Dr. Marcus Pereira (Columbia University Irving Medical Center): It's an honor to be here. I'm Dr. Marcus Pereira from infectious disease at Columbia.

The Burden of CMV on HCT Recipients

So let's start this session talking a little bit about CMV. Judging by the answers, a lot of you are quite familiar with the virus and its implications. But it's good to go over a little bit.

So as many of you will be aware, you know, the burden of CMV on HCT recipients, it's quite extensive. So and it's one of the most significant infections complications after HCT. And in fact, actually in the first six months after allogeneic HCT in CMV recipient-positive or

[00:12:00]

antibody positive recipients without prophylaxis, CMV tends to reactivate quite early and quite extensively, up to 41%.

And here you can see in the study comparing placebo with letermovir, the patients on placebo, they reactivated at a high rate and early on up to 41% in this population.

Now different types of HCT carry different risks of CMV reactivation. So for example, in cord blood transplant, you have actually even higher rates of CMV reactivation up to 64% in this particular case series.

Now for those of you who take care of pediatric patients, that rate is somewhere in between about 40% incidence rate of reactivation of CMV. So quite common and certainly an important complication.

CMV Reactivation Associated With Poor Outcomes in HCT Recipients

So the reason why we talked about CMV and focus so much on it is because it is associated with poor outcomes after HCT in our recipients. And that sort of poor impact, it comes in different

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ways. Certainly all-cause mortality has been associated with CMV reactivation, and some of it depends at the timing of reactivation.

Early reactivation, meaning less than 60 days post-HCT certainly carries a very high risk of all-cause mortality. But even late reactivation, meaning maybe the patient is already engrafted and - and may not even be on GVHD prophylaxis. That risk is still sustained.

And here, you can see in this particular study looking at all-cause mortality from CMV, that in the early days, sort of less than 60. That impact certainly is sort of directly proportional to the viral load. So meaning the higher the viremia or the DNAemia, you know, the higher the risk up to sort of an adjusted hazard ratio of 26.5. But even post day 60, the risk is quite extensive as well as you can see, it's also across the board.

So that's for all-cause mortality. How about GVHD? So we know that

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the relationship between CMV and GVHD is quite complicated. And in general, it's a bidirectional relationship, meaning CMV can lead to GVHD, but GVHD can certainly lead to CMV reactivation as well. But in the case where CMV is a risk factor for acute GVHD, certainly there's been an association. And that association, the impact is certainly across different spectra of GVHD, whether it's skin, gut or liver or even the grade or the severity of GVHD. All of those are associated with CMV reactivation.

Now, in addition to these two, certainly costs and hospitalizations, in terms of the increase and sort of more length of stay for our patients that those are all associated with CMV reactivation as well. So all in all, it's a pretty serious complication, as many of you will be aware.

Clinical Impact of CMV After HCT: Direct Effects

Now, that the impact of CMV comes in two ways, right. So we generally think of CMV causing direct impacts

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and indirect impacts. So in the direct spectrum, that's when we think about patients actually getting sick from CMV. Like any viral infection, it can cause symptoms and make patients sick.

And an tissue invasive disease is the one that we fear the most from CMV. Many of you may have seen a patient with direct impact in tissue invasive disease. So the ones that we generally think or worry the most are GI and pulmonary CMV disease. And certainly those are the most impactful. Thinking about GI CMV, the cumulative incidence rate can be about 2% by year two post-transplant. So not a lot. But for those patients who do get it, they can get quite sick.

CMV pneumonia can have even a greater impact with mortalities up to 50%. Certainly, maybe some of this data are historical, because the good news is that we don't see many of these patients anymore in terms of tissue invasive disease, and certainly that's welcome news.

Retinitis and CNS disease, generally, we think about those for

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patients with HIV and other immunocompromising conditions, but luckily not so much with stem cell transplant.

Here are some photos of patients with examples of CMV tissue invasive disease. This is a pulmonary CMV. This is GI CMV and so forth.

Clinical Impact of CMV After HCT: Indirect Effects

So we talked about direct impact. How about the indirect impact? And in some ways this is sort of the more import - important aspect of CMV. Luckily, we don't see as many patients directly sick. But this impact of indirect is certainly more extensive.

So the first one to talk about are opportunistic infections. It turns out that CMV is an immunomodulating virus, meaning that if it reactivates, it can actually further immunosuppress our patients. And the manifestation of that will be with a greater number of opportunistic infections.

So for example, invasive fungal disease, which obviously is a quite important type of infection in our patients directly

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related with rates of CMV reactivation, perhaps not early on. So this was a study looking at CMV and its correlation with invasive fungal disease, perhaps not early on. You see any kind of separation. But in those patients, after 200 days with CMV reactivation, you see a much greater rate of invasive fungal disease, whether that's aspergillus, rhizopus, you name it. Those are all correlated with CMV reactivation.

And - and obviously we know that well, and we see a lot of patients with invasive fungal disease. But you also have a relationship, perhaps with less common types of infections. So non-tuberculous mycobacteria, whether it's MAC, M. abscessus, chelonae. There are dozens of different types of NTMs, and many of them can be correlated with CMV reactivation in the setting of post-HCT.

So here's a study looking at that. And certainly you can see the separation being quite striking as well.

Clinical Impact of CMV After HCT

Now we talked

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a little bit about all-cause mortality and CMV post-HCT, and we don't need to sort of talk too much about it. But many studies have shown a correlation of clinically significant CMV and a differential in all-cause mortality, and certainly a significant sort of relationship, right.

So these are patients who develop clinically significant CMV in the red line. And you can see the separation with those who don't have clinically significant CMV.

Now, you know, there are many ways in which these indirect effect sort of impact the all-cause mortality. Perhaps one, as you can imagine, is through the GVHD and its bidirectional relationship, where you have CMV and GVHD, and one is impacting the other, and it can cause sort of a downstream sort of cascading effect.

Key Takeaways

So the key takeaways on the burden of CMV is that there are significant direct impacts. Certainly tissue invasive disease is an important and for clinicians

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is critical to be aware of. GI, pulmonary are the main ones. Luckily, they're not that common.

But the most clinically significant CMV infections are not really associated with tissue invasive disease, like I said. It's really the indirect effects that we worry most in terms of the burden of CMV.

Managing Risk of CMV in HCT Recipients

All right. So how do we manage this risk?

Risk Factors for CMV Infection

As you can imagine, we have spent over the decades a lot of time and thinking about how to mitigate that risk of CMV. And many of you are aware of the strategies. But going over the risk factors, you know, the main takeaway from this slide is that this is a dynamic sort of relationship between the risk factors and time after post-HCT.

So you have here sort of the first 30 days, days 30 to 100 and then after 100 days. And those risk factors change over this sort of timeline.

So in the beginning, as you can imagine, general risk factors for CMV and end-organ disease will include a CMV seropositive recipient, right. The CMV is

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in their bodies and has the potential for reactivating. But other factors like advanced age, the type of transfer we talked about, core transplant being a higher risk, and the conditioning regimen. So certainly between the different agents that can be used. Post-transplant cyclophosphamide has been highly implicated with CMV reactivation.

The CM - the presentation of CMV in the initial period. People may have asymptomatic DNAemia or viremia. End-organ disease is quite rare in the first 30 days because they're being monitored so closely, they're usually still in the hospital. And they might even be in prophylaxis.

All right. So what happens after day 30 and up to day 100? So they maintain - the - the risk factors that were early on are still quite significant. Obviously, being seropositive for CMV will remain a significant risk factor. But then you add a few additional risk factors, like the presence of GVHD and the treatment for GVHD. Those are going to increase the

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risk of CMV reactivation, and delayed T-cell recovery will also increase the risk for CMV reactivation. Those can be pretty straightforward, at least in understanding those risk factors.

CMV infection is common during this period, particularly in the high-risk patients who are not on prophylaxis. That's where that, you know, 40%, 41% of patients sort of come from. And CMV pneumonia, although rare, if it's going to happen, it might happen during this particular period. Okay. Intense immunosuppression and the potential for CMV to reactivate and cause disease.

All right, so what happens after 100 days? So you still have all of these risk factors. But now sort of you add more chronic risk factors such as steroid use perhaps for chronic GVHD. Again, delay in T-cell recovery. Now nonmyeloablative conditioning, right, because it can delay T-cell recovery will be a risk factor here. I had already pointed that out, but it's really important to include that here as well.

And as

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it comes with CMV, you know, past CMV reactivation is a risk factor for future reactivation. And that's an important concept. Your patients who have had CMV before, there's something about them that will keep their risk elevated.

Comparison of Strategies for Prevention of CMVi

All right. So what do we do to prevent CMV? I think many of you will be aware of our two main strategies: monitoring with preemptive therapy and antiviral prophylaxis. Right?

So let's talk about antiviral prophylaxis, meaning giving an antiviral to prevent CMV from reactivation during a certain period of time. It's highly effective and it actually prevents those indirect effects from CMV that we talked about, whether it's GVHD, opportunistic infections and so on.

But there are some drawbacks. Certainly it delays CMV immunity to the degree that your patient can create some sort of CMV immunity that's going to be pushed down the line because there's no CMV reactivating to trigger that response. And there will be a risk for post-prophylaxis, clinically significant CMV as well.

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Now, the drug that we're talking about is letermovir, as many of you will be aware. It does have some drug interactions that are important to be aware of. So tacrolimus, cyclosporin, sirolimus, the azoles for sort of antifungal prophylaxis and many others. So this is a drug that you always want to check in with your pharmacist to make sure that the dosing and other interactions are taking into account.

Now also important to note that letermovir does not have HSV and VZV activity, right? So if you think your patient is at risk and most of them are, you need to add an additional antiviral for prophylaxis because letermovir is not going to provide it.

All right. So how about monitoring with preemptive therapy? That's basically weekly CM - weekly CMV QNAT monitoring. It does allow for brief, low level - low-level viral replication and potentially immune priming, right. So there's potential some benefit there.

In the SOT world, we have shown that that might be beneficial. That's a little bit less

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clear in the HCT sort of types of patients. But certainly the thought is there.

There is always the low risk of late onset clinically significant CMV. Obviously that risk will stay there. And there are obviously some drawbacks, right. So significant logistical requirements of having your patient coming every week for lab monitoring and then somebody to track that lab, you know, and make a decision if it's detecting CMV whether to start preemptive treatment or not. So those are sort of, you know, a lot of logistical drawbacks for services that are always stretched in.

And the - the last one is that, you know, monitoring with preemptive therapy, there is some relationship with increased all-cause mortality. So that's obviously a problem.

Letermovir for Antiviral Prophylaxis: Efficacy and Safety

Let's talk in the next few slides about letermovir. This, many of you will be familiar with the double blind phase III clinical trial that sort of was the pivotal study for letermovir approval. It included 565 CMV sero-positive HCT transplant recipients. This is now many

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years ago.

And letermovir was given for 100 days and compared to placebo. The primary outcome was clinically significant CMV infection. And by all measures, this was a statistically significant result in that letermovir effectively prevented CMV from reactivating, whereas placebo did not. So this was a really significant result if directly led to letermovir being approved for HCT Patients.

Now, what was intriguing about that study, and this was sort of a secondary outcome looking at all-cause mortality, at week 14 and week 24, there was a signal that perhaps letermovir was also reducing all-cause mortality. That disappeared by week 48. But certainly there was a trend towards reducing all-cause mortality with letermovir. And that obviously was important to the researchers and to most programs adopting letermovir

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for prophylaxis.

Letermovir for Antiviral Prophylaxis: Efficacy and Safety of Extended Treatment

Now, that initial study was for 100 days. There was an extension study to include patients up to 200 days on letermovir thinking about perhaps there would be added benefits of preventing CMV from reactivating up to 200 days post-HCT. And by and large, you know, although the study was smaller, it did show that, you know, prophylaxis with letermovir was highly effective in preventing CMV from reactivating up to 200 days or past 200 days.

Interestingly, we looked again at all-cause mortality. And in this particular study, for various reasons about patient selection, there was no trend towards reduced mortality with letermovir. But the question remains because some studies have shown that letermovir can reduce all-cause mortality, but the data are not as striking as at least reducing CMV from reactivation.

Treatment of CMV in HCT Recipients

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

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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. 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 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.

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All right. So 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.

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What is also important for everybody to be aware that although 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 refractory CMV only, Dr. Chemaly will talk a lot more about that drug coming up.

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Treatment of CMVi in HCT Recipients: Considerations

In my last slide, 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

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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. This is what this bullet point is supposed to say, that, 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

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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 treatment is individualized. So it really is based on the resolution of symptoms and a negative QNAT on one to two consecutive measurements, whether those are weekly 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, and I'm going to put up this quote by him because it's one of my favorite quotes as well.

Dr. Chemaly: Thank you. Thank you. Yeah. I always like to start my presentation with this quote, becoming old probably, I need to find a new one. But really CMV, it is fascinating virus.

I don't think even we scratch the surface to understand CMV and its impact

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on our patient immune systems and as an immunomodulator virus. But a lot of things need to be learned. And as we learn about this virus, we'll be able to help better our patients, as you can see.

Major Advances in CMV Management Over 3 Decades

So 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 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

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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 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

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to see. What about stopping prophylaxis earlier when they have enough CMV, CMI or cellular-mediated immunity, or maybe prolonging prophylaxis when they lack the specific T cells for CMV. So there is a role for it. 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

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it breakthrough infections, but it's easy to treat. It's doesn't correlate with resistance 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

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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 what are the recommendations 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.

Patient Case 1

Now I'm going to go over a few cases. Two cases. This is the first one.

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It happened in our place before the era of maribavir, where a 61-year-old man with AML who underwent a matched unrelated donor transplant. He was a recipient, was positive, donor-negative and conditioning with fludarabine, busulfan, melphalan and ATG.

Patient developed CMV reactivation and CMV viral load was 950 IU/mL. It was pretty early CMV after transplant and he was started on foscarnet at 60 mg/kg every 12 hours and did fine. This was stopped two weeks later. At day plus 55, he had grade 3 skin GVHD and he was started on high dose methylprednisolone. And you can tell the patient is going to be in trouble.

Pretest 5

So the first question on this case, what would you recommend at this point? Would you:

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1. Start valganciclovir for secondary prophylaxis;
2. Restart foscarnet for maintenance therapy; or
3. Start oral letermovir for secondary prophylaxis; or
4. Call us - call ID, because I'm not sure really what to do in this case.

So please vote.

C, start oral. Okay, excellent. So it looks like you have a spread, but most of you said we start oral letermovir for secondary prophylaxis. Although letermovir is not indicated for secondary prophylaxis, there is some data, mainly from France initially and other parts of the world looking at letermovir for secondary prophylaxis, although outside the indication. But some of us will probably use it if you can get it for your patient, you may do that.

But we know –

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and the message from this, that this patient is going to be at high risk for another reactivation. This is the problem with CMV. It's not only one episode you treat, it's gone, like maybe bacteremia or other type of infections. This can recur and recur if patients still at risk and if we don't do much about it. So this is the first question.

Now, subsequently patient had recurrent CMV infection at 5,500 IU/mL while off foscarnet, he was not on secondary prophylaxis. So at that point, we started him on valganciclovir. It was after transplant so we could use valganciclovir 900 mg twice a day. And 14 days later, his CMV viral load declined. It took up to 14 days. So that's why be patient when you start—especially when patients on ganciclovir or valganciclovir don't jump the gun within a week or so because the viral load did

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not budge or it went up a little bit. So don't do that.

You know, it's going to take time with the mechanism of action of ganciclovir that it may take time for the viral load to go down. So patient has viral load decline. But his ANC declined to 550 as well. And he was transitioned at that point to valganciclovir 900 milligram once a day. We don't like to call it maintenance. So we moved away from maintenance therapy. We used to use it quite a bit for many years.

But the reason the first guideline for CMV from the American Society of Transplant Cellular Therapy few years ago, we moved away from using maintenance. We use secondary prophylaxis. That's what we're doing. It's not really maintenance therapy.

So five weeks later, his CMV viral load went up to 38,000 IU/mL and—while on valgan. And at that point, of course, you have to send genotype assay.

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We submitted. And this is part of the recommendation of the new guideline. Send genotype assay as soon as you suspect resistant or refractory, sent a genotypic assay because they take time to get the answer. But don't wait to switch therapy. It can take at least a week to get the result back. Switch therapy.

And here what we did, we switched to foscarnet at 60 mg/kg twice a day, renally adjusted, and his viral load declined to 950 IU/mL. So he responded. But unfortunately, it happened quite a bit that his renal function worsened and it has severe nausea also. So we tend to forget that many other side effects of foscarnet not only kidney dysfunction, but also electrolyte abnormalities, nausea, ulcers, genital ulcers sometimes can happen. It could be pretty painful as well.

So at that point, what we did, we switched them back to valgan at 450 twice a day, renally adjusted, but his viral load remained around 1,200 IU/mL.

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And then one week later we got the genotypic assay bag, and patient had a UL97 mutation which conferred resistance to ganciclovir only. When you have UL97, usually no cross-resistance with foscarnet or cidofovir, but it could be with maribavir for specific mutation. I will talk about it later on.

Pretest 6

So my next question, what would you recommend at this point? Would you:

1. Increase the valgan to 900 twice a day and add GCSF support;
2. Restart foscarnet monotherapy;
3. What about combination therapy with ganciclovir and foscarnet;
4. Start IV cidofovir; or
5. Consult IVs that I'm not sure what to do.

And this is before the era of maribavir and we're a little bit limited with the choice and the choices what we have were pretty toxic. So please vote.

[00:43:00]

Do you see the result? All over the place. Yeah, actually interesting. Yeah. I don't know. I don't have the right answer, to be honest with you. It's all about your own preference, what you do in your institution. You know, would you increase valgan, ganciclovir, but high dose valganciclovir to overcome this mutation? Yeah, probably because it depends on the mutation. Sometimes you have low level resistance when you look at UL97 mutation.

What we used to do, we double the dose or, you know, or two thirds of the dose of ganciclovir. So you go up to 7.5 mg/kg versus 10 mg/kg. But you add GCSF support if you can.

Now, would you use foscarnet monotherapy in someone with kidney dysfunction going to end up on dialysis? We had to do it sometime.

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And I don't know how many of you remember this era like five years ago or six years ago, we were so busy on our stem cell transplant service in our institution where we consulted on these cases were pretty common. They were not uncommon.

Actually, when we look at that, the incidence was 30%, what we call refractory CMV infection after allotransplant. So it's not uncommon kind of occurrence. We used to get—you know, now these days is much less with the primary prophylaxis we do.

So I'm going to close the voting. So as I said, there's no real answer.

Now for IV cifofovir, we'll make a quick point. We use it early on, try to see if we can control CMV reactivation. In my mind, it's very suboptimal. Other than the serious side effect from nephrotoxicities to even myelosuppression. But also, it's not a great drug to treat at least viremia. It could be better for CMV retinitis

[00:45:00]

in the HIV population. But call us at this point, we may find something else.

And this is, you know, the reason why each one are really not the perfect solution in this or perfect answer in this case.

Okay. So what we did? We went with high dose IV ganciclovir and said because of the mutation, low level resistance and the viral load went down to 950 IU/mL. But stayed around this level. And of course patient has severe neutropenia, thrombocytopenia despite, you know, GCSF support and platelet transfusion at the same time.

But guess what? We all predicted I'm sure that this patient is going to do well when and this is probably a surrogate marker of the immune system of the underlying problem and other complications that patients have. It's not really CMV, CMV. It's showing, you know, as kind of

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indirect effect of what's going on with the patient and their whole total immune system as well.

So patient died at the end with septic shock from E. coli and multiple organ failure. And this is what happened usually with patients with complicated CMV infections or continue - or persistent viral load. They don't die from CMV per se directly. They don't die from end-organ disease. It's minimal. We had few patients who may end up dying from CMV pneumonitis or GI, not GI disease, mainly unless they get GI bleed, but mainly from pneumonitis. But it's not common. They die from other causes.

And as I said, that's why CMV - the indirect effect of CMV. And it's what's going on with the patient as well at the time. That's why their CMV is not under control. So.

GCV Treatment Is Associated with Neutropenia

And we all know that ganciclovir treatment associated with neutropenia, and why this is important is not

[00:47:00]

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. Dr. Pereira went over this data. At the same time, lower overall survival or increase in non-relapse mortality by either neutropenia from ganciclovir or neutropenia 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. And this

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is a nice summary review from Dr. Avery, where she looked at nephrotoxicity and the cause of mortality in this patient SOT or in HCT at the same time.