Dr. Camille Kotton joins Sara to talk about refractory/resistant CMV and what she sees in the future for management of the troll of transplantation! 

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Hi everyone.

Welcome to Febrile, a cultured podcast about all things infectious disease.

We use consult questions to dive into ID clinical reasoning, diagnostics and anti-microbial management.

I am your host, Sara Dong, and I am a Med-Peds ID fellow.

I am joined here today by Dr.

Camille Kotton, who is the clinical director of the Transplant ID and Immunocompromised Host program at Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School.

She has previously served as chair of the ID Community of Practice of the American society of Transplantation, as well as president of the Transplant ID Section of The Transplantation Society.

Highlights of her time as president include development of the international guidelines on CMV management after solid organ transplantation.

Dr.

Cotton has also authored the past three versions of the AST travel medicine guidelines and has been an author of the CDC Yellow Book chapter on immunocompromised hosts and travel for the past decade.

Her clinical interests include vaccinations in transplant candidates and recipients, CMV, zoonoses and travel and tropical medicine and the transplant setting.

She is also a member of this CDC Advisory Committee on Immunization Practices and has been heavily involved in national decisions regarding COVID-19 vaccines.

Thanks for coming, Camille.

Great to be here with you.

I'm very excited that you're here.

Uh, before we jump in, we're doing our classic question as everyone's favorite cultured podcast, could you share some piece of culture that you've enjoyed recently?

I have really been, I think because of Peloton, I've really been enjoying music, um, again.

I feel I've been listening to so, so much science and medicine lately.

I've actually, this might be a little embarrassing, but taken to listening to Jackson Brown really loud in the car on my way to work.

And it's just awesome.

That's perfect.

That's exactly the kind of thing I hope people will answer with.

Today's consult question is actually building off of our last episode, where we talked about a 70 year old, uh, renal transplant patient who had abdominal pain and diarrhea related to CMV.

And so we're going to just adjust and build off of that case, but to refresh everyone's memory and to give you, uh, insight into the case, I'm still going to give you a little bit of background.

So this was a 70 year old male.

He had end-stage renal disease, secondary to hypertensive nephropathy, and had a deceased donor renal transplant about a year and a half ago.

He was CMV donor positive, recipient negative, and came in with about a month of fatigue, abdominal pain and diarrhea.

His maintenance immunosuppression is tacrolimus and mycophenolate.

So inpatient, he is started on IV ganciclovir, has some improvement in diarrhea and his first two viral loads for week one and week two are about the same.

They're 6.2 log.

And then 6.25 log.

He is on full dose ganciclovir, and the transplant team has decreased his immunosuppression slightly, but a team member calls you and says, "I'm worried, the first viral load hasn't significantly decreased."

and I think this is a question that we get a lot and I was hoping you could explain the timeframe and the anticipated response to antiviral therapy in cases like this of CMV disease in transplant patients.

Sure.

Well, this is kind of a classic case.

I will say this is somebody at significant risk of, major, CMV disease in that they were, um, donor CMV, donor positive, recipient negative.

Also the age of 70, um, you know, we're doing a lot more transplants and people in their 70s.

And we've learned a lot about the immune system, certainly with COVID-19 we've learned a lot about the immune system, And we see that also with CMV that older folks, D+R- also have trouble, um, clearing CMV.

And they seem to have worse CMV, somewhat anecdotal.

Um, but definitely something we see clinically.

And then the fact this person, it sounds like had a month of symptoms before they came in.

So the disease often seems to be pretty entrenched, you know, like significant and a little harder to eradicate in that setting.

This has, this topic of the viral load monitoring has come up with each version of the CMV guidelines.

And I have to say it.

The first CMV guidelines meeting, I had 40 odd experts in the room from all over the world.

And I was so excited.

Cause I thought maybe they could explain to me why we start with a specific viral load, and then one week out, we often either see the same number or sometimes even an increase.

Um, cause I thought they would be able to explain that to me.

So what we called it, was actually not viral load, but CMV DNAemia is actually the term that we should use.

And that's what we use in the guidelines.

And it actually helps to really understand why your numbers aren't coming down because all we're measuring is DNA in the bloodstream.

Like it doesn't reflect the live virus, dead virus, it's none of that.

It's just the amount of DNA in the bloodstream.

And you have to think that if you started treatment, maybe you lysed a bunch of cells.

You know, maybe there's a bunch of more dead CMV circulating.

So we often say that you can see a bump or at least not a fall at week one.

But usually, what we said in the guidelines, is by week two, you should see some type of decrease in the level of CMV DNAemia.

I have to say, I still sit, refer to it as far of a load because that's what we use colloquially.

But when you think about CMV DNAemia, it does make sense that your DNA levels don't just plummet with initiation of therapy.

I also think that when we use ganciclovir, we see a little longer, um, DNAemia.

Then I've noticed that when patients are on foscarnet, it seems to be, um, tough acting foscarnet and they seem to have a more, um, rapid decrease in their DNAemia.

Although that's not really a reason to use foscarnet because of the associated toxicities, but nonetheless, it is, um, something I've, I've sort of noticed over time.

So then I guess I would say back to you, so then what happened by week two of intravenous ganciclovir?

So at this point, the viral load goes to right around five log and kind of stays there for two, really the next two weeks.

And so the question of could this be resistant or refractory CMV disease comes to the forefront.

And, you know, this case is quite general, but I wanted us to pit stop first and say, how do we define what is refractory CMV, resistant CMV?

Because I think we have to be on the same page for the definition to be able to understand what's our threshold to test for resistance, and when do we need to change agents?

That is a great topic.

So, right.

So good job sort of not bringing it up at week one because, uh, no one thinks that at week one, we're going to be making the diagnosis of resistant refractory disease, but usually by week 2, 3, 4, you know, sort of heading into that area, by which time we should have seen a response in the level of DNAemia as well as a clinical response.

So that's where we should start to think of the clinical diagnosis of resistant/refractory disease.

And that is actually first and foremost, a clinical disease.

Like you, you know, you look at the patient, how have they responded to therapy?

Are they still having diarrhea?

Are they still having their CMV symptoms?

Um, one and then two has their, um, DNAemia not improved over time.

Um, or is it kind of more or less stayed stagnant and not decreased the way you hoped?

So it's interesting.

Um, the term resistant/refractory disease is actually I think a really nice one.

It's something that we developed, really kind of fleshed out, in a working group called the CMV Forum, which is a variety of different CMV experts come to the table.

And it's interesting because it's people from academics, clinical medicine, diagnostic companies, um, therapeutic companies, the FDA, the European agencies.

And so, everybody's sort of comes to the table and agrees on the terminology.

And the first part of the disease should be refractory.

And this patient has clinically refractory disease in that their level, their DNAemia hasn't fallen the way you liked.

Um, so they have clinically refractory disease.

And that actually encompasses a lot of people.

It is a time where we would recommend, as in the flow chart in the CMV guidelines that we've published, um, International CMV Guidelines, third version, Transplantation, 2018.

That we would recommend that you send resistance testing, which is sequencing of the usually UL 97 and UL 54 genes.

And then they may find a specific gene that suggests a certain level of resistance to ganciclovir, valganciclovir.

We don't recommend that with that initial week one high level, but then subsequently that's where we'd start to, recommend sequencing.

The sequencing can be pricey, so we don't just send it, um, kind of willy nilly, but, um, when it's indicated it certainly can help a lot.

And if they find a resistance gene, which, you know, I have kind of mixed success.

Sometimes I clearly have a patient who has clinically resistant against the disease to ganciclovir , but there's no resistance gene found.

And then sometimes they do find a gene.

I will say CMV is quite heterogeneous.

So that's one thing we often think of these as being very homogeneous, but there are, it obviously makes sense that it would be quite heterogeneous in the body.

So I think sometimes we just miss the capacity to make the diagnosis of resistant disease.

But when we do have resistance genes identified, I usually look up what the level of resistance is to ganciclovir.

I often use the publications by Sunwen Chou.

I look at the ratio of, um, the resistance mutation to, um, wild-type virus and see, you know, if it's a low level ganciclovir resistance situation, then I, then I would probably go on and try to use, um, higher dose ganciclovir and see if I can overcome that mutation.

For whatever reason, I always seem to hit the jackpot and get something that's really highly resistant to ganciclovir, at which point, sometimes I try high-dose ganciclovir, as I'm waiting for the resistance testing and come back.

But then I often don't have success with that.

And many of my patients until now have had to go onto foscarnet for treatment.

What you already did often, the things that we do, which is number one, reduce the immunosuppression.

I'll ask, can we reduce any further?

Cause that's really, CMV is really a disease of over immunosuppression.

And so one of the ways to get rid of CMV can be, you know, significantly reducing the immunosuppression.

Of course you don't want to lose the organ transplant or bone marrow transplant in the meantime, but that is a significant component.

Sometimes if they have like, hypogammaglobulinemia, I'll ask, like, could we replace their immunoglobulins with either IVIg or CMV immunoglobulin, which is really just IVIg that's enhanced for CMV highly positive donors, but those are sort of the basic things I do at that, at that juncture.

So in the scenario you're describing, send resistance testing and then contemplate-- what am I going to do as I wait for resistance testing to come back.

If they're sick, I would often , and by sick, I mean, life-threatening disease, sight threatening disease, you know, you're really kind of worried, this person looks pretty bad.

I would usually go with foscarnet.

And then if you're like, well, it just seems kind of mild to moderate.

Like not great, but not so bad.

Then I'll try the high dose ganciclovir, and that's usually 10 mg/kg IV Q12 hours.

We often give pretty close to that dose, but many of these people have reduced renal function, so then you can cut it back somewhat.

I have to say, I really, I personally don't have as much success with that, but that's what we often do as we're waiting for resistance testing to come back.

A common question we get is, oh, can't we just do all of that with valcyte.

But I think once you have resistant, you're suspicious of, resistant refractory disease.

That's a good time to go with intravenous ganciclovir.

You know exactly the dose being delivered.

You mentioned this person has diarrhea, maybe they have malabsorption, maybe there's something else going on.

So that's a good time to go with intravenous therapy if you are worried about resistant refractory disease.

And you've kind of touched on this as you go.

What are the key factors that you think the ID fellows and trainees need to think about when they're sort of weighing, in that early phase -- do we think that this is a patient that more likely is going to have refractory or resistant infection versus not?

Yeah, that's a good question.

So, you know, who gets resistant refractory disease?

So it is people on more significant immunosuppression.

So maybe there they are, what we call high immunologic risk.

Like maybe they're highly sensitized, kidney transplant recipients.

Maybe they had like an ANCA vasculitis and went into transplant already getting like rituximab and immunosuppression in the background and then got even more immunosuppression.

And you're already thinking like, oh, this is risky.

If they went into transplant on Bactrim prophylaxis, that's probably a marker of somebody who's going to have problems on the other side.

Um, you know, they went in on immunosuppression.

The D+R- population is almost exclusively, CMV donor positive, recipient negative population, is almost exclusively where we see resistant virus develop.

That's about 20% of transplants in the United States.

And then, so this patient, you, you mentioned the D+R- and the age also, um, I've had a variety of older folks develop resistant, refractory disease, and it's hard because then, you know, we'd been turning to foscarnet or, um, for a few years, we were enrolling in the maribavir trial, which was a phase two, or then phase three trial, looking at maribavir for resistant/ refractory disease and comparing it with standard of care, which was either high dose ganciclovir, foscarnet or cidofovir, you know, whatever investigator, um, choice was picked.

And I did have several patients in the maribavir arm, it's not a blinded trial in that they're either getting pills or intravenous therapy, so no blinding there.

I had people who did really, really well with, um, maribavir.

And then my last pit stop before we go on is, you know, you've mentioned some of the genetic testing or the resistance testing we're sending.

Can you give sort of a high-level overview of what that test is looking at?

So there are just a couple of commercial laboratories in the US.

Um, and if people are listening to this outside of the United States, I know that resistance testing can be hard to come by.

Some of the commercial labs in the United States will accept specimens from abroad, but that's just a little more challenging for the shipping and all of that, but it's not something that's readily available.

It's only done at a very small number of commercial labs.

And then basically they take the virus and they sequence it.

And then they're looking for the UL 97 and UL 54 genes.

Over 90% of initial mutations will be, with ganciclovir, will be in the UL 97 gene.

And then subsequently, um, some of these people actually go on and accumulate additional mutations, and those can be in the UL 54 gene.

And we are even doing additional sequencing, looking for maribavir resistance and then letermovir resistance now that we have both of those.

But the most common one and some programs for cost-savings just sequence UL 97 initially, because that's where you'll see the vast majority of resistance genes for ganciclovir.

Yeah.

So our patient ends up having a UL 97 mutation.

And what do you think on adjusting therapy for this patient?

Yeah, so I look at the mutation and it's a little tricky to figure out.

They don't actually spell out in the information they send to you, you know, like the ratio of mutant wild-type and what the likelihood of ganciclovir success would be.

So then I usually look it up in the Sunwen Chou papers, which I save in Dropbox and, um, do a lot of Ctrl+F there.

Um, although he has a really nice section in the CMV guidelines where he describes a lot of the mutations, but not necessarily like the level of resistance conveyed.

Um, and depending on the mutation that we find, if it's, you know, pretty highly resistant to ganciclovir that's usually, I would just switch to foscarnet.

Um, I will say that in December the FDA approved maribavir for use in resistant/ refractory disease.

So I haven't actually used it yet.

We are really fortunate in that we don't actually have such high rates of resistant/ refractory disease.

If I take a step back, one of the big ways to avoid getting resistant, refractory disease is always dosing ganciclovir correctly, the valcyte prophylaxis correctly.

And where I've heard of programs that have rates of 10 and 20% resistant/ refractory disease, it's usually because they haven't, uh, dosed ganciclovir or valcyte, um, post-transplant usually valcyte these days, valganciclovir, rather than intravenous ganciclovir.

And when they underdose valganciclovir, that's where you get resistance mutations.

So first and foremost, dose the prophylaxis correctly.

That is key.

I always say that's the Cardinal sin.

Some people cut the dose in half when they have leukopenia.

Well, they're not doing anybody any favors.

In that that really increases the risk of resistant/ refractory disease.

I always say, if you need to, if you have really bad leukopenia with valganciclovir post-transplant, hold the drug.

I would personally give like acyclovir or famvir, valacyclovir for disseminated zoster prophylaxis.

And then I would just do weekly monitoring for CMV, what we call preemptive therapy and just monitor weekly for 12 to 16 weeks.

And if they do develop CMV, treat, but, um, Yeah.

Um, so first and foremost, always dose your drugs correctly upfront, and you won't get to this problem situation.

I'm glad you brought that up because I was hoping we would circle back at some point if I could remember, about making sure we have appropriately dosed medication, both for prophylaxis, and you know, a lot of these patients have renal worsening, renal dysfunction because of whatever their end organ disease, so making sure that we, as the ID team keep on top of the dosing.

Right.

It can be really challenging in this population to know what their renal function is.

And, um, I hate to admit that I was listening to another podcast, um, of course, there's only this podcast, right, to listen to?

But you know, it's not like every day.

So I was listening to an Annals of Internal Medicine and they were going on and on about calculating the GFR.

Cystatin C can be an inflammatory marker.

And I was thinking, boy, this is why I have so much trouble as an infectious disease specialist to figure out the GFR, but you know, for not so much in pediatrics, but especially like some of our , kind of chronically ill adults, many lose a lot of muscle mass, you know, waiting for liver transplant, heart transplant, whatever it might be.

They lose a lot of muscle mass.

They, some can have like quite low GFR.

But their creatinine might be like one.

So you think like, oh, the Creatinine is one, you know, their GFR 70, we're good.

But actually there's a lot of other factors that go into that.

So it's really hard to figure out their true kidney function.

I always say the best, best, best way to prevent resistant/ refractory disease is dosing the Valcyte correctly, valganciclovir, ganciclovir correctly, either for prophylaxis or for treatment.

And I go, there's a table in the CMV guidelines, and I always say this table needs to be like followed perfectly.

And if you do, you stay out of the woods.

So what I was saying before, we see maybe one to two cases of resistant/ refractory disease per year at Mass General, fortunately.

So luckily we avoid it, but lately people that have come in have been in the, uh, phase three maribavir versus, um, investigator initiated treatment trials.

Now we do have this option of having maribavir, which you know, is pretty game-changing.

Um, that's exciting.

It is really exciting to have something new.

I mean, we've had several new anti CMV treatments come out.

Letermovir for prophylaxis in bone marrow transplant patients.

Not a therapeutic drug.

It's a prophylactic drug, has a really low barrier to resistance.

It takes just a few viral replication cycles to develop resistance to letermovir.

So, um, It's great to have maribavir.

It's an oral treatment.

Until now I was putting people in the hospital usually for two to three weeks on intravenous foscarnet with like labs twice a day, heavy, heavy.

It's so tough.

And you know, when you tell the patient what's going to happen.

Like, you know, you're gonna be here for two to three weeks, you're going to get your Mag [magnesium] and your Phos [phosphorus] and your K [potassium] repleted all the time and we're going to give it to you oral and IV and it's just, oh, and it's really kind of like a metabolic madness.

And then it's always a shame to be giving it to someone who's at a kidney transplant and then they have nephrotoxicity and you're kind of like wondering what you're doing and that you're potentially harming the kidney.

Although I will say that, so I never get outpatient foscarnet.

I just don't do it.

I don't feel that it's safe enough.

But inpatient I've had a really good experience giving foscarnet with respect to toxicity, heavy, heavy, heavy monitoring, following, you know, labs like twice a day until they're really in some kind of steady state, but it often is twice a day for two to three weeks.

Um, I've had a really good success but it's obviously a nightmare for the patient.

So all of a sudden we have a drug where basically, you know, go take these pills twice a day.

I'll see in clinic next week.

As long as they're clinically well, and can go home on.

Complete game changer, right?

Yeah.

Yeah.

I think as my other question, let's say this patient had a UL 54 and a UL 97.

Maybe they have a foscarnet mutation.

You know, how, how do we tackle that?

Obviously not a quick answer.

Yeah.

Well, and especially the more they get exposed to, uh, the more mutations they accumulate over time.

And we do have these devastating cases where they accumulate multiple mutations.

It's usually people who are profoundly immunocompromised.

We do see, I would say, every year I have like one or two cases of people who have just really, really, really refractory CMV.

They have like a decent absolute lymphocyte count.

They're not on that much immunosuppression.

And for the life of me, I cannot clear their CMV and it just keeps coming back.

So there are those people.

They, there are genetic factors that, um, we don't test for in a clinical scenario, but have been identified in research settings.

Um, and other issues such that some people really just keep having CMV and those are the people that get, that accumulate a bunch of mutations.

And some of them actually even pass away.

It's been pretty, pretty rare in recent times, but some people actually do pass away from like fully resistant CMV.

That's why it's important to manage them really, really, really well from the get go.

And I think really careful fastidious management.

That's why I'm proud of the CMV guidelines that we wrote in that, it kind of, is like if you kind of follow the rules and do really good management and really careful testing and whatnot, usually you don't end up in a pickle, but by the time when you do end up in a pickle, often it's hard to kind of crawl out of that mess.

Yeah, I agree.

And then I think there is a section in the guidelines on this, but the other question I was going to ask is using CMV specific immune monitoring.

Are you using that?

How are you using that?

Yes.

Um, so that's a great question and a sort of a hot topic.

So there are a couple of tests out there.

There's the QuantiFERON- CMV, which is sort of like QuantiFERON TB.

Um looking for, uh, you know, a T-cell response to CMV.

So that's not commercially available, but has been used in multiple research settings.

And it's really does, look, does look sort of promising, um, especially in CMV positive folks, um, determining either the length of prophylaxis or their risk of recurrent disease after the end of treatment.

Although, like I said, in the beginning, we never really worry that much about the seropositive folks to begin with.

So the fact that we now have a new diagnostic toy, sort of isn't really all that useful, cause it hasn't, hasn't been shown to really be helpful in the D+R- population.

There's another similar test called T-SPOT CMV which is like the T-SPOT TB.

Um, and I actually helped lead the largest trial in kidney transplant recipients.

And really what we wanted is to find for, especially for the D+R- population, how long do we need to give prophylaxis for?

Like, can we just get three months, six months, nine months, you know, is there a way of looking at the end of prophylaxis and saying, okay, you're all done.

You're not going to get CMV.

We're going to stop your prophylaxis, you know, month five, month eight, whatever it was.

But it's kind of a catch 22 because we're trying to use this immune monitoring tool for people who are not immune.

So it, it didn't work out.

It did work really well for the seropositive population so that we could know the optimal duration of prophylaxis for them, but we already knew that they were going to be pretty okay anyway.

So, I'm sort of like, why do we spend additional money on them when they weren't really the problem ones?

So unfortunately those two have not worked out so well for the D+R-.

, Viracor has, um, a CMV specific, uh, test.

But interestingly I think there's only one publication that's a really mixed population.

And basically we don't have published data on its use.

It is commercially available.

I know many people send it.

I often say like, what's the utility in sending it because often they have like highly resistant/ refractory disease or recurrent CMV.

And I say, I'm kind of, I was brought up sort of old school, um, and we were taught to not send tests that are expensive unless you absolutely need them.

But I would say like, Well, what do you think that patient's going to have?

And they're like, well, they're going to have not much immune response to CMV and I'm like, yeah, we knew, we knew that, like we knew that.

So, um, I think we need a lot more data on the testing that's being done at Viracor.

We're not actually allowed to send it through my hospital because of the lack of data.

Um, And so they don't want to pay for something for which we don't have really a known clinical outcome or that it's not really clinically useful.

Um, and as I mentioned, it's pretty expensive, so yeah, I sort of, that's the like, you know, mystique of CMV.

If we could have things that would predict the risk of infection/ recurrent infection with these diagnostics, that would be wonderful.

Maybe five to 10 years ago, I was really optimistic and now less optimistic.

One thing that would be great as if we had a good CMV vaccine.

Maybe then we could use an immune monitoring test so that we could know, like with vaccines, with or without prophylaxis, I mean, hopefully the vaccine so good we wouldn't need prophylaxis.

That would be awesome.

But if, if we did have the capacity to say, maybe do a hybrid approach, maybe those tests would be useful in that setting.

Moderna is starting, um, trials of CMV vaccines, uh, mRNA CMV vaccines in women of childbearing age.

And so I'm waiting in the wings and hopefully, they will do a similar study in transplant recipients eventually.

That's exciting.

I mean, that's a great segue, you know, I was going to end by asking you, what do you think is the most exciting thing that you're sort of on the lookout for, for CMV and transplant?

I think there's a ton of exciting things I feel like are constantly coming out, but anything in particular you want to highlight?

Yeah.

Well, um, I guess so we've looked for CMV vaccines for over 50 years, both for the congenital CMV space, as well as for immunosuppressed patients.

So I guess I'm cautiously optimistic that may be Moderna and others may have novel approaches to CMV vaccine development.

Unfortunately, it's been a lot harder.

We had a nice review with Stanley Plotkin recently of all the various approaches that were underway.

Um, City of Hope has an interesting, uh, vaccine largely for the stem cell population.

But there's sort of nothing that looks like, you know, huge on the horizon.

Um, but that, that would be wonderful.

I do want to mention there's some interesting stuff going on with CMV specific T-cells that are out there.

That's largely for like really refractory disease, but that's kind of interesting.

Um, and now that we finally have multiple therapeutic options, it'll be interesting to see if we might be able to come up with some cocktail approaches to decrease the risk of antiviral resistance development.

So that's something that's sort of in the future, but you do, you do wonder if combinations of various antivirals might help the specific patients or maybe with specific cases of resistant/ refractory disease.

Well, thank you so much for coming.

Any closing thoughts?

I'll leave it open one more time, but we covered a lot of topics that are both in the guidelines, but also thinking about these sort of that edge of what what's next and what we do in these complicated patients.

Yeah.

I think it's, it's a, it's a challenging field and I think it requires sort of a real understanding of a lot of different factors, which is kind of what we love in ID, right?

And sort of reading the tea leaves and, and careful interpretation.

I've certainly had the good fortune of working with, um, international experts on guideline development.

And I've learned a tremendous amount from them.

I'm happy to have emails and discussion and discuss cases, and I can introduce people to the right people to talk to if needed or whatever.

Cause it does take.

It it's more challenging than one than one might think it should be, especially maybe not 98% of the cases, but maybe like a lot of things in ID that, to those 2% of cases that are hard for us.

And then, you know, certainly feel welcome to call on your CMV friends, uh, for additional help.

Thanks to Camille for joining Febrile today and coming up next is a series about congenital infections.

And I cannot wait for you to hear these.

They're awesome.

So another plug for the Febrile survey, if you haven't filled it out yet.

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Don't forget to check out the website, febrile podcast.com to find our consult notes with links to references from the episode as well as our library of ID infographics.

Thanks for listening.