minimize any future risk of worsening kidney function. Her current regimen is relatively safe from a kidney function, but there’s lots of opportunities for other regimens that will be equally safe or safer. An INSTI regimen is safe from both a renal perspective as well as a drug-drug interaction perspective, and the direction I would be leaning for her right now. It avoids any concern for NRTI resistance that she has, including the K103N, and also provides a regimen that is potent and has a high barrier to resistance.

Eileen, what are your thoughts in terms of a new regimen for her?

Eileen:
There are several potential alternatives. I agree with you that switching to an anchor drug of an INSTI is the way I would be leaning. There’s no reason why we would expect her to have any INSTI resistance. She has no prior exposure and wouldn’t have had transmitted resistance at the time she acquired it 20 years ago. We didn’t have integrase inhibitors. So we can feel like we’re on really solid ground there.

As you mentioned, we know she has efavirenz-based resistance, but no evidence of resistance to rilpivirine and no recent exposures that would have suggested that would have been induced, so I would be thinking about a couple different possibilities.

She is a switch, so one possibility would be dolutegravir/rilpivirine in a combined oral pill. Another possibility would be Biktarvy. From the perspective of thinking about her renal function, we know that TAF is much safer than TDF, and there is data to support its use going down to quite low renal function and then once on dialysis. There’s a narrow window for which it’s generally a little bit more tricky to use when a GFR is quite low but not yet at dialysis levels. But that is not where she’s at right now. So we could consider that.

We could consider dolutegravir plus F/TAF. And we could also consider cabotegravir/rilpivirine. That would be the injectable medication given once a month or once every two months, FDA approval for both of those dosing schedules. And in general, the requirements for that are that you don’t have any pre-existing evidence of resistance to the components.

Now, one possibility here would be to consider doing additional testing to feel more secure in our therapeutic choice. One option you would have would be to do proviral genotyping. Would that be something you would consider in a patient at this juncture?

Chris:
I like all the alternatives you just suggested, Eileen. I probably would prioritize an INSTI, although she probably would do okay on rilpivirine/TAF/ FTC. Biktarvy would be a good option for her. Dolutegravir and rilpivirine also a very reasonable option. I may even consider dolutegravir plus lamivudine. It does reduce any concern of having any tenofovir product in terms of her evolving kidney function and should work well in terms of her prior test history.

I don’t think additional testing is needed, but should she have a high interest for long-acting antiretroviral therapy, that is injectable cabotegravir and rilpivirine, I would certainly consider obtaining proviral DNA testing just to have added reassurance that she does not have any underlying NNRTI resistance that could compromise cabotegravir and rilpivirine.

Eileen:
there’s lots of options here. I like the introduction of the dolutegravir/3TC. There is some debate about whether or not to consider that if there’s any possibility of an M184V in the history, and that is one of those choices that can be quite specific to the particular case.

I also love the question of proviral genotyping. As you mentioned, there’s some data to suggest that proviral genotyping may be predictive of response in combination with or non-response in combination with other factors that may predispose to trouble specifically for cabotegravir/rilpivirine. We’re not really very strong on data using proviral genotyping to predict the response to other regimens. (I think we should probably do a podcast on that one in the future and how and when to consider doing proviral genotyping, how it’s different from regular genotyping and what the choices would be.)

In this particular case, let’s imagine that we settled on dolutegravir/rilpivirine and made the switch for her and that she did great. Of course, we have to remind her that she has to take dolutegravir/rilpivirine with a full meal, aiming for about 450 calories. And of course, although we didn’t mention it, we did check her hepatitis B serologies and confirm that she’s hep B immune and would not have any additional risk by switching off of the FTC and TDF, which were providing hepatitis coverage. Again, those 2 notes for dolutegravir/rilpivirine only approved for switch therapy.

The patient’s already suppressed prior to using it. Consider the fact that rilpivirine does require a full meal for absorption. And also remember to check your hepatitis B status whenever you’re taking someone off of hepatitis B active medications. Any other thoughts, Chris, to close this out?

Chris:
Yeah, I can bring this back around to the drug-drug interactions, always have to think about those. She is of the age where a provider may be talking to her about osteoporosis, or she may be taking her own initiative to add calcium supplementation, and just to be reminded that she needs to avoid taking the calcium at the same time as the dolutegravir/rilpivirine.

Eileen:
What a great point and also, you know, maybe adds fuel to our fire of eliminating tenofovir, which despite all of its many, many benefits does have some impact on bone density. And if that becomes a primary concern, looking for ways to not use it while maintaining viral suppression is certainly a reasonable thing to do.

Chris:
Thanks for this case, Eileen, I thank all the listeners so much for your time and attention.

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.