October 19, 2025 • 34 mins
In this episode, Zale sits down with Dr. Benny Jeng, head of the ZEDS study which investigated the role of longer time antiviral treatmetn for patients with HZO with ocular involvement. They review the results of the study and disuss whether long term oral antivirals reduces zoster recurrences and the severity and duration of post-herpetic neuralgia.
This episode is sponsored by Thea Pharma Canada - https://www.theapharma.ca
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This episode is sponsored by Thea Pharma Canada - https://www.theapharma.ca
Become a supporter of this podcast: https://www.spreaker.com/podcast/blind-spot-the-eye-doctor-s-podcast--5819306/support.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Speaker 1 (00:10):
Hey everybody, I'm XAEO Mednik and welcome to another episode
of blind Spot. This episode is sponsored by THEO Pharma Canada.
THEA pharm of Canada is the Canadian subsidiary of THEA,
Europe's leading pioneering and innovative eye health brand. Founded in
nineteen ninety four by Henri Schibre. With five generations of history,
the Chubret family has been dedicated to I care for
(00:30):
more than one hundred and fifty years. Their commitment to
improving lives is born of their pioneering spirit. They continue
to lead the worldwide preservative free movement in eye care.
They've created innovative delivery systems. They've focused on making products
accessible and cost effective for patients. They live this mission
every day because everyone should have the same opportunities to
see the world through healthy eyes. So thank you THEO
(00:53):
Pharmer Canada for supporting Blindspot. The Heads Trial was a
seminal study that was done in evaluating different treatment options
for Herbie's simplex virus. Recently, at the end of twenty
twenty four, the preliminary results from the z Study were published.
A study that looked at different treatment options for zoster virus.
In particular, the study look to examine what is the
(01:16):
role for longer term anti viral prophylaxis for patients who
are experiencing hseto. For many years, the paradigm has been
that while the virus certainly plays a role in the
eye disease of hid oh, a lot of the havoc
reached by h STOH is more so related to the
inflammation that is set off by the cascade of the virus. Yet, anecdotally,
(01:37):
many have wondered, is the virus more active than we think?
Is the zoster virus itself contributing to more damage than
we had previously given credence to And if that's the case,
should we be more aggressive with our anti viral approach
in the treatment of h OH, perhaps even months after
the presenting episode. I'm joined today by Corneas Specialist Doctor
(01:58):
Benny Jeng. Doctor Jeng is the the professor and chair
of the University of Pennsylvania School of Medicine, Department of Ophthalmology,
and shae I Institute. He was a lead researcher in
the Zoster eye disease study, better known as Zed's all Right,
Doctor Benny Jang, Welcome to the podcast. Thank you so
much for joining me, Thank you for having me. I've
(02:18):
done a couple episodes. We've done about forty episodes now,
but I've done a couple episodes focusing on shingles and
on simplex, and obviously today we're going to be focusing
on shingles. A theme that's come up a couple times,
and I guess recently because we just did an episode
on topical gan cyclovir. A theme that's come up is
this notion, which I believe is what prompted the z study,
(02:40):
that maybe the virus was more impactful in the disease
kind of occurring in the eye than we'd initially thought
it was. When I was in residency, what I had
learned was that, you know, in HSV, it's really the
virus that wreaks a lot of the havoc, whereas in
hzi OH in zoster, the virus obviously has something to
do with it, but it's kind of the cascade that's
(03:01):
set off by the virus that leads to a lot
of inflammation. And that's the reason why, for example, we
see RHSV patients who are often kept on a cycle
of your prophylactically for a long time, but for zoster,
they're not because we view this more as an inflammatory process.
Walk me through that paradigm and what maybe prompted this
(03:23):
study which you were integral in the z study to
revisit the idea of is the virus more active than
we'd thought, and thus should that prompt us to start
treating it with more antivirals.
Speaker 2 (03:37):
So that's a really great question, a really great background
for this. You know, both Herpes simplex and vercella's astro
virus are obviously Herpe's viruses, but they're not the same.
They are very very different. You know, it has been
long thought and we treat it as such that you know,
the findings of Verceella in the eye are oftentimes inflammatory,
(04:01):
but we have more and more evidence that there are
actually you know, active viral components to the process. Right,
So you know, when we talk about against cyclavia for
the eye, you know, there has been a fair amount
of evidence showing that those pseudodendrites that we see on
you know, zoster patients, they actually do have active viral
(04:25):
particles in them. Okay, so that's why you can treat
them with antivirals because there's virus in them. Increasingly. What
we've also grown to understand is that this latency that
people have, because when you have zosterophthomicus, twenty five percent
of individuals that you see in your office, they're going
(04:46):
to have chronicer recurrent disease at five years. Okay, So
that means one in four patients that you see walking
into your office, you're going to be really good friends
with them, right, They're going to be back all the time.
And and what is this recurrent disease? So people talk
about being quite sent for a period of time, having
some latency going on, and then all of a sudden
it recurs. All right, what's going on there? So it
(05:06):
is more and more believed that during these periods of
quote unquote latency, it is that the viral transcription and
translation is held in check just barely by an intact
immune system, right, and anything that knocks that down tips
it over to clinical transcription, okay, and then there's some
viral replication. So that is a thought process behind, Well,
(05:31):
what if we use anti virals kind of like we
use in the head study, for example, low dose to
suppress this for those individuals who may be at risk
of recurrence, would this help decrease the number of in
this particular case for the Z study cornial endpoints.
Speaker 1 (05:50):
I'm glad you brought that up, this idea of kind
of latency and couiescence, coiescence and recurrence, because I know
when I've used the term recurrence before, some people have
corrected me and they've said in residency and now too.
I'm obviously always still learning, and I'm humbled off and
on this podcast, But the idea that it's not really
a recurrence, and I think it sounds like that's what
(06:11):
you're getting at, that it's not necessarily a recurrence. It's
more that it's always there, like you're saying, it's just
been kept in check. And the reason that's important is
because as we get into the study design, as I
was thinking about this topic, I was wondering, were you
looking at the number of recurrences people had or is
that not quite the framework with which you look at
And it sounds like it's not so much recurrence. Is
(06:33):
it sounds more like just a disease that is chronic
and is kind of maybe a little bit latent, but
it's not that it's ever really gone away. And then
it's coming back.
Speaker 2 (06:46):
More or less. But the only way that we could
set up a trial is by using end points, and
so then we do have to use recurrent endpoints, right,
And you know, the inflammatory component of this can be
in reaction into you know, viral replication of course, right,
So that's the most common endpoint, you know, stromo careatitis immune,
(07:08):
stromo caretitis non equtizing, although you know, you know, pseudodendrites
an act actually active virus is certainly an endpoint possibility.
Speaker 3 (07:18):
So walk me through.
Speaker 1 (07:19):
I know there were kind of a couple objectives in
the study. The primary objective, and I'll read out what
was listed was to find out whether or not twelve
months of low dose valley cyclovir treatment compared with placebo
de leaves time to development of new or worsening specific
eye disease manifestations of H said. Oh, and then the
secondary objective within that framework was looking a little bit
(07:42):
longer at the results of eighteen months. What were the
specific variables you were looking at that would qualify as
as an episode or a sign of activity.
Speaker 2 (07:52):
So the specific endpoints we looked at were, you know,
dendro form, epithyl caretitis, oftentimes the pseudo dendrite that we
see stromo carotitis, endothelial carotitis or disco formed caro titus,
depending on what you want to call it, iritis, and
then stromo carotitis with ulceration, which we actually didn't see
as an endpoint. The most common one you can imagine
was the stromo carotitis, the immune stromo carotitis that we saw.
Speaker 1 (08:16):
And I want to go back to one other thing
you said there, which I just made a note. If
you said one and four patients are going to kind
of be best friends with you for a while, is
that one and four patients who come in and they've
got shingles in the V one distribution, or one and
four patients who come in and they've got some sort
of ocular manifestation of that shingles.
Speaker 2 (08:36):
Correct the latter the letter, so ocular manifestations, and then
they're going to be your best friend.
Speaker 3 (08:41):
Gotcha? Gotcha?
Speaker 1 (08:41):
So you're not saying one in four patients who got
V one's auster, because we'd be really busy if that were,
If that.
Speaker 2 (08:47):
Were really busy. Now, if you look at the statistics, though,
you know, for individuals who have V one's auster, you know,
up to sixty stick sixty seven percent of individuals have
some sort of ocular finding. Now, grant most of it
is conjunctive itis, right, but that's a lot. Two thirds
of people have some sort of ocular involvement. It's a
(09:08):
lot in terms of.
Speaker 1 (09:09):
The general methodologies, and I want to focus more obviously
on some of the results and conclusions, not that methodologies
are not important. Which patients were generally recruited for this studies.
How long had these patients had h set?
Speaker 2 (09:22):
Oh?
Speaker 1 (09:23):
Were these patients who had kind of been diagnosed a
long time ago with HZTO and had been kind of
in clinic and out of clinic with ocular manifestations, or
were these patients who prior to the studies starting had
not presented yet.
Speaker 2 (09:36):
So this is a great question because I get a
lot of questions about this and was a little bit
of confusion. Okay, So the inclusion criteria were very specific,
and so these were individuals who had some episode of
zoster and the V one distribution at some point in
the past. Okay, So it could be anywhere from very
recent to years years ago, and they had to have
(09:59):
had one of these cornial endpoints, so they had to
have some ocular cornial manifestation in order to be able
to enroll in this study. So we did not enroll
individuals just because they had zostrothoumicus. Okay, these were not people.
They had to have had one of these episodes and
(10:20):
then we put them on in the trial. We randomize
them to see if we could delay another occurrence of
this endpoint.
Speaker 1 (10:28):
Gotcha, So that makes sense. It was patients who had
been active at one point. Let's give them the anti viral,
see if we can make them less active, not looking
at patients who had never been active.
Speaker 2 (10:40):
That is correct, because then the study sample size would
be like tens of thousands of individu.
Speaker 1 (10:47):
A lot of work in a little bit less specific
in ms of in terms of what you're looking at.
Speaker 2 (10:52):
Right, So this is distinctly different. The dosing here is
distinctly different than that which you would give for someone
who has an acute zhauster outbreak. Right, you know, the
high dose anti virals for seven to ten days when
they first had the skin outbreak. This is different. This
is you know, low dose suppressive at some point later
when they have demonstrated, you know, some sort of cornial manifestation.
Speaker 1 (11:15):
So, like you said, you could be talking to somebody
who six years ago had zoster since then has had
some episodes where they've been quiet, not episodes, some periods
where they've been quiet. Then maybe they've had an episode
where a couple of pseudodendrites have appeared, then gone away.
Maybe an episode a couple of years later where they
had an interstitial carotitis type of picture gone away.
Speaker 3 (11:38):
These are the types of patients you're treating.
Speaker 2 (11:40):
As one hundred percent correct, And we did stratify now
that you mentioned that that we did stratify the amount
of time before that they had some sort of episode
like this, So you know, we classified them as recent
or chronic onset disease based on six months as a cutoff.
(12:01):
So they could have had you know, V One's uster
ten years ago and then five years ago had their
first cornial endpoint. Okay, then they have chronic disease, that's
what we called it. But they could have had you know,
V One's uster ten years ago, and then you know,
three months ago, had their first episode of stromo carotitis. Okay,
(12:22):
then they would be enrolled into the strata of less
than six months, So recent onset disease.
Speaker 1 (12:29):
Gotcha, now, Obviously there's a lot of different results that
come out of these studies. But broadly speaking, actually before
we say the results, just to clarify the low dose
valley cyclaviar treatment, what was the treatment that these patients
were put on?
Speaker 2 (12:45):
So it randomized to one gram of vallet cycle OFVIA
once daily versus placebo.
Speaker 1 (12:51):
Okay, and that kind of fits with the general paradigm
of how most of us look at the treatment of.
Speaker 3 (12:58):
That.
Speaker 1 (12:59):
It's kind of double the tree even of HSV, I think,
whereas HSV it's five hundred milligrams UH once a day.
Broadly speaking, what did the results show? Did this anti
viral treatment reduce the number of recurrences, episodes of corneal endpoints?
Speaker 3 (13:18):
How did it end up? And were you surprised?
Speaker 2 (13:21):
So well, okay, so I'll go through the results yea.
Speaker 3 (13:25):
Yeah, yeah, yeah, okay.
Speaker 2 (13:27):
And then I'll go through some qualifiers. Okay. So based
on our pre specified you know, statistical stuff, you know,
including the power that we're looking at and the delta
that we're looking at because we're looking for thirty percent reduction, Okay,
just defining it as clinically relevant, we did not hit
(13:51):
our primary endpoint at twelve months. Okay, so the P
value was zero point zero nine. We did hit our
end point at a eighteen months with the P zero
points here with three. Okay. Now this is like kind
of this is where we had to think about how
we're going to interpret this, you know, statistical significance versus
clinically meaningful. All right. So at twelve months, our hazard
(14:14):
ratio was point seven to seven, So point seven to
seven means a twenty three percent reduction, okay, and then
our hazard ratio at eighteen months was point seven three,
which is a twenty seven percent reduction. All right, So
twenty seven percent happens to be statistically significant, but twenty
three just missed it. You know, that's statistical. But how
(14:36):
do we decide clinical relevance? Is that? You know, if
I was the patient, would I say that that's meaningful
to me for reduction? All right? So that's up for interpretation.
You know, we can get into it later. But you know,
I believe that had we hit enrollment goals, then we
would have his statistical significance and then this wouldn't be
(14:57):
a question.
Speaker 3 (14:58):
Right, But that's.
Speaker 1 (14:59):
Still quite statistic, that's still quite significant, right, I mean
twenty three percent reduction at twelve months, twenty seven percent
reduction in eighteen months.
Speaker 2 (15:09):
So from a clinical standpoint, I think it is very meaningful, right,
But you know a lot of people look at just
the statistical numbers. Is it is the p lessons zero
point zero five, Right, It's somewhat arbitrary. So if you
ask me that, no, we did not hit our endpoint,
our primary endpoint, but I do think it's clinically meaningful.
Speaker 3 (15:28):
Okay.
Speaker 2 (15:30):
The other thing that we found in pre specified analyzes was,
you know, we looked at we thought that there would
be a difference in the strata whether your recent onset
or your younger patient, and what we found was that
in the younger patients those lessons sixty and those with
recent onset disease, there seem to be a suggestion of
(15:50):
benefit with the P value of zero point zero six
and a hazard ratio point sixty three. So a thirty
seven percent reduction very clinically means but just miss statistical significance.
You know, the confidence interval includes one and so I
think it's still meaningful. The other there's a couple of
(16:12):
things that we actually found that are that were in
post talk analysis, but I think are very meaningful, and
these are statistically significant. But again post talk, if we
combined you know, we had four strata, right, because you
have a kind of a punnet square type thing with
age and recent versus chronic onset disease. If you just
combined the recent onset strata, so it doesn't matter what
(16:32):
age you are, and you had recent onset disease within
six months of being enrolled, and those who are on
Vallet Cyclavier had a statistically significant reduction and endpoints compared
to Placebo. Okay, So what that tells us is it
doesn't matter how old you are, but if you had
disease within the last six months some cornial endpoint and
(16:53):
you're on Vallet cyclavier, if you get put on Vallet cyclaviar,
you will benefit significantly statistically.
Speaker 3 (17:00):
Okay.
Speaker 2 (17:01):
And then the other very interesting thing that we found
is we didn't just take people out of the study
once they hit an endpoint. We allowed the investigator to
treat them appropriately, and then they stayed on whatever they're
randomized after that, okay. And what we found is that
people actually had multiple end points and against this is
post hoc analysis, but of the people who had these
(17:22):
more than one end point. If you were treated with
value cyclober, you actually had less end points, fewer end points, okay,
And each time you have an end point it results
in scarring and decrease vision. And so when you're on
value cyclober, you decrease the number of end points that
you have. So that's the basic premise the first part
(17:44):
of our study.
Speaker 3 (17:45):
So a lot of really powerful results there.
Speaker 1 (17:47):
Again, I appreciate they're not statistically significant all of them necessarily,
some of them perhaps, but the clinical significance. And for
people listening to this who who aren't familiar with statistics,
point oh five is kind of that number you want
to be below. So when you said point oh six before,
the reason we laughed is because point oh six is like, oh,
you're so close to point oh five. So statistically it
(18:09):
doesn't count, but in the real world it certainly is impactful.
So just to review a couple of the numbers you
said there, twenty three percent reduction of twelve months, twenty
seven percent reduction at eighteen months. The benefit was greater
in patients who were less than sixty with a recent
onset disease and with recent onset disease. Two separate things
(18:29):
and there was a decreased number of end points in
a lot of these patients. Based on these results, were
you able to make recommendations in terms of vallet cyc
lavie prophylaxis and treatment.
Speaker 2 (18:41):
Yeah, so based on this, based on being you know,
looking at from a clinical standpoint, not necessarily statistical standpoint,
but for all of the things that we just talked about,
we draw from this that we would recommend treating individuals
who have had a remote history of zoster in the
v one and it cornial endpoint at some point, we
(19:02):
would recommend treating them with one year of vallet cyclavira
at one once a day.
Speaker 1 (19:08):
When you treat them for one gram for a year
one day. You spoke about transcription earlier. Is the thought
that that should be enough to kind of get rid
of the virus and that you're not going to run
into this problem again or are you expecting that, Yes,
it is going to still be doing its thing, albeit
(19:31):
doing its thing that's very scientific, albeit.
Speaker 3 (19:33):
At a lower level.
Speaker 1 (19:34):
And then when the immune system isn't as healthy as
it should be, it is going to act up again,
and then you would need another course. And I know
that you didn't look at that would be another study.
But what's the idea about the patho physiology of what's
going on with the virus after that one year.
Speaker 2 (19:50):
So that's a really good question, and it goes into
how we interpret the data. I think that treating them
for that one year does, you know, not only just
keeps the virus in check, but I think it does
knock it out to some degree, Okay, and that's why
we see a lasting effect, because you know, we stop
treatment at twelve months, and then we watched them off
(20:12):
of treatment for another six months, and there was not
only a lasting effect, but it apparently took us into
statistical significance. Right, Yeah, So I do think that there
is some viroucidal activity from this that can have a
lasting effect. We're not even sure if it's necessary to use,
you know, either a full gram or a full year.
(20:36):
We don't know. What we're going to look at in
the near future is compliance with the medication, so we
can see how much they're actually taking, because that might
help us sort out, well, maybe you only need six
months of treatment, we don't know, or nine months or
maybe half a gram.
Speaker 1 (20:54):
How has this changed the way you look at a
patient who comes in who hasn't necessarily had recurrences but
comes in primary HZ and then maybe they've got a
little something doesn't quite meet the criteria from the study.
Are you more keen to say to anybody who's got
any ocular involvement from the get go, you know what,
(21:16):
you should just take a year of oral valley cyclo Bear.
Speaker 2 (21:20):
That's a really good question. I think if we say
what happens if someone comes in I'm a cornea specialist
and have any cornial finding, I'll put them on it, Okay,
no question. But the other ones, you know, like a conjunctivitis,
I don't know that I will put someone on it
for conjunctivitis, or at least I can't draw a conclusion
from the study to say that, right, but certainly for
(21:42):
anything corneal I would definitely highly recommend it.
Speaker 1 (21:45):
Before we move on to the element of the study
that focuses on poster pedic neuralgia, I'm curious, and this
might be a silly question, but for me, when I
see a pseudodendrite, I was confused for a while, like, oh,
why am I seeing pseudodendrite years later? For example, because
like you said that is active virus. Did you see
any pattern where patients with pseudodendrites might have responded with
(22:10):
recurrent pseudodendrites years later that they responded even better than
a patient with let's say, a recurrent iritis that happened
years later, because we know that in that situation that
maybe the iritis is the virus we don't quite know,
but the pseudodendrite we definitively know is actually virus. Was
there any extra benefit seen? Was that something that was
(22:30):
looked at.
Speaker 2 (22:32):
Wasn't something that was looked at. We have a lot
of exploratory analyses to do, and so it's one of
the things that we're going to look at. I honestly
don't know if we're going to have enough data for it,
because there were not that many individuals with the dender
form epatheal carotitis or even iritis, and I don't know
that our analysis will be robust enough.
Speaker 3 (22:53):
Makes makes sense?
Speaker 1 (22:55):
So question two, So you also looked at poster pedic neualogya,
which affects a lot of people, and optomologists probably don't
see as much of that because often that is seen
and managed a little bit more by GPS and other specialists,
Not that we don't care about it, but the reality
is a lot of the times we're not managing some
of those systemic medications.
Speaker 3 (23:14):
Now, the traditional.
Speaker 1 (23:15):
Paradigm has been you give valet cyclovier within the first
seventy two hours, and that's going to reduce the risk
of hope of post her pedican neuralgia. So this was
looking at, well, what if you give lo doos treatment
for twelve months with oral valet cyclovia, is that going
to even further reduce post her pedican neuralgia?
Speaker 3 (23:35):
Two questions there. I'll start with one question.
Speaker 1 (23:38):
Was it arbitrary the initial study when they said let's
start it within three days and if you don't start
it within three days, then there's no point in starting
it afterwards. Because obviously what this is looking at is, well,
maybe we should just be a little bit more aggressive.
Speaker 2 (23:58):
Well, again, I think the different populations that we're talking
about here, because again, to qualify for this study, right,
there's specific criteria that have nothing to do with an
acute onset of the disease. So again I want to
make sure we separate that out. What we're doing in
this instance is those people who have had we're looking
(24:21):
at those people who have had cornial findings at any point,
if they had post repetic neuralgia and we treated them
with this low dose valley cycler didn't have any effect on.
Speaker 1 (24:34):
Them, gotcha. So that that is a different framework than
what I just presented there.
Speaker 2 (24:39):
It is completely different than the acute treatment that were
that you had mentioned.
Speaker 1 (24:43):
Right.
Speaker 2 (24:44):
So in our study, as it turns out, of the
five hundred and twenty seven people we screened, seventy three
individuals actually had post repetic neurologia at the time of enrollment, Okay,
and we define that as a score of three out
of ten on the Zoster Brief Pain Inventory scale.
Speaker 3 (25:05):
So what did the results show for that?
Speaker 2 (25:07):
Well, the result showed our first thing, which is not
surprising at all, is that more people had posted bad
neurogia who were older than sixty. Not a surprise at all.
But what we did find is that while using valley
cyclviear didn't reduce the prevalence overall, it did reduce the
(25:29):
prevalence at eighteen months for those individuals younger than sixty.
So for younger individuals taking vallet Cyclavia for a year
decreased effectively the chance of having poster pretic neurologia at
eighteen months. That was one thing that we found. We
found a couple of interesting things. The other thing that
we found was that in the less than sixty years,
(25:51):
so again the younger age group, again those with chronic disease,
their pain scores were statistically significantly lower at both twelve
and eighteen months if they're on the Valley cyclavier. Okay,
And there was also a suggestion of this in those
who were older, but it was much more effective in
(26:12):
those who are younger. And then what I think is
also very interesting and applicable in this world today where
pain medications is problem. If you look at all the participants,
there was a significant decrease in pain duration at eighteen months, okay,
and then on top of that, there was a statistically
(26:34):
significant reduction in the dose of neuropathic medications that had
to be taken at twelve and eighteen months. That's very important, right,
because even though this isn't a pain medication, it treats
the disease such that people are using less pain medications.
Speaker 1 (26:50):
I think that's incredibly important for a lot of people
to know, because when somebody comes into me and they're
saying I've got poster pedic neuralgia. As an of the themologist,
like I said, Earl, I'm kind of thinking I feel
bad for you, obviously, but that's not necessarily my domain
because I'm not as familiar with some of these pain meds.
But the notion that well, maybe if we better treat
the actual core of the disease, which is with the
(27:13):
anti viral, that can actually reduce the pain you're in,
and that's not a paradigm that's really been popular.
Speaker 2 (27:20):
Right, And assessing how much neuropathic pain medication they need
is actually a prespecified analysis, so it's not wasn't post hawk,
So I mean, I think it's very significant. I think
it's very important.
Speaker 1 (27:33):
So in general, let's say a patient comes in not
necessarily to you, but to their GP or their neurologist
and they've got pain. Are the results of this study,
I don't want to say strong enough yet, but are
they suggestive that this should be thought of as something
that you know what, maybe they don't have any ocular issues,
(27:54):
but the fact that they've got post or pedic neuralgia
in general, doctors in general should be more ready to
offer oral a cycler or vale cyclviar.
Speaker 2 (28:05):
Yeah, I mean that's that's a good point because I
I don't know necessarily that you would tie you know,
cornial findings to poster pedic neurologia, right, and so in
this population that had poster pedic neurologia, there was a fact, right,
So you know, I would say, based on the studies,
(28:25):
based on the study that we did, I would recommend
a year of suppressive value cyclavier for any exhaust patient
that had poster re pedic neurologia.
Speaker 3 (28:34):
Exactly.
Speaker 1 (28:35):
That's what I'm getting at, right, because you're looking at
patients with corneal findings here, but we don't necessarily know
that the fact that they had corneal findings is distinctly
associated with the fact that they have the poster pedic neurologia.
Speaker 3 (28:46):
Those could be two separate things, right, So that's great,
I think. So don'tre jen.
Speaker 1 (28:56):
What surprised you, if anything about the results? Did you
get what it sounds like bad research? Did you get
what you were looking for? Because you're just supposed to
be you get what you get. You ask the question,
you get the answer. But what surprised you about the results,
if anything?
Speaker 2 (29:12):
Well, so Can I tell you what surprised me about
running this trial?
Speaker 3 (29:18):
Yes, okay, all surprises are welcome.
Speaker 2 (29:21):
What surprised me about running this trial was the fact
that we did not have equipoise amongst our investigators. Okay,
when we did a survey fifteen years ago before this
trial started, fifty six percent of CORNEA specialist believe that
you can do this therapy because it was like for
(29:43):
simplex and it would work. Okay, but they had nothing
to go on. There's no data, no studies that would
show that this would be true. There's two different viruses,
and they felt that if you treated this way allah
the head study, that it would work. No data. So
the the trial starts, we get ninety five centers up
and running Corny specialists as the primary investigators of all
(30:07):
these studies, and then we do a survey about how
the investigators believe whether this would work or not. Over
seventy percent of the investigators believe that this therapy would work.
So the problem you can see here is that if
you're a potential study participant or patient and you're being
(30:27):
asked to participate in this and you say, well, what
do you think doctor? You think it works? And the
doctor says, well, I think it works. Now, who's going
to sign up for the study? Right? This hampered our enrollment,
actually it it you know, knowingly or unknowingly. You know,
investigators' personal feelings can influence patients, right, and so this
(30:51):
hampered our ability to enroll. And so we ran the
trial for as long as we could, and then, you know,
for feasibility purposes, we stopped it early. And so had
we had more patients, I think we would have his
statistical significance the findings that we see here. I'm not
surprised because this is what we were hoping to prove.
This was our hypothesis.
Speaker 3 (31:09):
I might have misurgery there.
Speaker 1 (31:11):
You said seventy percent of investigators believed it would work.
Speaker 2 (31:16):
Seventy some, Yeah, seventy some.
Speaker 1 (31:19):
So wouldn't that lead to more patients saying, yes, I
do want to participate in the study.
Speaker 2 (31:24):
No, because you're they're saying, I believe it would work.
Let's put you in the study and get you randomized
so you might not get it.
Speaker 3 (31:30):
Oh, gotcha, gotcha? Gotcha?
Speaker 2 (31:33):
Right? This is not an obviation.
Speaker 3 (31:36):
True, they were proving your thoughts.
Speaker 1 (31:38):
They were proving your point too well, that patients said, Oh, well,
I'm not going to do it, okay, gotcha?
Speaker 2 (31:43):
Yeah, yeah, for real, real, I mean, we I enroll
lots of randomized trials, and I have to make sure
that I really don't know the answer.
Speaker 1 (31:52):
Well, clearly I don't do any randomized trials with mine there.
Speaker 3 (31:56):
But okay, so that.
Speaker 1 (31:57):
That illustrates the point quite well. So it's interesting because
this theory has been out there for a while. This
certainly lends credence to it, but the fact that seventy
percent of CORNEA specialists already kind of felt that way,
yet it takes so long to get to a point where, okay,
let's actually prove this. I don't know if it speaks
to anything other than the fact that things can sometimes
(32:19):
move slowly, and maybe it suggested sometimes we should follow
our guts even if the evidence isn't there, because the
evidence will come. Now, that's not necessarily the safest way
of approaching everything, but people obviously did have the right
idea for many years that you know, maybe we should
be a little more aggressive with the antivirals, and unfortunately
(32:39):
that meant less people coming into the study. But it
is I think a valuable lesson as we kind of
examine our own approaches to treating patients sometimes who are
a little bit more complex and who are refractory to
the typical treatments, for.
Speaker 2 (32:54):
Sure, and I agree with you on that on all
your points, but I do think that having run this
study as long as it took and as much money
as it costs to run it, and you know, we're
kind of proving what we think we already know. All
that data on post re pedic neurologia, I think is
fascinating and I think that it may spawn future studies
on how best we can you know, even treat these patients,
(33:17):
and not just with pain medications, but balle cyclovia seems
to work to cut down pain as well.
Speaker 1 (33:23):
And absolutely in this era where we've got a pain
pill crisis, which you mentioned earlier, amazing if you're a
nanty viral which is not addictive as far as I'm aware,
can supplant some of those treatments.
Speaker 3 (33:39):
Doctor.
Speaker 1 (33:39):
So, doctor Benjijing, thank you so much for joining me.
Really really really valuable to have somebody who is running
the study obviously talk to us about about the process
and about the results. And you've done a great job
at explaining the results and really the conclusions and recommendations
that come out of that.
Speaker 3 (33:55):
So so so delighted that you took the time out
of your busy schedule.
Speaker 1 (33:59):
Thank you for the Trinity, and thank you everybody for
listening to another episode of blind Spot.
Speaker 3 (34:04):
Have a great day.
Hey everybody, I'm XAEO Mednik and welcome to another episode
of blind Spot. This episode is sponsored by THEO Pharma Canada.
THEA pharm of Canada is the Canadian subsidiary of THEA,
Europe's leading pioneering and innovative eye health brand. Founded in
nineteen ninety four by Henri Schibre. With five generations of history,
the Chubret family has been dedicated to I care for
(00:30):
more than one hundred and fifty years. Their commitment to
improving lives is born of their pioneering spirit. They continue
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They've created innovative delivery systems. They've focused on making products
accessible and cost effective for patients. They live this mission
every day because everyone should have the same opportunities to
see the world through healthy eyes. So thank you THEO
(00:53):
Pharmer Canada for supporting Blindspot. The Heads Trial was a
seminal study that was done in evaluating different treatment options
for Herbie's simplex virus. Recently, at the end of twenty
twenty four, the preliminary results from the z Study were published.
A study that looked at different treatment options for zoster virus.
In particular, the study look to examine what is the
(01:16):
role for longer term anti viral prophylaxis for patients who
are experiencing hseto. For many years, the paradigm has been
that while the virus certainly plays a role in the
eye disease of hid oh, a lot of the havoc
reached by h STOH is more so related to the
inflammation that is set off by the cascade of the virus. Yet, anecdotally,
(01:37):
many have wondered, is the virus more active than we think?
Is the zoster virus itself contributing to more damage than
we had previously given credence to And if that's the case,
should we be more aggressive with our anti viral approach
in the treatment of h OH, perhaps even months after
the presenting episode. I'm joined today by Corneas Specialist Doctor
(01:58):
Benny Jeng. Doctor Jeng is the the professor and chair
of the University of Pennsylvania School of Medicine, Department of Ophthalmology,
and shae I Institute. He was a lead researcher in
the Zoster eye disease study, better known as Zed's all Right,
Doctor Benny Jang, Welcome to the podcast. Thank you so
much for joining me, Thank you for having me. I've
(02:18):
done a couple episodes. We've done about forty episodes now,
but I've done a couple episodes focusing on shingles and
on simplex, and obviously today we're going to be focusing
on shingles. A theme that's come up a couple times,
and I guess recently because we just did an episode
on topical gan cyclovir. A theme that's come up is
this notion, which I believe is what prompted the z study,
(02:40):
that maybe the virus was more impactful in the disease
kind of occurring in the eye than we'd initially thought
it was. When I was in residency, what I had
learned was that, you know, in HSV, it's really the
virus that wreaks a lot of the havoc, whereas in
hzi OH in zoster, the virus obviously has something to
do with it, but it's kind of the cascade that's
(03:01):
set off by the virus that leads to a lot
of inflammation. And that's the reason why, for example, we
see RHSV patients who are often kept on a cycle
of your prophylactically for a long time, but for zoster,
they're not because we view this more as an inflammatory process.
Walk me through that paradigm and what maybe prompted this
(03:23):
study which you were integral in the z study to
revisit the idea of is the virus more active than
we'd thought, and thus should that prompt us to start
treating it with more antivirals.
Speaker 2 (03:37):
So that's a really great question, a really great background
for this. You know, both Herpes simplex and vercella's astro
virus are obviously Herpe's viruses, but they're not the same.
They are very very different. You know, it has been
long thought and we treat it as such that you know,
the findings of Verceella in the eye are oftentimes inflammatory,
(04:01):
but we have more and more evidence that there are
actually you know, active viral components to the process. Right,
So you know, when we talk about against cyclavia for
the eye, you know, there has been a fair amount
of evidence showing that those pseudodendrites that we see on
you know, zoster patients, they actually do have active viral
(04:25):
particles in them. Okay, so that's why you can treat
them with antivirals because there's virus in them. Increasingly. What
we've also grown to understand is that this latency that
people have, because when you have zosterophthomicus, twenty five percent
of individuals that you see in your office, they're going
(04:46):
to have chronicer recurrent disease at five years. Okay, So
that means one in four patients that you see walking
into your office, you're going to be really good friends
with them, right, They're going to be back all the time.
And and what is this recurrent disease? So people talk
about being quite sent for a period of time, having
some latency going on, and then all of a sudden
it recurs. All right, what's going on there? So it
(05:06):
is more and more believed that during these periods of
quote unquote latency, it is that the viral transcription and
translation is held in check just barely by an intact
immune system, right, and anything that knocks that down tips
it over to clinical transcription, okay, and then there's some
viral replication. So that is a thought process behind, Well,
(05:31):
what if we use anti virals kind of like we
use in the head study, for example, low dose to
suppress this for those individuals who may be at risk
of recurrence, would this help decrease the number of in
this particular case for the Z study cornial endpoints.
Speaker 1 (05:50):
I'm glad you brought that up, this idea of kind
of latency and couiescence, coiescence and recurrence, because I know
when I've used the term recurrence before, some people have
corrected me and they've said in residency and now too.
I'm obviously always still learning, and I'm humbled off and
on this podcast, But the idea that it's not really
a recurrence, and I think it sounds like that's what
(06:11):
you're getting at, that it's not necessarily a recurrence. It's
more that it's always there, like you're saying, it's just
been kept in check. And the reason that's important is
because as we get into the study design, as I
was thinking about this topic, I was wondering, were you
looking at the number of recurrences people had or is
that not quite the framework with which you look at
And it sounds like it's not so much recurrence. Is
(06:33):
it sounds more like just a disease that is chronic
and is kind of maybe a little bit latent, but
it's not that it's ever really gone away. And then
it's coming back.
Speaker 2 (06:46):
More or less. But the only way that we could
set up a trial is by using end points, and
so then we do have to use recurrent endpoints, right,
And you know, the inflammatory component of this can be
in reaction into you know, viral replication of course, right,
So that's the most common endpoint, you know, stromo careatitis immune,
(07:08):
stromo caretitis non equtizing, although you know, you know, pseudodendrites
an act actually active virus is certainly an endpoint possibility.
Speaker 3 (07:18):
So walk me through.
Speaker 1 (07:19):
I know there were kind of a couple objectives in
the study. The primary objective, and I'll read out what
was listed was to find out whether or not twelve
months of low dose valley cyclovir treatment compared with placebo
de leaves time to development of new or worsening specific
eye disease manifestations of H said. Oh, and then the
secondary objective within that framework was looking a little bit
(07:42):
longer at the results of eighteen months. What were the
specific variables you were looking at that would qualify as
as an episode or a sign of activity.
Speaker 2 (07:52):
So the specific endpoints we looked at were, you know,
dendro form, epithyl caretitis, oftentimes the pseudo dendrite that we
see stromo carotitis, endothelial carotitis or disco formed caro titus,
depending on what you want to call it, iritis, and
then stromo carotitis with ulceration, which we actually didn't see
as an endpoint. The most common one you can imagine
was the stromo carotitis, the immune stromo carotitis that we saw.
Speaker 1 (08:16):
And I want to go back to one other thing
you said there, which I just made a note. If
you said one and four patients are going to kind
of be best friends with you for a while, is
that one and four patients who come in and they've
got shingles in the V one distribution, or one and
four patients who come in and they've got some sort
of ocular manifestation of that shingles.
Speaker 2 (08:36):
Correct the latter the letter, so ocular manifestations, and then
they're going to be your best friend.
Speaker 3 (08:41):
Gotcha? Gotcha?
Speaker 1 (08:41):
So you're not saying one in four patients who got
V one's auster, because we'd be really busy if that were,
If that.
Speaker 2 (08:47):
Were really busy. Now, if you look at the statistics, though,
you know, for individuals who have V one's auster, you know,
up to sixty stick sixty seven percent of individuals have
some sort of ocular finding. Now, grant most of it
is conjunctive itis, right, but that's a lot. Two thirds
of people have some sort of ocular involvement. It's a
(09:08):
lot in terms of.
Speaker 1 (09:09):
The general methodologies, and I want to focus more obviously
on some of the results and conclusions, not that methodologies
are not important. Which patients were generally recruited for this studies.
How long had these patients had h set?
Speaker 2 (09:22):
Oh?
Speaker 1 (09:23):
Were these patients who had kind of been diagnosed a
long time ago with HZTO and had been kind of
in clinic and out of clinic with ocular manifestations, or
were these patients who prior to the studies starting had
not presented yet.
Speaker 2 (09:36):
So this is a great question because I get a
lot of questions about this and was a little bit
of confusion. Okay, So the inclusion criteria were very specific,
and so these were individuals who had some episode of
zoster and the V one distribution at some point in
the past. Okay, So it could be anywhere from very
recent to years years ago, and they had to have
(09:59):
had one of these cornial endpoints, so they had to
have some ocular cornial manifestation in order to be able
to enroll in this study. So we did not enroll
individuals just because they had zostrothoumicus. Okay, these were not people.
They had to have had one of these episodes and
(10:20):
then we put them on in the trial. We randomize
them to see if we could delay another occurrence of
this endpoint.
Speaker 1 (10:28):
Gotcha, So that makes sense. It was patients who had
been active at one point. Let's give them the anti viral,
see if we can make them less active, not looking
at patients who had never been active.
Speaker 2 (10:40):
That is correct, because then the study sample size would
be like tens of thousands of individu.
Speaker 1 (10:47):
A lot of work in a little bit less specific
in ms of in terms of what you're looking at.
Speaker 2 (10:52):
Right, So this is distinctly different. The dosing here is
distinctly different than that which you would give for someone
who has an acute zhauster outbreak. Right, you know, the
high dose anti virals for seven to ten days when
they first had the skin outbreak. This is different. This
is you know, low dose suppressive at some point later
when they have demonstrated, you know, some sort of cornial manifestation.
Speaker 1 (11:15):
So, like you said, you could be talking to somebody
who six years ago had zoster since then has had
some episodes where they've been quiet, not episodes, some periods
where they've been quiet. Then maybe they've had an episode
where a couple of pseudodendrites have appeared, then gone away.
Maybe an episode a couple of years later where they
had an interstitial carotitis type of picture gone away.
Speaker 3 (11:38):
These are the types of patients you're treating.
Speaker 2 (11:40):
As one hundred percent correct, And we did stratify now
that you mentioned that that we did stratify the amount
of time before that they had some sort of episode
like this, So you know, we classified them as recent
or chronic onset disease based on six months as a cutoff.
(12:01):
So they could have had you know, V One's uster
ten years ago and then five years ago had their
first cornial endpoint. Okay, then they have chronic disease, that's
what we called it. But they could have had you know,
V One's uster ten years ago, and then you know,
three months ago, had their first episode of stromo carotitis. Okay,
(12:22):
then they would be enrolled into the strata of less
than six months, So recent onset disease.
Speaker 1 (12:29):
Gotcha, now, Obviously there's a lot of different results that
come out of these studies. But broadly speaking, actually before
we say the results, just to clarify the low dose
valley cyclaviar treatment, what was the treatment that these patients
were put on?
Speaker 2 (12:45):
So it randomized to one gram of vallet cycle OFVIA
once daily versus placebo.
Speaker 1 (12:51):
Okay, and that kind of fits with the general paradigm
of how most of us look at the treatment of.
Speaker 3 (12:58):
That.
Speaker 1 (12:59):
It's kind of double the tree even of HSV, I think,
whereas HSV it's five hundred milligrams UH once a day.
Broadly speaking, what did the results show? Did this anti
viral treatment reduce the number of recurrences, episodes of corneal endpoints?
Speaker 3 (13:18):
How did it end up? And were you surprised?
Speaker 2 (13:21):
So well, okay, so I'll go through the results yea.
Speaker 3 (13:25):
Yeah, yeah, yeah, okay.
Speaker 2 (13:27):
And then I'll go through some qualifiers. Okay. So based
on our pre specified you know, statistical stuff, you know,
including the power that we're looking at and the delta
that we're looking at because we're looking for thirty percent reduction, Okay,
just defining it as clinically relevant, we did not hit
(13:51):
our primary endpoint at twelve months. Okay, so the P
value was zero point zero nine. We did hit our
end point at a eighteen months with the P zero
points here with three. Okay. Now this is like kind
of this is where we had to think about how
we're going to interpret this, you know, statistical significance versus
clinically meaningful. All right. So at twelve months, our hazard
(14:14):
ratio was point seven to seven, So point seven to
seven means a twenty three percent reduction, okay, and then
our hazard ratio at eighteen months was point seven three,
which is a twenty seven percent reduction. All right, So
twenty seven percent happens to be statistically significant, but twenty
three just missed it. You know, that's statistical. But how
(14:36):
do we decide clinical relevance? Is that? You know, if
I was the patient, would I say that that's meaningful
to me for reduction? All right? So that's up for interpretation.
You know, we can get into it later. But you know,
I believe that had we hit enrollment goals, then we
would have his statistical significance and then this wouldn't be
(14:57):
a question.
Speaker 3 (14:58):
Right, But that's.
Speaker 1 (14:59):
Still quite statistic, that's still quite significant, right, I mean
twenty three percent reduction at twelve months, twenty seven percent
reduction in eighteen months.
Speaker 2 (15:09):
So from a clinical standpoint, I think it is very meaningful, right,
But you know a lot of people look at just
the statistical numbers. Is it is the p lessons zero
point zero five, Right, It's somewhat arbitrary. So if you
ask me that, no, we did not hit our endpoint,
our primary endpoint, but I do think it's clinically meaningful.
Speaker 3 (15:28):
Okay.
Speaker 2 (15:30):
The other thing that we found in pre specified analyzes was,
you know, we looked at we thought that there would
be a difference in the strata whether your recent onset
or your younger patient, and what we found was that
in the younger patients those lessons sixty and those with
recent onset disease, there seem to be a suggestion of
(15:50):
benefit with the P value of zero point zero six
and a hazard ratio point sixty three. So a thirty
seven percent reduction very clinically means but just miss statistical significance.
You know, the confidence interval includes one and so I
think it's still meaningful. The other there's a couple of
(16:12):
things that we actually found that are that were in
post talk analysis, but I think are very meaningful, and
these are statistically significant. But again post talk, if we
combined you know, we had four strata, right, because you
have a kind of a punnet square type thing with
age and recent versus chronic onset disease. If you just
combined the recent onset strata, so it doesn't matter what
(16:32):
age you are, and you had recent onset disease within
six months of being enrolled, and those who are on
Vallet Cyclavier had a statistically significant reduction and endpoints compared
to Placebo. Okay, So what that tells us is it
doesn't matter how old you are, but if you had
disease within the last six months some cornial endpoint and
(16:53):
you're on Vallet cyclavier, if you get put on Vallet cyclaviar,
you will benefit significantly statistically.
Speaker 3 (17:00):
Okay.
Speaker 2 (17:01):
And then the other very interesting thing that we found
is we didn't just take people out of the study
once they hit an endpoint. We allowed the investigator to
treat them appropriately, and then they stayed on whatever they're
randomized after that, okay. And what we found is that
people actually had multiple end points and against this is
post hoc analysis, but of the people who had these
(17:22):
more than one end point. If you were treated with
value cyclober, you actually had less end points, fewer end points, okay,
And each time you have an end point it results
in scarring and decrease vision. And so when you're on
value cyclober, you decrease the number of end points that
you have. So that's the basic premise the first part
(17:44):
of our study.
Speaker 3 (17:45):
So a lot of really powerful results there.
Speaker 1 (17:47):
Again, I appreciate they're not statistically significant all of them necessarily,
some of them perhaps, but the clinical significance. And for
people listening to this who who aren't familiar with statistics,
point oh five is kind of that number you want
to be below. So when you said point oh six before,
the reason we laughed is because point oh six is like, oh,
you're so close to point oh five. So statistically it
(18:09):
doesn't count, but in the real world it certainly is impactful.
So just to review a couple of the numbers you
said there, twenty three percent reduction of twelve months, twenty
seven percent reduction at eighteen months. The benefit was greater
in patients who were less than sixty with a recent
onset disease and with recent onset disease. Two separate things
(18:29):
and there was a decreased number of end points in
a lot of these patients. Based on these results, were
you able to make recommendations in terms of vallet cyc
lavie prophylaxis and treatment.
Speaker 2 (18:41):
Yeah, so based on this, based on being you know,
looking at from a clinical standpoint, not necessarily statistical standpoint,
but for all of the things that we just talked about,
we draw from this that we would recommend treating individuals
who have had a remote history of zoster in the
v one and it cornial endpoint at some point, we
(19:02):
would recommend treating them with one year of vallet cyclavira
at one once a day.
Speaker 1 (19:08):
When you treat them for one gram for a year
one day. You spoke about transcription earlier. Is the thought
that that should be enough to kind of get rid
of the virus and that you're not going to run
into this problem again or are you expecting that, Yes,
it is going to still be doing its thing, albeit
(19:31):
doing its thing that's very scientific, albeit.
Speaker 3 (19:33):
At a lower level.
Speaker 1 (19:34):
And then when the immune system isn't as healthy as
it should be, it is going to act up again,
and then you would need another course. And I know
that you didn't look at that would be another study.
But what's the idea about the patho physiology of what's
going on with the virus after that one year.
Speaker 2 (19:50):
So that's a really good question, and it goes into
how we interpret the data. I think that treating them
for that one year does, you know, not only just
keeps the virus in check, but I think it does
knock it out to some degree, Okay, and that's why
we see a lasting effect, because you know, we stop
treatment at twelve months, and then we watched them off
(20:12):
of treatment for another six months, and there was not
only a lasting effect, but it apparently took us into
statistical significance. Right, Yeah, So I do think that there
is some viroucidal activity from this that can have a
lasting effect. We're not even sure if it's necessary to use,
you know, either a full gram or a full year.
(20:36):
We don't know. What we're going to look at in
the near future is compliance with the medication, so we
can see how much they're actually taking, because that might
help us sort out, well, maybe you only need six
months of treatment, we don't know, or nine months or
maybe half a gram.
Speaker 1 (20:54):
How has this changed the way you look at a
patient who comes in who hasn't necessarily had recurrences but
comes in primary HZ and then maybe they've got a
little something doesn't quite meet the criteria from the study.
Are you more keen to say to anybody who's got
any ocular involvement from the get go, you know what,
(21:16):
you should just take a year of oral valley cyclo Bear.
Speaker 2 (21:20):
That's a really good question. I think if we say
what happens if someone comes in I'm a cornea specialist
and have any cornial finding, I'll put them on it, Okay,
no question. But the other ones, you know, like a conjunctivitis,
I don't know that I will put someone on it
for conjunctivitis, or at least I can't draw a conclusion
from the study to say that, right, but certainly for
(21:42):
anything corneal I would definitely highly recommend it.
Speaker 1 (21:45):
Before we move on to the element of the study
that focuses on poster pedic neuralgia, I'm curious, and this
might be a silly question, but for me, when I
see a pseudodendrite, I was confused for a while, like, oh,
why am I seeing pseudodendrite years later? For example, because
like you said that is active virus. Did you see
any pattern where patients with pseudodendrites might have responded with
(22:10):
recurrent pseudodendrites years later that they responded even better than
a patient with let's say, a recurrent iritis that happened
years later, because we know that in that situation that
maybe the iritis is the virus we don't quite know,
but the pseudodendrite we definitively know is actually virus. Was
there any extra benefit seen? Was that something that was
(22:30):
looked at.
Speaker 2 (22:32):
Wasn't something that was looked at. We have a lot
of exploratory analyses to do, and so it's one of
the things that we're going to look at. I honestly
don't know if we're going to have enough data for it,
because there were not that many individuals with the dender
form epatheal carotitis or even iritis, and I don't know
that our analysis will be robust enough.
Speaker 3 (22:53):
Makes makes sense?
Speaker 1 (22:55):
So question two, So you also looked at poster pedic neualogya,
which affects a lot of people, and optomologists probably don't
see as much of that because often that is seen
and managed a little bit more by GPS and other specialists,
Not that we don't care about it, but the reality
is a lot of the times we're not managing some
of those systemic medications.
Speaker 3 (23:14):
Now, the traditional.
Speaker 1 (23:15):
Paradigm has been you give valet cyclovier within the first
seventy two hours, and that's going to reduce the risk
of hope of post her pedican neuralgia. So this was
looking at, well, what if you give lo doos treatment
for twelve months with oral valet cyclovia, is that going
to even further reduce post her pedican neuralgia?
Speaker 3 (23:35):
Two questions there. I'll start with one question.
Speaker 1 (23:38):
Was it arbitrary the initial study when they said let's
start it within three days and if you don't start
it within three days, then there's no point in starting
it afterwards. Because obviously what this is looking at is, well,
maybe we should just be a little bit more aggressive.
Speaker 2 (23:58):
Well, again, I think the different populations that we're talking
about here, because again, to qualify for this study, right,
there's specific criteria that have nothing to do with an
acute onset of the disease. So again I want to
make sure we separate that out. What we're doing in
this instance is those people who have had we're looking
(24:21):
at those people who have had cornial findings at any point,
if they had post repetic neuralgia and we treated them
with this low dose valley cycler didn't have any effect on.
Speaker 1 (24:34):
Them, gotcha. So that that is a different framework than
what I just presented there.
Speaker 2 (24:39):
It is completely different than the acute treatment that were
that you had mentioned.
Speaker 1 (24:43):
Right.
Speaker 2 (24:44):
So in our study, as it turns out, of the
five hundred and twenty seven people we screened, seventy three
individuals actually had post repetic neurologia at the time of enrollment, Okay,
and we define that as a score of three out
of ten on the Zoster Brief Pain Inventory scale.
Speaker 3 (25:05):
So what did the results show for that?
Speaker 2 (25:07):
Well, the result showed our first thing, which is not
surprising at all, is that more people had posted bad
neurogia who were older than sixty. Not a surprise at all.
But what we did find is that while using valley
cyclviear didn't reduce the prevalence overall, it did reduce the
(25:29):
prevalence at eighteen months for those individuals younger than sixty.
So for younger individuals taking vallet Cyclavia for a year
decreased effectively the chance of having poster pretic neurologia at
eighteen months. That was one thing that we found. We
found a couple of interesting things. The other thing that
we found was that in the less than sixty years,
(25:51):
so again the younger age group, again those with chronic disease,
their pain scores were statistically significantly lower at both twelve
and eighteen months if they're on the Valley cyclavier. Okay,
And there was also a suggestion of this in those
who were older, but it was much more effective in
(26:12):
those who are younger. And then what I think is
also very interesting and applicable in this world today where
pain medications is problem. If you look at all the participants,
there was a significant decrease in pain duration at eighteen months, okay,
and then on top of that, there was a statistically
(26:34):
significant reduction in the dose of neuropathic medications that had
to be taken at twelve and eighteen months. That's very important, right,
because even though this isn't a pain medication, it treats
the disease such that people are using less pain medications.
Speaker 1 (26:50):
I think that's incredibly important for a lot of people
to know, because when somebody comes into me and they're
saying I've got poster pedic neuralgia. As an of the themologist,
like I said, Earl, I'm kind of thinking I feel
bad for you, obviously, but that's not necessarily my domain
because I'm not as familiar with some of these pain meds.
But the notion that well, maybe if we better treat
the actual core of the disease, which is with the
(27:13):
anti viral, that can actually reduce the pain you're in,
and that's not a paradigm that's really been popular.
Speaker 2 (27:20):
Right, And assessing how much neuropathic pain medication they need
is actually a prespecified analysis, so it's not wasn't post hawk,
So I mean, I think it's very significant. I think
it's very important.
Speaker 1 (27:33):
So in general, let's say a patient comes in not
necessarily to you, but to their GP or their neurologist
and they've got pain. Are the results of this study,
I don't want to say strong enough yet, but are
they suggestive that this should be thought of as something
that you know what, maybe they don't have any ocular issues,
(27:54):
but the fact that they've got post or pedic neuralgia
in general, doctors in general should be more ready to
offer oral a cycler or vale cyclviar.
Speaker 2 (28:05):
Yeah, I mean that's that's a good point because I
I don't know necessarily that you would tie you know,
cornial findings to poster pedic neurologia, right, and so in
this population that had poster pedic neurologia, there was a fact, right,
So you know, I would say, based on the studies,
(28:25):
based on the study that we did, I would recommend
a year of suppressive value cyclavier for any exhaust patient
that had poster re pedic neurologia.
Speaker 3 (28:34):
Exactly.
Speaker 1 (28:35):
That's what I'm getting at, right, because you're looking at
patients with corneal findings here, but we don't necessarily know
that the fact that they had corneal findings is distinctly
associated with the fact that they have the poster pedic neurologia.
Speaker 3 (28:46):
Those could be two separate things, right, So that's great,
I think. So don'tre jen.
Speaker 1 (28:56):
What surprised you, if anything about the results? Did you
get what it sounds like bad research? Did you get
what you were looking for? Because you're just supposed to
be you get what you get. You ask the question,
you get the answer. But what surprised you about the results,
if anything?
Speaker 2 (29:12):
Well, so Can I tell you what surprised me about
running this trial?
Speaker 3 (29:18):
Yes, okay, all surprises are welcome.
Speaker 2 (29:21):
What surprised me about running this trial was the fact
that we did not have equipoise amongst our investigators. Okay,
when we did a survey fifteen years ago before this
trial started, fifty six percent of CORNEA specialist believe that
you can do this therapy because it was like for
(29:43):
simplex and it would work. Okay, but they had nothing
to go on. There's no data, no studies that would
show that this would be true. There's two different viruses,
and they felt that if you treated this way allah
the head study, that it would work. No data. So
the the trial starts, we get ninety five centers up
and running Corny specialists as the primary investigators of all
(30:07):
these studies, and then we do a survey about how
the investigators believe whether this would work or not. Over
seventy percent of the investigators believe that this therapy would work.
So the problem you can see here is that if
you're a potential study participant or patient and you're being
(30:27):
asked to participate in this and you say, well, what
do you think doctor? You think it works? And the
doctor says, well, I think it works. Now, who's going
to sign up for the study? Right? This hampered our enrollment,
actually it it you know, knowingly or unknowingly. You know,
investigators' personal feelings can influence patients, right, and so this
(30:51):
hampered our ability to enroll. And so we ran the
trial for as long as we could, and then, you know,
for feasibility purposes, we stopped it early. And so had
we had more patients, I think we would have his
statistical significance the findings that we see here. I'm not
surprised because this is what we were hoping to prove.
This was our hypothesis.
Speaker 3 (31:09):
I might have misurgery there.
Speaker 1 (31:11):
You said seventy percent of investigators believed it would work.
Speaker 2 (31:16):
Seventy some, Yeah, seventy some.
Speaker 1 (31:19):
So wouldn't that lead to more patients saying, yes, I
do want to participate in the study.
Speaker 2 (31:24):
No, because you're they're saying, I believe it would work.
Let's put you in the study and get you randomized
so you might not get it.
Speaker 3 (31:30):
Oh, gotcha, gotcha? Gotcha?
Speaker 2 (31:33):
Right? This is not an obviation.
Speaker 3 (31:36):
True, they were proving your thoughts.
Speaker 1 (31:38):
They were proving your point too well, that patients said, Oh, well,
I'm not going to do it, okay, gotcha?
Speaker 2 (31:43):
Yeah, yeah, for real, real, I mean, we I enroll
lots of randomized trials, and I have to make sure
that I really don't know the answer.
Speaker 1 (31:52):
Well, clearly I don't do any randomized trials with mine there.
Speaker 3 (31:56):
But okay, so that.
Speaker 1 (31:57):
That illustrates the point quite well. So it's interesting because
this theory has been out there for a while. This
certainly lends credence to it, but the fact that seventy
percent of CORNEA specialists already kind of felt that way,
yet it takes so long to get to a point where, okay,
let's actually prove this. I don't know if it speaks
to anything other than the fact that things can sometimes
(32:19):
move slowly, and maybe it suggested sometimes we should follow
our guts even if the evidence isn't there, because the
evidence will come. Now, that's not necessarily the safest way
of approaching everything, but people obviously did have the right
idea for many years that you know, maybe we should
be a little more aggressive with the antivirals, and unfortunately
(32:39):
that meant less people coming into the study. But it
is I think a valuable lesson as we kind of
examine our own approaches to treating patients sometimes who are
a little bit more complex and who are refractory to
the typical treatments, for.
Speaker 2 (32:54):
Sure, and I agree with you on that on all
your points, but I do think that having run this
study as long as it took and as much money
as it costs to run it, and you know, we're
kind of proving what we think we already know. All
that data on post re pedic neurologia, I think is
fascinating and I think that it may spawn future studies
on how best we can you know, even treat these patients,
(33:17):
and not just with pain medications, but balle cyclovia seems
to work to cut down pain as well.
Speaker 1 (33:23):
And absolutely in this era where we've got a pain
pill crisis, which you mentioned earlier, amazing if you're a
nanty viral which is not addictive as far as I'm aware,
can supplant some of those treatments.
Speaker 3 (33:39):
Doctor.
Speaker 1 (33:39):
So, doctor Benjijing, thank you so much for joining me.
Really really really valuable to have somebody who is running
the study obviously talk to us about about the process
and about the results. And you've done a great job
at explaining the results and really the conclusions and recommendations
that come out of that.
Speaker 3 (33:55):
So so so delighted that you took the time out
of your busy schedule.
Speaker 1 (33:59):
Thank you for the Trinity, and thank you everybody for
listening to another episode of blind Spot.
Speaker 3 (34:04):
Have a great day.
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