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 Hoffmann, and I’m here with my friend and colleague Eileen Scully. Today, we’ll be presenting another case of HIV clinical management.

Eileen, what do you have for us today?

Dr. Eileen Scully:
Hi, Chris. It’s great to be here. Today I thought I would challenge us. We have a 56-year-old gentleman with a history of atrial fibrillation, poorly controlled diabetes, and HIV, who has longstanding challenges with adherence to medications, and comes in for a routine visit.

Before this visit, he had screening labs notable for an estimated GFR of about 65, normal complete blood count, and liver function tests. He had an HIV viral load of 7,500 copies per mil, and a CD4 count of 240.

He reports that he struggles with side effects from his medications, and in particular, he feels that those are worse with the medications that he takes for his HIV. His HIV history is notable for a diagnosis initially more than 25 years ago. He does have a nadir CD4 count of less than 200. He has had some opportunistic infections in the past, including oral thrush, but none that have left significant consequences for him.

We have limited records of his care, but there are some periods during which he was incarcerated, during which he had high adherence to medications and achieved viral suppression. And then many other periods where there’s what I would describe as spotty records. So you have a viral load here, a presentation to the emergency room there, but not consistent care.

He’s had long exposures, at least based on his prescription history, to both dolutegravir/abacavir/3TC as a single pill combination and also to bictegravir/emtricitabine/tenofovir alafenamide. He has not had full viral suppression over the past 5 years despite active prescriptions for those medications.

So Chris, we’ll start off here. You just got this case synopsis, and you know, this patient doesn’t actually exist, but many similar ones do. You’re walking into the room. What other data do you want to hear about, and what other things do you want to learn from the patient?

Chris:
Great case, interesting, and a common presentation, Eileen.

Number one in my questions is whether he has intermittent low-level viremia, which we’ve discussed on a previous podcast, or if this is virologic failure, either because of adherence challenges or because of HIV drug resistance. Some lab work would be very helpful to sort that out. Getting more records is something we often want but are unable to obtain, but any previous HIV drug resistance testing, genotyping, or proviral DNA analysis would be also helpful. And ideally, a list of some other regimens beyond his most recent integrase strand transfer inhibitor or INSTI-based regimens would be helpful.

Eileen:
When I approach a case like this, I do it very similarly. One question I always have when someone comes in with a non-suppressed viral load is what their actual set-point viral load is.

As we’ve discussed before, the set-point viral load from the research-based definition is where your HIV viral load settles out after the period of acute infection, when you’ve settled into chronic infection, and represents a combination of factors, including both your virus and your immune response, and can range in number.

Some people can have what we would call a low set-point viral load, less than 10,000 copies, and some people have very high set-point viral loads, greater than 100,000 copies. In general, women tend to have a slightly lower set-point viral load, about 1.5 log lower than men, but they still progress to AIDS or advanced HIV at the same rate. An individual’s set-point viral load is where they land in the absence of any exposure to medication.

We don’t know if his set-point viral load is 7,500 or in that range, or if that indicates that he’s been taking intermittent medications. That’s one of the key features we always want to sort out when someone comes in with non-suppressed viremia—is this under the pressure of medications, or is it totally unpressured? That’s one detail I’d be looking for.

He’s also opened up a little bit about some of his barriers to adherence, particularly the adverse effects that he attributes to these medications.

To fill in some more of the details that you specifically asked for, we do have a history of viremia greater than one million on several occasions over the last 5 to 10 years. That indicates that this is not likely to be his set-point. Rather, he’s got a much higher set-point viral load without treatment. The million is probably in the setting of an acute illness or some other provoking factor, but it’s not likely that his set-point in between those episodes is as low as 7,500. So we can presume that he’s likely been taking some medications, just not enough.

He also reports multiple different types of adverse effects when you explore that a little bit with him. Examples of this include dizziness with protease inhibitors, which he feels very strongly that he wants to avoid. You also asked for details about his prior regimens, and I can summarize that by going by class. So he’s got more than 20 years of HIV experience. He’s had broad exposure to the nucleoside reverse transcriptase inhibitor class, including abacavir, lamivudine, and emtricitabine/tenofovir, both disoproxil and alafenamide formulations, and also zidovudine back in the day.

He also has exposures to non-nucleoside reverse transcriptase inhibitors, including both efavirenz and etravirine and doravirine. Although the latter, he only had about 1 month of a prescription, and then that was canceled because it was not covered by insurance. That’s occurred in the last few years.

As far as protease inhibitors, he had lopinavir/ritonavir in the distant past, and more recently has been prescribed darunavir a few times in the last few years as providers have attempted to find a regimen that is palatable to him and also effective. Although, as I mentioned earlier, he does feel like that is associated with dizziness.

And as far as INSTI or integrase strand transfer inhibitor exposure, he’s had raltegravir in the past and more recently has been prescribed, as I mentioned, bictegravir and dolutegravir.

So anything that’s sticking out to you from those prior regimens, Chris?

Chris:
First, I agree that this is possibly treatment failure given the viral load of 7,500. And you mentioned some viral loads in the millions, which makes a strong case for the fact that he is getting some drug exposure that is partially suppressing his viral load. Either he is intermittently taking the medications and has low drug concentrations, causing incomplete suppression, or he has HIV drug resistance.

One of the big questions I would have after now understanding some of his side effects and concerns with medications is getting a sense of missed doses—how well he’s been able to adhere, whether for insurance reasons, side effect reasons, or other reasons, to get a better sense of whether this is simply inadequate exposure to drugs or emergent HIV drug resistance.

Eileen:
We did talk a bit more about his medications and how he uses them. He reports that another recent adverse effect he attributed to his HIV medications was sleepiness with the bictegravir/emtricitabine/tenofovir alafenamide. He was concerned about this and felt that maybe the medication was too strong for his body.

That’s the kind of thing that a number of patients have said to me over the years, being concerned about the dose or the milligram quantity. I do spend a good amount of time talking to patients about how the dose itself isn’t necessarily the most important thing to consider because that’s based on chemical structure and other things. It’s really discussing with your doctor what the right medication is for you. But in this case, let’s imagine that his choice, with that idea in mind, is that he was taking a half a pill every other day, so definitely getting subtherapeutic doses and getting them regularly. So what is this to you at this point?

Chris:
A few things. One is that he has, for whatever reason, somewhat limited understanding, perhaps hasn’t had you as a provider to go through the nuances of drug levels so that he has a better understanding of that, which also may reflect his prior use of antiretroviral therapy during his 20-plus years of being on antiretroviral therapy. Given the variety of agents he’s been on, some stopped possibly because of side effects, one because of insurance coverage. Others may have been stopped because of concerns about treatment failure, which puts him at very high risk for HIV drug resistance to a variety of agents, including the NRTIs and NNRTIs, as well as INSTIs, and potentially protease inhibitors as well. Designing another regimen will need to take into account the side effects he’s had, concerns he’s had, tolerability for him, but also all the drug resistance data that we can assemble.

Eileen:
I agree, Chris. I love the way you pulled out that there are multiple factors. There’s at least one example of insurance coverage leading to discontinuation of a medication. There’s also his report of adverse effects. And we haven’t explored how hard it is for him to take medications daily. But I think the point here is exactly that for most people—it’s not only one thing.

If you are predisposed to have a challenge with medication and then there’s an insurance challenge on top of it, that’s going to be a toxic combination in terms of getting medications to the body. So thinking about all of these things together becomes really important.

One other point to mention is that we often use refill history to give us a surrogate of adherence to medications. But to be mindful that this can sometimes appear that someone is regularly taking their medications, in particular, if there’s automated pharmacy delivery of pills to the home. I’ve had individuals come into the office before with bags and bags of medications because they haven’t been actually taking them, but the pharmacy is reliably delivering them. So that can be a tool where if an individual has to go to the pharmacy to get their meds, can helpfully show us when they are unable to do that. There are certain situations in which that refill history is not very reliable. The devil is in the details, and finding out how people receive their medications, when they take it, and what their barriers are is really how we’re going to be able to move things forward and craft a therapeutic plan that the patient can work with, and we all get the result we want, which is viral suppression and better health.

We repeat labs at this visit, and we get a genotype, which I know you’re excited to hear about. And the results are notable for the following: In the reverse transcriptase, we have mutations impacting the nucleoside reverse transcriptase inhibitors, or NRTIs, that include an M184V. For the non-nuc reverse transcriptase inhibitor class, we have a K103N. For the protease inhibitors, we have an A71T. And then for the INSTs or integrase strand transfer inhibitors, we have a T97A, an E138K, and a Q148H.

We also sent a Trofile on this virus, which tests for maraviroc susceptibility, and that shows us dual mixed virus.

So Chris, before we go through an interpretation of the genotype, can you describe how you approach a genotype and where you go to interpret patterns or to look up these mutations when you’re providing care in the office?

Chris:
So number one, the genotype reflects most accurately resistance to what a patient is currently on. As we’ve already described, this gentleman is at high risk for resistance to his current regimen, given subtherapeutic dosing over a period of time. He could have other drug resistance related to agents that he was on previously that are less fit and are no longer being identified through consensus sanger sequencing. So that’s the number one thing. We know that he has the resistance mutations that you’ve described, but there may possibly be additional ones, and I’ll just go through those in a moment.

The second thing is, I used to have many of these, or pretty much all of them, in prior years. But with so much of HIV care not focused on resistance mutations and such complex care as this gentleman needs, I now always turn to web-based help for this, including the Stanford HIV Drug Resistance Database and HIVassist.org, which provide great interpretation of the mutations, including fold change of IC and also guidance of which regimens are most likely to be effective.

Eileen:
Chris, those resources are perfect. And just in case any listeners don’t do HIV care all the time, let’s walk through very quickly what the genotype tells you.

The M184V, for example, refers to a change from a methionine, which is an amino acid in a protein, at position 184 to a valine. So they’re not that complex, or they can look kind of like hieroglyphics. It’s just telling you that a part of the protein is changed based on a genetic change in the virus, and that change has occurred because the mutated version does better against the antiretroviral agent to which it is resistant.

You mentioned that fold change and inhibitory concentration, or IC50, are among the measures that we use. What that means is if you were to take this virus and grow it, and then put the medication in the same well with it, how much less would you get of the virus, so showing us if we’re able to inhibit the replication of the virus in the presence of drug. And every time you get a mutation, the drug works a little bit less well. At some point, the drug doesn’t matter anymore. The virus is replicating at 100 % and moving on as if nothing were happening, and that’s when we have full resistance. Changes in the virus proteins allow it to function even when the drug is there, and in some cases, they completely eliminate the effect of the drug, and in other cases, they just reduce it. That’s why sometimes when we see a mutation, we no longer would choose the drug, and sometimes we would still use the drug, but know that it’s not working quite as well, that there’s been a reduction in the efficacy of the medication.

Now maybe you can take us through what the mutations in this particular patient mean to you.

Chris:
So first with the M184V—complete resistance to lamivudine and emtricitabine. Again, he may have some other NRTI mutations from prior regimens, but probably not to tenofovir, which he is currently on. He’s on tenofovir alafenamide, I believe, with his current regimen.

Then, going on to the NNRTIs, he has the K103N, which leads to pretty much complete resistance to efavirenz and nevirapine, but not resistance to etravirine, doravirine, or rilpivirine.

Moving on to the PI and INSTI mutations—here, some of the online resources can be very helpful because very few mutations cause total resistance to modern PIs or modern integrase strand transfer inhibitors, but a number of mutations or a specific combination of mutations can. Even then, there may be some partial activity that can still lead to benefit in a drug regimen for these agents. For the protease inhibitors, the A71T is from prior lopinavir exposure, but shouldn’t affect susceptibility to darunavir.

For the INSTIs, he has a number of mutations that demonstrate prior exposure to either raltegravir or elvitegravir. Specifically, the T97A, E138K, and Q148H are a combination that can be caused by exposure or inadequate exposure to those INSTIs. Rarely does resistance occur with darunavir or bictegravir. However, when there’s already one or more resistance mutations from prior generations of INSTI exposure, like raltegravir/elvitegravir, then resistance mutations can progress. That said, he has complete resistance to raltegravir and elvitegravir and substantially reduced susceptibility to dolutegravir and bictegravir as well as cabotegravir. There are still potential benefits from use of INSTIs for him, although given his overall resistance pattern, he likely has a superior regimen that could be developed.

Then, finally, in terms of the Trofile, you already mentioned that he has the dual mixed virus, which means maraviroc will have no benefit for him in a regimen.

Eileen:
Thanks for that masterful interpretation. I completely agree. As many of us use the Stanford resistance database, as you mentioned earlier (and we’ll link to that website in the show notes), that’s a great place to go for resources about mutations. I would caution people, though, that for, in particular, complex patterns, like for integrase inhibitors strand transfer resistance, you need to look not just at the chart at the top, but to scroll down to the mutations here because, for example, the Q148H on its own causes a loss of susceptibility in the range of 2- to 5- or 2- to 10-fold for dolutegravir and bictegravir. But the combination of all 3 of these mutations that are present, which includes also the E138K and the polymorphism or accessory mutation T97A, reduces the susceptibility to dolutegravir and bictegravir by greater than 10-fold. That’s a substantial increase in the amount of resistance you have to think about, and if you just look at the chart at the top, you might not pick up on that subtlety of how these mutations can interact with each other.

As you mentioned, fortunately, this is uncommon. So resistance to dolutegravir and bictegravir is not something we see routinely in practice, and many of the mutations that emerge from prior exposure to raltegravir and elvitegravir don’t actually substantially reduce the efficacy of our most modern generation, bictegravir and dolutegravir.

Unfortunately for this individual, he has the hit of the prior exposure to raltegravir without full adherence, likely led to some resistance, and then the more recent continued exposure to subtherapeutic doses to the optimal agents we have now, and even they’re not perfect. If you take them with enough frequency to have drug around, but not suppress replication, it is possible to develop resistance, and that is what has happened in this hypothetical case.

You mentioned that the A71T doesn’t have much in the way of implications for darunavir, which is true. He has had exposure to darunavir over the last several years, presumably in a similar pattern to what he’s doing currently, because that does seem to be a consistent story that he tells, that he in general titrates his medications, trying to find the right level of what he feels is right for his body. This is a nice case to see that darunavir is quite resistant to the emergence of mutations. And so with those short exposures, even with subtherapeutic levels, he managed to not get substantial resistance.

I agree with you that this is going to make developing a regimen for him quite challenging. And while we might not be able to come up with a perfect one in this discussion, I thought maybe we could spend the rest of the time talking about how we might build a regimen that would work with the patient in terms of thinking about what will be best for him and how he takes medications and what his concerns are, and also how we might employ novel agents in this case.

In theory, you could give this individual or someone like him a darunavir-based regimen, and he would likely achieve viral suppression if he was able to take it every day. If he tells you, or a patient, any patient says, “I am not going to take that medication,” then you are at an impasse. You may know intellectually that medication will work, but medications that don’t enter the body don’t cause viral suppression. So we have to work with patients.

I do think it’s important to warn people and to say, “you know, we do have this available, and if you’re willing to work with me, we could try it again for a short period, see if something has changed in the way your body handles this medication, maybe other medicines you were on in the past you’re not on anymore, but can we make one more good-faith attempt?” If the patient is willing to engage in that, I think it’s a great idea to go ahead because we have so much data on that.

I say that because, as we talk about these novel agents that are available now, they are transformative for patients who need them, but we should be mindful of the fact that they’re studied in relatively small groups of individuals, and we have nowhere near the level of data and understanding of how they work as compared to our more established agents. It’s incumbent on us as providers to discuss that clearly, to say we have the most evidence for this one, and are you sure that we really can’t do it again? But then always being respectful of patients’ limitations, and also the fact that you know what, people are individuals and they do respond to medications differently, and it’s possible that he does have a side effect. And that is a real experience that we should validate.

So why don’t we talk a little bit about novel agents, quote unquote, that we might use. These are salvage or second-line types of options, not the ones that come up in your first-line treatment recommendations. We can start with injectable agents. As you know, many people might have already thought for a case like this, one great way to get around a problem with daily adherence is to switch to something that doesn’t require it. And so, cabotegravir/rilpivirine, available as either once a month or once every 2 months, injectable therapeutic, would be an attractive option for that reason. However, his amount of insidious resistance takes that off the table. So, unfortunately for this individual, that’s not going to be our easy solution.

So let’s talk about some of the “newer kids on the block” in terms of novel agents that can be used. We’ll start with fostemsavir. This is an entry inhibitor, binds to GP120 and prevents attachment to the CD4 binding site. It’s indicated for individuals that are heavily treatment-experienced with multidrug-resistant HIV and is dosed twice a day.

The evidence for this comes from about 200 patients. It had a good primary endpoint response of day 8 change from baseline HIV viral load. Relatively good side effect profile to about 10% nausea, 4% diarrhea and headache. Does have a few drug-drug interactions that should be checked, and no data in pregnancy or lactation, but no necessary adjustment for hepatic or renal issues.

Overall, that’s an entry inhibitor that has promise for individuals with multidrug resistance in combination with other background regimens. But it does require twice-a-day dosing. So a bit of a negative there for fostemsavir.

One of our other new kids on the block is ibalizumab. This is an intravenous medication. It’s an IgG4 antibody that binds to the CD4 cell and prevents a conformational change, so similar to fostemsavir in terms of mechanism in the conformational change prevention, but binding on the other side of the equation and prevents the virus from entering.

The FDA indication for this is for heavily treatment-experienced experienced with multidrug resistant HIV infection, defined as resistance to ART from 3 classes who are experiencing treatment failure on their current regimen. This is dosed with a single loading dose of 2 grams over 30 minutes, or now can be administered as a push over 90 seconds intravenously, and then maintenance doses that occur every 2 weeks, either over 15 minutes as an infusion or as a push over 30 seconds.

Again, well-tolerated—diarrhea was most common, up to 20 % of individuals. Some individuals with rash, nausea, headache, but generally well tolerated. There is some data about resistance emergence over time. But again, this is a medication for which you have documented evidence of adherence because the individual has to come in to get the infusion, or it has to be administered at home by a healthcare provider. So some benefit there of the directly-observed therapy, but also a major commitment on the part of patients to be in a healthcare setting or have a home care nurse every 2 weeks.

Our final new kid on the block from a therapeutic perspective is lenacapavir. We’ve mentioned this in the context of HIV pre-exposure prophylaxis. It’s also got an FDA indication for heavily treatment-experienced individuals with multidrug resistance who are failing their current antiretroviral therapy.

This is dosed with a subcutaneous injection and an oral load, and then followed by every-6-month injections after that. This had good results in its registrational trial, although I’ll mention quickly that it only included about 72 patients, some of whom were randomly assigned to receive lenacapavir plus their failing drug regimen for the first 14 days and then switched to an optimized background, and others who were immediately switched based on their viral load stability. So again, well tolerated—most common side effects are injection site reactions, which occur in up to 65% of patients. But it did provide an increase in virologic suppression and a clinically meaningful increase in CD4 count. There are some drug-drug interactions to be aware of here, directly acting oral anticoagulants, and those should be checked carefully before starting.

And then also it’s something to consider that the medication will persist in the body for more than 6 months, so you need to be pairing it with something that includes a regimen that is also being delivered during that time. So in this case, we would need to have a conversation about what oral medications we’re going to pair something like an injectable with. So any thoughts or experience from using those types of medications in your clinical practice?

Chris:
Great summary, Eileen. So each of these agents has a real advantage. Fostemsavir is the only agent in that class, very little drug resistance to it and very well tolerated, downside of twice daily dosing. Lenacapavir very nice because every-6-month injections, but it does require pairing with other agents. And for him, those other agents would have to be daily oral agents. Or I guess it could be ibalizumab, which, as you pointed out already, has the downside of an infusion every two weeks. There can be some insurance challenges with Ibalizumab and lenacapavir as well.

In summary of what could work for him, first, I would do just as you were suggesting, review again side effects he had and potential drug-drug interactions that may have been leading to that. I believe you mentioned he was concerned about dizziness with darunavir, which could have been from the ritonavir or cobicistat boosting if he was on an antihypertensive that was boosted with that, causing some dizziness. Or it could be from another reason.

You mentioned that he thought the INSTIs were causing daytime sleepiness. INSTIs are associated with insomnia, less so bictegravir, but other INSTIs more so. Sometimes I encourage patients to take them in the morning so they do not have insomnia at night. It could be insomnia causing poor sleep at night, leading to daytime somnolence. So, carefully reviewing those side effects or perceived side effects and then moving forward with a plan to try a regimen and immediately address any concerns or side effects, either by offering him the potential of switching regimens or addressing those side effects and seeing if there’s a drug-drug interaction or other modification that can be addressed to overcome that.

In terms of agents that could work based on his resistance, as we’ve already discussed, tenofovir alafenamide or disoproxil fumarate, should work. NNRTIs like etravirine or doravirine could work. In addition, darunavir boosted with cobicistat or ritonavir would also work. We know that maraviroc, INSTIs, 3TC, and other NRTIs like efavirenz or nevirapine will not work.

At this point, what I often do is go to hivassist.com and put in the resistance mutations, put in his comorbidities, and any key other medications that we’re concerned about drug-drug interactions with, and see what that resource provides at the top of the list, then go back to the patient and review again—side effects, daily versus twice daily dosing, and injection options.

Eileen:
I love your approach, Chris. These novel agents do have a place. They are probably not the first ones we would think about. The basic fundamental approaches of understanding the barriers for an individual patient and their biggest priorities and their care remain the bedrock of finding effective treatment. But I do hope that discussing these novel agents, putting out there how they’re administered, how they work, helps us to potentially use those when they can be added to other medications that we’re more familiar with.

Having more options and giving people more choice can offer us the opportunity to get those last few people who still have not achieved viral suppression over the line to our goals towards ending the epidemic and keeping the community viral load suppressed.

Chris:
And the first step is building that patient-provider relationship, as is being done with this patient and moving forward with that. He’s made the first step to come to the office, and now it’s up to his providers to engage with him and develop a plan that will work for him.

Thanks so much for our discussion today, Eileen. Very much appreciate it. And I also thank all of our 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.