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 antimicrobial management.
Thank you so much for your patience with getting some new
episodes here on the podcast.
I know there has been a little bit of a break as I try to keep up, but I have
several episodes on their way to you and I'm super excited to share with you
the most recent recording, which is live from ID week 2025 in Atlanta, Georgia.
I am joined by Drs.
Camille Kotton and Roy Chemaly to discuss a case and some of the challenges in
diagnosis and management of refractory HSV infection in immunocompromised patients.
This episode was recorded at IDWeek 2025 during one of the affiliated events.
Our guests today and my role as moderator were sponsored speakers by AiCuris
Anti-infective Cures for the event.
However, this content was planned, produced, and reviewed solely by Febrile.
Hope you enjoy.
Hi everyone.
Welcome to our session today.
We are live from the ID Week Learning Lounge.
Thank you for joining us.
I'm Sara Dong.
I'm your host and moderator today, and we have something special.
This is actually going to be a Febrile podcast live recording here from IDWeek.
And I hope some of you are already listeners, but if not, Febrile
is a cultured podcast about all things infectious disease, and
so I'm very excited to have two illustrious guest stars here with me.
I'm gonna let them say hello and introduce themselves and we'll get started.
Thank you.
I'm Camille Nelson Cotton and I'm the Clinical Director of Transplant and
Immunocompromised Host Infectious Diseases at Massachusetts General Hospital, and
I'm really delighted to be with you today.
I'm Roy Chemaly.
I'm also Infectious Disease specialist, uh, Professor of Medicine and the Chair
of the Infectious Disease department at MD Anderson Cancer Center in Houston, Texas.
And I'm very happy to be surrounded by my colleagues here.
Some rock stars here.
Okay, so before we talk about a case today, I always ask one question on
our podcast, uh, as everyone's favorite cultured podcast, if our guests can share
a little piece of culture, basically just something non-medical that they enjoy.
Uh, maybe I'll start with you, Roy.
With me.
Okay.
Thank you.
So I had to think a little about that, but really, you know, in my
mind it's like really what give me not really happened, maybe serenity.
And you're gonna be surprised like sipping coffee every morning.
This is how I start my day and it's the best time of the day for me.
I think so.
So that is my culture moment.
Love it.
So I've had the good fortune of recently traveling to India where
I went to the, um, heart and lung and abdominal transplant meetings
and visited CMC Valore, um, medical school, and also went to Brazil.
And I was so interested in just hearing about the culture of different
transplant programs throughout the world.
And I think there's just so much to learn from each other.
So that's my somewhat, um, geeky but, uh, culture, um, for the day.
Perfect.
Okay guys, so, Roy and Camille are gonna help me out with a case today.
I'm gonna get started and then pretty soon you'll see some pictures up on the screen.
So we have a 65-year-old woman with acute myeloid leukemia who
underwent a mismatched unrelated donor allogeneic stem cell transplant.
She received fludarabine with busulfan conditioning and post-
cyclophosphamide for GVHD prevention.
Her course was complicated by acute upper gastrointestinal and skin GVHD,
and so she began systemic steroid treatment about day+40 post-transplant.
She was on HSV infection prophylaxis with valacyclovir dosed at one gram.
She developed some ulcers, I'll show you some pictures here.
She has some ulcers on her buccal mucosa, lips, nose, and then two on her
tongue, which popped up around day 48.
So you can see some examples here.
Given these new lesions and concern for malabsorption, she
was changed to IV acyclovir 10 mg/kg dosed three times daily.
HSV PCR was sent from a lesion and confirmed to be HSV.
She didn't really improve over the next week to week and a half.
So at this point has been transitioned to IV foscarnet therapy.
So I have to ask our experts, what do you guys think?
Is this refractory HSV infection?
Uh, maybe I can get started.
So, yeah, defining refractory is very important and for years, uh, we
didn't have any kind of standardized definition for refractory HSV infection.
We, we developed one for CMV, but not for HSV.
From the transplant associated viral infection forum, work with Camille and
other expert, to define for clinical trial use, what we, uh, put there is
someone with mucocutaneous lesions not improving or having new lesions after at
least seven days of good anti HSV therapy.
Uh, making sure the right route and the right dosage, uh, as well.
And this is meant for clinical trials, but also it can be used at the bedside
when it come to refractory infection.
Definitely it's really important to make the diagnosis of refractory
disease and then think about sending resistance testing.
Resistance testing can take numerous weeks to return.
So while we're waiting, we manage this as a refractory disease similar
to how we manage, you know, how we think about CMV, but this is sort of
a, a different, especially because they're much longer wait times in
getting the resistance testing back.
Yeah.
So do you guys see this outside of stem cell transplant?
Uh, yeah, absolutely.
First I wanna say that it's not uncommon, this kind of scenario that
you presented, especially someone who becoming heavily immunocompromised,
immunosuppressed early on after transplant or even after induction chemo
for leukemia patient, lymphoma patient on multiple line of therapy, myeloma.
I can go on and on outside of transplant where you may encounter this
kind of refractory and or resistant herpes simplex (HSV) infections.
And we do see it sometimes in people with HIV and then we see it in the solid organ
and other immunocompromised populations.
It's fairly rare, but when it happens, it can be quite devastating.
So it's really important to recognize the clinical syndrome.
Yeah, and we have some pictures up here just listing out some of
these risk factors that we think about for refractory HSV infection.
And so, you know, at this point I mentioned that our patient has been
on IV foscarnet therapy, which I'm sure many people in the audience have
struggled with, I will say, um, you know, is this what we're stuck with?
IV foscarnet and all its limitations?
Are there other options available to us?
So I would say unfortunately we are stuck with foscarnet alternative
therapy, uh, for this kind of infection.
Although having lots of experience foscarnet where we had to use it on many
occasion for CMV infection or for herpes simplex, we know it is an effective drug,
but it become affected when it goes at high incidence of serious toxicities.
We are all familiar with nephro toxicities from foscarnet as
well as electrolyte imbalance and many other toxicities as well.
And in addition to foscarnet, in very specific cases, we sometimes
can use topical antiviral therapy, topical cidofovir.
Um, interestingly, we need to have that compounded and often the compounding
agent, not the drug itself, but the compounding agent can be quite expensive
and it's often not covered by insurance.
So I've had prices in the range of $1500, $2,000 just for some
basically topical therapies.
So, um, sometimes it seems like a good choice, but can be very
challenging to either obtain and or get covered by insurance.
And, and I want to add to that beyond caution the audience,
sometimes we have big lesions and you use topical, uh, cidofovir?
Uh, it has to be compounded.
Wanna make sure that it's compounded the right way, but it can still cause
some side effect, can get absorbed.
We had few cases, not many, only maybe one or two.
Uh, and we publish on one when they develop renal toxicity from topical
cidofovir, versus Fanconi syndrome and other kind of side effect that you have to
be aware of as well when you use topical.
It's a really good point, especially because these lesions can be
fairly big and the skin is open, so at higher rates of absorption.
And then we put it on often, multiple times a day.
And so that's a, that's a really important thing to consider.
The toxicity of all of these therapies is significant, so
that's always a concern for us.
So for this patient, I mentioned we're not really making progress,
we don't have clinical improvement.
What are your next steps at this point for evaluating this
patient for, for treating them?
So when we're thinking about refractory disease and we're
switching to different therapies?
Um, yeah.
As you can see in this algorithm here, right?
Usually we first of all recognize the refractory HSV infection
risk, and then often switch to intravenous foscarnet therapy.
I always ask my pharmacist for help, and I personally always keep people in
the hospital when they're on foscarnet.
I don't send them home, I don't think it's safe.
And then really importantly, early send resistance testing because,
uh, it can take quite a while for the resistance testing to come back
sometimes a month or even longer.
It can really be problematic.
And then once you had the resistance results, you know, you
can see as marching through this.
If it is still acyclovir susceptible, foscarnet susceptible, then it
should work to try them on either intravenous acyclovir or high dose
valacyclovir, or potentially consider, uh, investigational therapies.
And that's where we think about things like pritelivir,
when it's available.
Obviously if it's acyclovir resistance, then we probably want something like
foscarnet or investigational therapy, or if it's acyclovir susceptible, as
you can see on the right hand side of the slide, and foscarnet resistant,
go, go with, potentially intravenous cidofovir, which, many of us are not
really using significantly and it could be quite challenging to get or
potential investigational therapy.
And probably I would add that's also the main thing when we develop
this algorithm, you know, want to give alternative therapy, right?
But also wanna make sure that providers recognize refractory early on.
And because I know in the old days when we are faced with this kind of, uh,
patient with all this non well, we keep on pushing with foscarnet or even high dose
acyclovir and we don't know what to do, but recognizing the refractory early on
and maybe switching therapy based on geno topic testing, it could improve outcome.
But we realize big unmet need when we have alternative therapy, very toxic drug.
We need a new drug that are safer and effective in treating this kind of,
uh, scenarios, this kind of infection.
That's why, you know, at least hopefully, you all probably heard about the
press release that we're gonna have.
Uh, you know, the primary endpoint was met for pritelivir and mucocutaneous
HSV resistant refractory infection.
So hope is on the horizon, I would say, to have kind of oral and safer
drug to treat this kind of infection.
So stay tuned, more to come in the future.
So.
And I would also also include any good transplant infectious disease note always
contains the line, please try to reduce immunosuppression as much as possible.
Um, which is easier said than done.
And I think a lot of the patients that I have seen with resistant HSV are quite
immunocompromised and not necessarily by exogenous immunosuppression, but
stem cell transplant or whatnot.
So it's always easier said than done to reduce the immunosuppression, but
that's always part of the algorithm.
And thanks for highlighting the phase three data.
I will be talking about the phase two data later this afternoon.
I'll be speaking at 3:51 PM and it will be in room, uh, B 213-214.
Um, so if you're interested in hearing the earlier phase two
data, um, it will be presented.
Perfect.
Okay.
Well, tell us a little bit about our patient.
Unfortunately, our patient had to stop foscarnet prior to healing
of lesions due to renal toxicity.
The patient received imiquimod 5% cream and did also have the cidofovir 1%
oral solution as adjuvant treatments.
Um, but this patient ultimately received compassionate use pritelivir,
and actually had complete response after about 40 days of therapy.
Is there anything else that you guys can share with us, with, you
know, experience in cases like this?
Yeah, actually this is one of the case that we published in the CMI recently,
one of our fellows, Tali Shafat, put this picture together and, uh, interesting.
As you all know, probably, uh, phase two and phase three open label.
So we could tell what patient is getting and this what we follow
progression and, and our experience.
We enroll many patient either on the phase two, phase three trial or, under
the Compassionate use Program and our experience, uh, with many patient
that you see the improvement rather quickly after you switch to pritelivir.
And we documented this in pictures, uh, based on the protocol and based
on what we've seeing clinically.
So, yeah, that's why it is an interesting, effective drug we could tell.
So it was not surprising when we saw the press release that it met the
primary endpoint because we could see it firsthand, patient responding.
And this patient, you know, need to keep in mind patient who get these
kind of infections with no improvement.
They're very complicated.
You know, this patient had many other complications.
This was a heavily immunocompromised, they have other type of infection at the
same time, and you expose them to toxic drug, make their outcome probably worse.
And we're talking about ultimate outcome sometimes, uh, either
oncology outcome or mortality.
So having a drug, which is oral drug, but it's effective and safer for a drug.
And seeing, uh, the improvement and the impact on this kind of
infection, actually, it is important for a significant, at least we
accomplish something, uh, for our patient with new antiviral and.
And al also to address, in addition to what we see clinically, but
the patient experience, right?
So this is incredibly painful and people are often really suffering.
It can be at multiple sites and certainly when they're on
foscarnet, that is not easy.
And this is often in the setting of recent stem cell transplant or other therapies.
So they're going through a lot and I really respect the patient experience
and how therapies that are much easier, like oral therapy are easier for them
with, uh, far fewer side effects.
It's really wonderful to offer them something with less
toxicity and fewer complications.
You've already sort of started listing your wishlist of what you would want,
but what do you see on the horizon for helping us with refractory HSV?
What do you hope for?
I feel like that'll be a nice place to end on, and then we'll see if
the audience has any questions.
Uh, so we talked about the HPI inhibitors.
So, one of the HPI inhibitor, which is pritelivir, is helicase primase inhibitor
has specific mechanisms of actions.
There's no gross resistance, and this is important to know between HPIs
versus acyclovir, uh, or even foscarnet.
So this is important when you are suspecting resistant to either of the
commercially available drug, at least from your field, you know that it,
if it's gonna work, gonna work with no worrying about cross resistance.
I always tell, uh, this drug that, you know, we've been working in the antiviral
field for the past 20 years, myself and Camille, and we want to really bring
new strategies and new agent to the market in a way to help our patient.
And this is so important.
And, you know, and we were successful so far for CMV and now
we feel great about having a new antiviral, which is pritelivir.
Hopefully, hopefully, it met the primary endpoint, we see by next year coming
to the market to help our patient.
At the end, it's really about our patient going through transplant, going
through cancer therapy, solid organ transplant, and we wanna really help
them to go through their journey in the best way possible, preventing infection,
treating infection, keep them alive to recover from their underlying disease.
And this is our hope.
Hopefully we get there before we retire.
With all of the amazing cancer therapies, biologic therapies for
autoimmune disease, organ transplant.
It's wonderful when infection can really take a back seat and have, you
know, treatment and prevention can have minimal toxicity, minimal side effects,
and sort of not be first and foremost.
Unfortunately, many of the patients that I've cared for with refractory resistant
HSV, have really had the HSV be their most significant issue at that point.
So it would be great if it could be well treated and, um, yeah, take a
backseat and hopefully enhance the quality of life and overall outcomes
for this vulnerable population.
I add one quick thing as well, that, you know, Camille mentioned a little bit.
Now with the major advancement in treating hematologic malignancies in
transplant, in cellular therapy, and probably in solid organ transplant,
we gonna see more and more.
We are gonna be faced with more challenging infectious complications
because our patients are living longer, but they are more immunosuppressed,
going through multiple line of therapy to get to the last strategy, the new
innovations and, uh, new strategies.
So we are start to see high acuity and severity of infection when
patient get admitted, including viral infections, uh, you know, from
CMV to herpes simplex and other.
So is this gonna, unfortunately gonna stay with us.
We're not gonna get rid of it, but we need to work hard.
How to prevent it better, or how to add better treatment option to these patients.
You're definitely right.
In the past decade, there was a survey by the CDC and we've actually doubled
the number of people in the United States who identify as immunocompromised.
Now it's at 6.6% identify as immunocompromised.
So we've made a lot of progress and we've certainly seen that,
but we need to make sure that we have really good preventative and
therapeutic options for, um, infectious disease in that, in that setting.
We are really excited for the future ahead.
I heard at ID week about an HSV vaccine even that might be on the horizon.
So hopefully there'll be multiple modalities and, lots of ways
that we can help patients.
Well, we left a little time so that if folks in the audience had questions
for our guests, uh, you may just, if you shout out to me and I'll repeat it
or, um, you can walk up to the front.
Oh, we can hand a mic if we need to.
Any questions that folks have?
Thank you so much.
We come from Florida, Miami.
Um, thank you.
Um, my question is about the cidofovir.
How do you mix it and how you apply it?
Cidofovir needs to be compounded, so you need to have a compounding
pharmacy, or, my inpatient pharmacy had previously done that.
But it's actually really challenging.
At least it's been in my clinical experience.
I don't know what yours has been, but it's actually really hard to get compounding
done and then covered by insurance.
And it's, it seems shockingly challenging, like a couple thousand
dollars to get a relatively small amount.
Our pharmacists were always yelling at me saying, use very little and
don't wipe it off, because it's actually sort of liquid gold.
But there are some compounding pharmacies that can take care of that for you.
Yeah.
And, uh, I wanna add also.
Yeah, I totally agree.
And you have to make sure you get the right concentration because,
I remember one patient mess up, give them higher concentration and
they got into trouble with that.
Uh, but also the, the, all of the question is, does it work?
We don't know, right?
So topical cidofovir or imiquimod.
We use it because we have no other alternative.
We wanna do whatever it takes for our patient and we try that.
But I dunno, I'm not sure.
Because we always use it in combination with other drugs as well, with all
the other drugs that available.
So something you have to keep in mind as well.\
Hi, uh, here.
I'm Nadine from Milwaukee, Wisconsin.
Question about a patient who would been on Valtrex suppression for genital HSV now
suddenly starts having multiple outbreaks.
The management of this patient.
Is it, are you thinking this is now getting into a resistance zone?
Or what should we do next and what are the treatment options for someone like that?
So yeah, so the question is about having, uh, outbreak of herpes simplex
on multiple occasions and what to do.
So, yeah.
And when we see this quite often, unfortunately, I had one
patient following in the clinic.
She come every month.
It's like unbelievable.
Like at the same time of the month where she has an outbreak.
So what I did initially, you know, you put her on prophylaxis again,
and you test for, uh, resistance, no resistance, refractory.
That's the underlying cyclic neutropenia.
That's why she get them when, but even on suppressive therapy,
sometimes it doesn't work.
So what I did, I increased the dose of, it's not really prophylaxis anymore,
you know, it's not like one gram a day.
I put them first on one gram twice a day, and then three times a day because
it was a recurring outbreak every month, and it's still happening, unfortunately
now, the last time it happened, because she did not take the prophylaxis.
So, you know, I had to, you know, but, but, you know, but it, it's, uh, sometime
it is hard, uh, you don't know what to do, except increasing the dose of acyclovir.
Yeah, I, I completely agree.
Um, it's just that sometimes you will have full resistance and then
we need a better preventative option.
And I don't think most of us would be giving like cidofovir every
two weeks as was done for CMV.
I mean, that's really toxic.
Um, so that's really, uh, a huge unmet need is the ongoing prophylaxis situation
for somebody who really needs it.
I will say on a stewardship front, I usually try to stop the
acyclovir as soon as it seems safe.
I do find some people who are on acyclovir for a very long period
of time, so I do try to stop and hopefully, hopefully decrease the risk
of resistance, although, we don't really know about whether it's better to be on
prophylaxis versus stop and then treat.
We often think that when we're treating, it might be a trigger,
at least for CMV, at a higher risk for developing resistance.
Um, but it's a, a problematic situation, but we're cautiously optimistic
that on the horizon there'll be, you know, options for both treatment of
resistant disease and potentially prophylaxis of resistant disease.
So it's a great, it's a great question and we're hopeful for the future.
Any other questions?
Well, I'll open it back up to you guys.
I was gonna say for kind of some closing thoughts.
Yeah.
So maybe, uh, uh, closing thoughts.
Yeah.
So yeah, so we, we, so we covered, uh, the main thing I would say from
what we presented is make sure you use the definitions of refractory,
although it meant only for clinical trial use, but I think it's helpful.
I hear it from many people throughout the country, uh, from everywhere
that it helped them at the bedside as well because, you know, we develop
this definition based on our clinical experience because it's hard.
If you look at the literature, it's all over the place.
How people define refractory infections, uh, not only herpes simplex but
maybe other viral infection as well.
So at least we have something more standardized, can help us at the bedside.
This way we can realize, or we can recognize refractory early on, we
always good to switch therapy early on than later on when it is progressing
or disseminating or having new lesions would be harder, uh, to treat.
And, you know, so we talked about that.
And now we talked also about the, hopefully a new HPI or
helicase primase inhibitor coming to the market with pritelivir.
Hopefully we are hoping next year, uh, now the data is under analysis
and we're looking forward to see the data published in the future.
Uh, this new strategy.
Definitely it's a great time to be in transplant ID.
We've had multiple new agents for CMV, you know, letermovir, which has been a game
changer for prophylaxis and then maribavir for resistant refractory disease.
And hopefully on the horizon we'll have new therapies for,
uh, refractory resistant HSV.
And we definitely welcome more tools in the toolbox.
Well, I just wanna say thank you again for this.
Um, for those of you who are here, we have some Febrile stickers in the
front and a few minutes in the room.
So if you do have questions, please feel free to come up, um, and say hello.
Thanks again for listening, everyone.
Happy to be back with you in action on Febrile.
Don't forget to check out the website febrilepodcast.com, where
you can find our Consult Notes, which are written complements to the
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Okay.