So we'll start with the introduction. My name is Roy Chemaly.

I'm the Professor of Medicine and the Chair of the Infectious Disease Department at MD Anderson Cancer Center in Houston, Texas. And I have with me Dr. Marcus Pereira, who's an Associate Professor of Medicine and the Director of the Clinical Services in the Division of Infectious Disease. And also, he is running the Transplant Infectious Disease program at Columbia University Irving Medical Center from New York.

Treatment of CMV in HCT Recipients

All right. So if your patient does reactivate, how do we treat CMV?

Treatment of CMVi in HCT Recipients: Limited Options

So you know, unfortunately we do have limited options for treatment of CMV, but they're not zero. First-line, as many of you will be aware, is ganciclovir and valganciclovir. This is a nucleoside analog. It inhibits the CMV DNA polymerase. It is - before it does that, it is phosphorylated by the viral kinase, UL97. Highly effective drug, but there are some important limitations to ganciclovir and valganciclovir.

The main one for our patient population is that about 20% to 60% of patients develop neutropenia. That is a significant number of patients and a significant side effect, and probably the reason why we never use valganciclovir for CMV prophylaxis in this patient population. Whereas in - in solid organ transplant patients, we do use valganciclovir.

There's also some caution with oral valganciclovir. If your patient doesn't have reliable oral absorption, for example, if they have severe GI GVHD, you probably do not want to use oral valganciclovir.

All right. So what's - what are the alternatives to ganciclovir? Is foscarnet. It's a pyrophosphate analog. It also inhibits the CMV DNA polymerase but this is directly. It does not need to be phosphorylated by the viral kinase. There are some also severe limitations with foscarnet, including high rates of renal dysfunction up to 60%, some of which don't recover and end up on dialysis, or at least with chronic kidney disease. So this is a serious limitation, serious toxicity.

There are also some changes in calcium and phosphorus metabolism and some neurotoxic effects. So it's not a very benign drug, very effective but very difficult to use drug.

Third-line and perhaps limited use. I haven't used this in a few years, is cidofovir. It’s a nucleotide analog. It inhibits CMV DNA polymerase as well. It's phosphorylated by cellular kinase. But just like foscarnet has very high rates of renal dysfunction. So also a pretty toxic complicated drug.

What is also important to - to - for everybody to be aware that although these - the drugs are available and can be used, you can prescribe, they are not recommended for CMV treatment. Letermovir, it's only approved for prophylaxis. In fact, actually there's a risk. There's a low barrier to resistance and there's high concern that you can lose that drug very quickly, in particular, the higher the viral load there is.

And maribavir, which is approved for resistance and - and refractory CMV only, Dr. Chemaly will talk a lot more about that drug coming up.

Treatment of CMVi in HCT Recipients: Considerations

Just some considerations on how we address and how we sort of manage that treatment. So we obviously monitor for symptoms and we monitor for the level of the viral load, right, with weekly CMV QNAT. It's important to understand that, you know, we should be using the same platform and the same specimen type, whether if you, you know, stick with plasma or stick with whole blood.

Don't go back and forth because there are extensive variations in how the results will be reported up to a log of difference. So you really want to stick to the same platform and the same lab, if possible.

You know, it's important to obviously monitor renal function and monitor other safety labs when you're using ganciclovir or foscarnet or cidofovir. And certainly for all of those medications, you want to adjust based on renal function. And perhaps to add here that, you know, what's not acceptable is to reduce the dose, for example, of ganciclovir based on leukopenia. You know, many providers or in the past providers would lower the dose of ganciclovir because their patient was developing leukopenia, and wanting to avoid that side effect will lower the dose, now setting up the risk for resistant or refractory CMV. So that's obviously an important caveat here.

Now the treatment, you know, what do you expect? It really takes a while for you to treat CMV and for the viral load to start coming down. In fact, actually, you shouldn't expect any major changes up to two weeks after initiating appropriate therapy. So it takes some time. And you really want to set up your patients for some patience here.

And the - and the treatment is individualized. So it really is based on the revolution - the resolution of symptoms and a negative QNAT on one to two consecutive measurements, whether those are weekly or - or the next week. You know, it really depends on the risk, but you do want to make sure that the viral load is undetectable before you stop treatment and consider secondary prophylaxis, which we're not going to talk about today.

CMV is my favorite virus, but make no mistake, CMV is not my friend.

And with that, I'm going to leave for Dr. Chemaly.

Dr. Chemaly: Thank you. Thank you. Major Advances in CMV Management Over 3 Decades

So - and there is - there were a few major advancements in the era of CMV over the past 20 to 30 years, I would say, coming to diagnosis. I don't know how many of you were practicing during the time where we used to do only shell vial culture versus antigenemia.

When I started around 23 years ago at MD Anderson, we did anti – CMV antigenemia for a few years until we moved to molecular testing. So I think molecular testing by, you know, doing PCR at least and having a quantitative viral load help us quite a bit. But at the same time, keep in mind we start to have more and more sensitive molecular assays, where what does it mean when you have very low viral load? Is it really reactivation or not? Or this is only background noise? So I want to caution you on that.

But of course it helps us to manage better our patient and to detect early on some CMV replication. But the other tool that we're trying really to define specifically its role in the - in - for CMV in the CMV is cellular-mediated immunity. You know, there is data, you know, out there published data on as a tool to predict CMV reactivation, but also how it can help us to decide if this patient need to be treated, if they have low level viremia.

I think this could be an area of research that we are conducting to see. What about stopping prophylaxis earlier when they have enough CMV, CMI or cellular-mediated immunity, or maybe prolonging prophylaxis when they don't - they lack the specific T cells for CMV. So there is a role for it. And we try to define - and we'll talk a little bit about it later on, how it made it to the guidelines as well. But stay tuned. We need more and more interventional study to show its impact.

I know in SOT patient population, they have a little bit more and a little bit better defined than us, but we need to work more on that. And the other advances for CMV first is letermovir for CMV prophylaxis. I think this has changed the whole paradigm of CMV and in a way that now these days CMV is not really that common, at least early on after transplant, if you're using CMV for prophylaxis.

We still see some breakthrough, if you want to call it breakthrough infections, but it's easy to treat. It's not really - it doesn't correlate with resistance to - to letermovir. But it can happen up to 18% in most of the studies and in the clinical trial as well again. But still it changed the whole paradigm. It shifted the paradigm of CMV, I would say, for CMV.

But now we have to deal with other complications of CMV, which is late CMV infection when you stop prophylaxis. So what's going to happen to this patient if they don't have enough CMV T-cell reconstitution, we need to keep an eye on this patient because they can still have serious CMV infection.

Now, the other drug, which was approved in 2021 to treat resistant and refractory CMV infection, which is maribavir. This is another era where you have very complicated patient after transplant where they have this refractory viral load still climbing or not budging, or someone with tissue invasive disease or CMV end-organ disease. And your alternative drug or second-line of pre-toxic drug which is foscarnet, cidofovir or other option alternative that we used to use.

Now we have at least a safer drug, oral option, which is maribavir. But how it position maribavir in our patient population when they have this infection?

And I will go over the recent guidelines how, you know, where we added maribavir to the guidelines at that point after its approval and how we - what - what are the recommendations in - in - in using it. So - but at least there's some good - you know, at least some headways, but still lots of unanswered questions when it comes to CMV. Still it happened. And what else we can do to better care for our patients after allotransplant at least.

GCV Treatment Is Associated with Neutropenia 

And - and we all know that ganciclovir treatment associated with neutropenia, but - and why this is important is not only because of neutropenia and losing the graft, which is very important for us, for you guys after transplant and for all of us. But the neutropenia is associated with bacteremia and invasive fungal disease. At the same time, lower overall survival or increase in non-relapse mortality by - by either neutropenia from ganciclovir or neutropenia as - as a virus can cause also myelosuppression by itself at the same time.

Foscarnet Therapy Is Associated With Nephrotoxicity

Foscarnet, same thing, nephrotoxicity. Well, what's bad about nephrotoxicity? Few studies showing actually, when you look at all-cause mortality that the main risk factor or main predictor, I would say, or independent predictor was renal dysfunction. Kidney dysfunction is associated with mortality, you know, when you have, you know, kidney dysfunction by itself from antiviral.

We did a few study a long time ago, and we saw this association.

Refractory/Resistant CMV

Okay. So let's talk a little bit about refractory and resistant CMV infection in this comp - in these complicated cases.

Refractory and Resistant CMV: New Definitions

First, we need to - you know, we knew that there were no standard definitions. What we - for refractory, especially for clinical trials. And when we start - you know, we need to develop new drugs to treat this condition. So how we define refractory, it was all over the place for a long time until we came up with a definition. And we updated recently the definition - the definition of refractory, where we - we - you know, where we – we - we put there that it is a CMV DNAemia that increases more than one log increase or it persists less than one log decrease after treatment. So it's not only increase in now viral load but also less than one log decrease.

So the efficacy is not there to reduce viral load after at least two weeks, you know, or at least two weeks of treatment with the right drug right route and the right dose at the same time. So I would caution don't jump the gun early. And we see it in our institution. Every institution where someone, you know, depends who you're running with, they could be more anxious than others. They don't want to wait. I sit here smiling and, you know, they call us said, let's wait a little bit. No, but we need to treat right away.

But give it some time, viral load by itself. You see, increased, you know, replication with, you know, increase in viral, different story. You know, you may start switching therapy earlier, but if it persists at the same level or went up a little bit, you know, over the, you know, two weeks give it a chance for ganciclovir to - or even foscarnet.

Now refractory CMV end-organ disease. Same thing. When you have signs and symptoms getting worse, not - but improving after two weeks of therapy in this patient population, then you may switch therapy and call it refractory.

Now when we talk about resistance, you have to have a genetic assay with mutation conferring resistance to any of these drugs. At least one, or if not more of this antiviral that we use for CMV.

Resistant and Refractory CMVi: Risks in HCT Recipients

So risk factors for resistant and refractory CMV infection, you know, usually happen after using antiviral for a couple of weeks, could be three, four, five weeks. It depends. Or you're using, you know, suboptimal dose for these antivirals and how - what - overall the risk is between zero to 10%. But you know, for - you know, if you look at refractory per se - and as I said before the era of letermovir, it could be up to 30% of all CMV reactivation and resistance usually is around 2%, 5%. So it's not that high when you check for mutations in this patient population.

Now, after the era of letermovir, we're the first one to show that even resistant/refractory went down, you know, resistant from 11% down to - to 3% in one of the studies that we conducted. When you prevent CMV, you have less chance for the virus to replicate and less chance for becoming refractory or resistant.

So prior antiviral drug exposure is very important risk factor, prolonged antiviral therapy, what we used to call maintenance also or lower the dose to keep patient to control CMV can put them at risk for resistant as well and recurrent CMV infection. Many others that you see listed here.

So refractory is much more common than resistant when - you know when you identify a mutation.

Identifying Resistant CMVi

And how we identify mutation? We talked about genotypic assays. You know, it is available.

You send it to a central lab.

And they look for mutation on either UL97, 54, 56, depends which drug you're suspecting resistance. If using ganciclovir, you go to UL97, foscarnet 54, and cidofovir as well. And letermovir, you have to ask for UL56 mutations. Be careful with the false positive to - to mix population with low viral load. When you have very low viral load, you can have some subpopulation with resistant some or not, but also false negative because of the sensitivity of the test to detect the subpopulation with resistance.

So you treat where they got better and then all of a sudden the viral load goes up because you selected for this mutant and you have, you know, now resistant virus as one.

Mutations Associated With Resistance

So we talked about UL97 mutations conferring resistance to ganciclovir. But now with maribavir also

the mechanism of action, which I'm going to go over it, it - you know, you have mutations on UL97 conferring resistance to maribavir. But two specific mutations keep in mind, C480F or F342Y. It is a - this mutation confers resistance to both, ganciclovir and maribavir, something that you keep in mind where you can't switch to maribavir if you have a C480F and patient on ganciclovir and vice versa.

UL54 for the three drugs listed here and 56 as we talked about, letermovir. And no cross-resistance between letermovir and the other drug that you see listed here.

Refractory CMV: Higher Risk for CMV Disease and Non-relapse Mortality

So why refractory is so important? Look at the burden of this infection. You have higher incidence of CMV disease but also increase in non-relapse mortality when you compare refractory to non-refractory CMV infection. And we did the same study, you know, that we hopefully will submit it for publication, we found the same thing. Impact on CMV disease, which is higher incidence, and also on non-relapse mortality in this patient population.

Treatment Options for Refractory/Resistant CMV

So what are the treatment options now these days? For UL97 mutation with high level resistance to ganciclovir, you have to switch. Don't go with high dose ganciclovir. You're going to cause more toxicities than - than, you know - than success in treating this patient.

We switched to either foscarnet or maribavir. This based on the recent guidelines we have the two choices depend on your situation. The patient can tolerate foscarnet or - or you can go to maribavir if you have good access to it.

Now, when you have low level resistant mutation for ganciclovir on the UL97, also either maribavir or foscarnet, but at the same time high-dose ganciclovir. I'm not sure how many will go to high-dose ganciclovir now these days, especially when we know myelosuppression is going to be pretty common in this patient population.

UL54 mutation, you cannot use foscarnet, especially the specific mutation for foscarnet. Then you go to ganciclovir or maribavir. But there is some mutations in the UL54 DNA polymerase conferring to either foscarnet and ganciclovir, or the three drugs as well, like cidofovir, not only foscarnet, ganciclovir, cidofovir, some mutations. This - at that point you have to go to maribavir and/or investigational agent, which is brinci, which I don't - I'm not sure - you know, hopefully, you know, it will be continue to be studied and investigated for CMV in the future, but stay tuned.

Now some UL97 mutations conferring resistance to maribavir you see listed here. Then you have to switch to other drug.

MD Anderson R/R CMV Infection Management Approach

What we do at - at our institution, you know, a patient being on valganciclovir, we switch - you know, so we have the algorithm. You go to either foscarnet or maribavir. And if patient has been on foscarnet, then you switch to either ganciclovir or maribavir. But keep in mind, for maribavir at least you have to have prophylaxis for herpes simplex and VZV separately. Same thing for letermovir as well.

Combination therapy. What we used to do for a long time, you know, when we didn't have much of choices and we stock patient where, you know, are having worsening infection with CMV, we used to go with foscarnet and ganciclovir either full dose or foscarnet full dose, ganciclovir-reduced dose, foscarnet-reduced dose versus ganciclovir full dose. But can you imagine the toxicities and what happened to the patient.

So it is kind of a discussion and lead to more resistance probably when you go to the reduced dose.

Now with maribavir what we - you know, what we are, you know, suggesting or proposing and it - and it went to the guideline to do combination foscarnet but when you have high viral load or hard to treat infection with tissue invasive disease, very short course of foscarnet with maribavir, then you can stop foscarnet and then move on with maribavir. So this is one of the new proposition or recommendation, I would say, in the new guidelines.

Assessing Other Treatment Strategies

Other alternative therapy for this kind of infection. You know, would you, you know, change your calcineurin inhibitor to mTOR, immunosuppression, which has some antiviral in vitro effect.

Some centers may do that. We don't in our institution.

What about CMV IVIG also? I know they use it quite a bit in the pediatric patient population after allo transplant, but we don't. I don't think it has a role to treat refractory CMV infection or resistant CMV infection.

We used to use quite a bit of leflunomide or artesu - leflunomide, not artesunate in the past. I remember when we published our experience on that a long time ago. You know, we don't use as monotherapy, of course, in combination, but try to control a little bit CMV by itself, not going to get rid of your viral load. And - and secondary prophylaxis is recommended. It's very important.

And CMV T-cell therapy, we have - you know, some institutional protocols access to CMV specific T-cell where you can use it and we know it is safe and could be effective.

Maribavir: Mechanism of Action

So maribavir is an option to treat this infection that we talked about. This is the mechanism of action where it inhibits UL97, where it has multiple impact on viral encapsidation nuclear egress and does not affect UL54. Of course, no cross-resistance, as you see, but ganciclovir need UL97 to be phosphorylated before they go to cellular kinase and - and exert their action on DNA polymerase.

When you inhibit UL97, then you cannot use ganciclovir in combination with maribavir. So something to keep in mind. Combination is antagonistic between maribavir, ganciclovir or valganciclovir. Okay, but not with foscarnet. That's why recommendation a short course of foscarnet with maribavir in some specific situation, of course.

Maribavir: Indications and Characteristics

So what are the indications and characteristics for maribavir approved for the treatment of post-transplant CMV infection? Of course, it’s refractory with or without genotypic resistance and resistant to - with, you know, when they refractory this drug listed its oral route, bioavailability is important, not myelosuppressive or nephrotoxicity, pretty safe. The only major side effects - main side effect which is did not lead to discontinuation of the drug during the trial is the dysgeusia or, you know - or taste disturbance as well.

SOLSTICE: Maribavir for Resistant or Refractory CMV

Hopefully, you are all familiar with the SOLSTICE study, where it led to the indication of refractory and resistant CMV infection for maribavir compared to the investigator-assigned therapy that we had. And looking at the primary endpoint, which is confirmed CMV clearance at the end of week eight.

SOLSTICE: Symptom Control and Confirmed CMV Viremia Clearance

And this is the result of the study that maribavir worked much better in clearing CMV viremia at week eight, 56% versus 24% on the IAT, and the effect continue up to week 20 as well.

Treatment-Emergent Adverse Events Reported by >10% of Patients

So it's an oral, effective and safer drug that now we have it and it made it to the new guidelines.

ASTCT Guidelines: Maribavir for Resistant/Refractory CMV Infections

But also we added maribavir recommendation for resistant/refractory CMV infection. And for the first time, the guideline where we make it optional to test for CMV cellular-mediated immunity in specific situation as well, which is interesting. It was kind of better for me. I've been, you know, a proponent of it for many years and, you know, and it made it because we start seeing, you know, the value of it in specific situation as well.

So for maribavir, as I mentioned, to the guidance to treat refractory CMV infection but what you remember at antagonistic effect was valgan or ganciclovir. Poor CNS penetration as well. Okay. You don't use it for CMV retinitis or encephalitis, although it is rare in our patient population. And you have to use an anti-HSV or VZV drug as well.

Now for preemptive therapy, we said in specific situation where the patient cannot tolerate foscarnet or ganciclovir, you may use it. Although the study done at AURORA study was negative, they didn't reach the primary endpoint but was very tight confidence interval. And we still think if it works for resistant refractory, why not for preemptive. So we - it made it to the guideline that it's an option in some situation where you cannot use the other drug.

You can, you know, maribavir could be an option as well, but it's not indicated for preemptive therapy as well.

ASTCT Recommendations: Managing Resistant/Refractory CMV Infections

Genotypic assay, do it right away. You know, don't wait. Some people have no access to it. In Europe mainly, or other parts of the world, they may not have access to it, but here we have. So send for genotypic assay and - but modify your treatment as well.

We talked about short course of combination foscarnet with maribavir. When you have viral - high viral load, we know maribavir may not be the perfect drug, but with short course of foscarnet together with maribavir, it may reduce the viral load and you continue with maribavir.

But keep in mind we have - ASTCT have a app where the guidelines are uploaded in the format of question and answers. So it's very easy to navigate and to get your answer, any question about CMV that you would like to be answered there.

Key Takeaways

So this is the key takeaway that prevention of CMV improve outcome. We know that. Resistant and refractory infection associated with bad outcome, we know that. And we need to - at least we have some option to treat or alternative therapy compared to the toxic drug that we used to use for long period of time.