CMV Disease in Transplant Recipients: Clinical Cases and Expert Opinion
Dr. Limaye:
Welcome to this continuing education symposium and panel discussion entitled CMV Disease in
Transplant Recipients: Clinical Cases and Expert Opinion.
My name is Ajit Limaye. I’m Associate Professor of Laboratory Medicine and Medicine
at the University of Washington in Seattle.
I’d like to thank the joint sponsors of this symposium, the Robert Michael Educational
Institute and the Postgraduate Institute for Medicine.
I’d also like to thank ViroPharma for their support for this program. And also to ASM and
IDSA for allowing us to host this satellite symposium.
Tonight’s format is going to be slightly different than a standard format in a couple of
different ways that I’d like to go over with you very briefly. I think people should keep in mind
that we’re presenting here not only to the audience that’s present in this room, but also we have
several of our colleagues from around the United States who are participating via a live Webcast
this evening.
I’ve asked each faculty member to speak for 20 minutes and present during their
presentation a case of CMV disease in a transplant patient. They have specifically included some
questions in their presentation and you will be provided with keypads and we’ll ask you to
participate by choosing – making a selection based on the questions that are posed, and then your
responses will be tabulated and discussed by the individual speakers.
I want to assure you that your names will not be associated with either correct,
unfortunately, or incorrect answers, so please vote freely, vote your conscience. You can do it
anonymously.
The Webcast participants will be able to view the questions and the answers as they’re
displayed and after each presentation I’m going to facilitate a ten-minute discussion with the
panelists. And at the end of the program we’ll open it up to the audience that’s here and ask
people to please come to the microphone and ask any questions that come up or that have been
generated during the course of the program.
We will also be taking questions that are submitted by participants of the Webcast and we
will announce those as they come up.
So before I begin, just a couple of housekeeping items. First, please, if you would, as a
courtesy to your colleagues, those around you, turn your electronic devices on the vibrate mode or
off for the duration of the symposium.
Second, you may have noticed that there are video cameras throughout that are recording
the program and that is again as part of the broadcasted Webcast that is happening concurrent
with this session here. We’d like to welcome our colleagues who’ve joined us through the Web.
Next, you should have on your table in front of you a packet or a workbook that has the
learning objectives for this evening’s program, as well as the full disclosure information for your
review.
Last, for those of you who wish to receive continuing education credit for this program,
you must complete the activity evaluation that is located at the back of the workbook and please
hand it to one of the attendants as you leave the program at the conclusion of the program.
So at this time, without further ado, I’d like to introduce the first case presentation and talk
by Dr. Michael Boeckh, entitled “CMV in Hematopoietic Stem Cell Transplantation.” Dr. Boeckh
is Associate Professor at the Fred Hutchinson Cancer Research Center and the University of
Washington in the Department of Medicine, the Division of Allergy and Infectious Diseases. Dr.
Boeckh, please.
Dr. Boeckh:
Thank you.
This case is one of 50–year-old woman who presents to us nine months after non-
myeloablative peripheral blood stem cell transplantation for ALL in first remission. Her pre-
transplant serostatus was VZV positive, CMV R plus, D plus, and HSV negative. Early
posttransplant complications included two episodes of CMV infection. One actually plus one
pretransplant. Acute graft-versus-host disease. And an upper respiratory tract infection with RSV.
She now has severe graft-versus-host disease, diagnosed approximately 4 weeks prior to
admission. Was treated with topical and systemic steroids and tacrolimus. She’s admitted to the
hospital with respiratory failure requiring intubation.
Some more history. Seven weeks prior to admission she actually had an episode of CMV
reactivation with plasma PCR level of 1100 copies, which was treated with valganciclovir,
initially with 900 milligrams per day twice weekly. And then she was switched to 450 milligrams
per day after 1 week without further virologic testing. And was ultimately switched back to low-
dose acyclovir prophylaxis for VZV, 2 days prior to admission.
She was on atovaquone, 1500 milligrams per day for PCP prophylaxis. Received acyclovir
800 milligrams BID. Fluconazole and penicillin prophylaxis. At the time of admission the
prednisone dose was increased to 2 milligrams per kilogram.
There was a CT scan on admission. You can see bilateral interstitial infiltrates, but also
some areas of consolidation. Perhaps a little bit more apparent here on this slide.
So the first question is regarding the differential diagnosis and this particular question, we
have five options here. A, is viral pneumonia, due to either CMV or respiratory viruses. Fungal
pneumonia. C, bacterial pneumonia. D, BOOP. Or E, all of the above. I’d like you to please make
your choice.
So the majority voted for all four options, followed by viral pneumonia. I think actually
the viral pneumonia is probably most likely, but all other options are possible here, based on the
underlying immunosuppression. PCP is possible due to atovaquone, where we have some reports
of breakthrough infections. Bacterial pneumonia is possible in this setting of severe graft-versus-
host disease, where we can have some bacterial invasion and dissemination. And a noninfectious
process is theoretically possible, too. And so we also thought it was E.
So let’s go to the next question. The patient was immediately started on a broad-spectrum
antibacterial regimen. The question is which additional agents would you add at this point
empirically? We don’t have any diagnostic tests yet. A, High-dose Bactrim® plus ganciclovir
induction therapy. B, High-dose Bactrim, ganciclovir induction therapy and aerosolized ribavirin.
C, High-dose Bactrim, ganciclovir induction and voriconazole. D, all four drugs. Or E, No
additional empiric therapy at this point. You just wait for the BAL and then do a directed therapy.
Please make your choice.
Interesting. This time it’s not that clear. The majority would go for high-dose
trimethoprim-sulfamethoxazole, ganciclovir and voriconazole. That’s a very reasonable choice.
This is followed by just ganciclovir and Bactrim. And I think that’s a valid option, too. We
actually opted for A in this particular case because we expected the fungal diagnosis relatively
quickly and the patient had some liver dysfunction, so we didn’t want to jump in with
voriconazole right away.
So here are the first results now. The IT aspirate showed GPCs, GPRs, gram-negative
rods, so a mixed flora and yeast. And the stain showed also gram-positive cocci and gram-
negative rods. The viral DFAs were negative for adenovirus, RSV, FLU, parainfluenza and
human metapneumovirus. PCP DFA was negative. Shell vial for CMV was still pending. Also
virus multiplex, respiratory virus. PCR was still pending at that time point. Galactomannan from
the BAL was positive at 1.8. Aspergillus PCR still pending. Legionella DFA negative. But the
CMV PCR from the plasma came back with 2 million copies per mL.
Meanwhile, the case really deteriorated rapidly as you can see here. This was massive
pneumonia. So the question is, based on these results and the clinical course, how would you
further alter the therapeutic regimen? A, Switch to foscarnet. B, Add foscarnet. C, Add
voriconazole. Again, we had not given voriconazole at this point. D, Add both foscarnet and
voriconazole. Or E, No change. Please make your choice.
Okay, 43% opted for D, which is adding foscarnet and voriconazole. I think that is a very
reasonable choice. That’s actually what we did. But the others have some merit, too, I would say.
Except perhaps not treating the fungal infections. Because at the time the presumed working
diagnosis was that we probably had CMV pneumonia at the time and drug resistance was at least
possible, I would say, if not probable, based on the prior event and valganciclovir exposure at
inappropriate dosing for several weeks. And the extensive valganciclovir exposure and
ganciclovir exposure over the course of a transplant. So the combination treatment of ganciclovir
and foscarnet can be justified, but it can also be justified to give only foscarnet. But I’ll talk about
this in a second.
There’s also, based on current criteria, this is probably pulmonary Aspergillosis and I’ll
talk about this in a second, and bacterial pneumonia is present here, too, based on the cultures and
the stains.
So there is actually some utility of using the Aspergillus galactomannan assay on the BAL
fluid and this has been documented by two studies, which both indicate a high sensitivity and a
good or excellent positive predictive value. So I think a result plus the CT manifestation and the
presence of CMV altogether make – and Aspergillus involvement here – plausible. And I think
treatment is reasonable.
Ganciclovir resistance is actually more common after solid organ transplantation than it is
after stem cell transplantation. However, there are specific situations where we really have to be
suspicious of CMV resistance and have to act accordingly.
And this slide here kind of summarizes the clinical scenario where we have to suspect
ganciclovir or antiviral resistance. It typically occurs after prolonged administration of an antiviral
drug, either pre- and/or posttransplant. And subclinical CMV reactivation. Subclinical CMV
reactivation is promoted either by low antiviral drug levels or by an intense immunosuppression,
which only causes insufficient suppression of the CMV reactivation. If these two parameters
come together, CMV resistance will become more likely.
So in this particular patient we did actually have what I would call a high-risk situation,
where the patient was ganciclovir-experienced. She had received several episodes of preemptive
therapy, both pre- and posttransplant. And had also received low doses. The viral load increase
could not be documented here, but it was enormous, with 2 million copies per mL in an R-plus
patient. After stem cell transplantation, that’s an excessively high viral load in plasma. And she
also belonged to a high-risk, an underlying transplant setting, which is stem cell transplant with a
high degree of immunosuppression.
In contrast, a low-risk situation for ganciclovir and CMV drug resistance is if we have a
drug-naive patient, somebody who has never received ganciclovir or foscarnet, is extremely
unlikely to have upfront resistance. And somebody who has the viral load increase only during
the first few weeks after transplant is also highly unlikely to show resistance ultimately. And if
the patient is in addition in a low-risk setting, as outlined here.
Viral load increase early during antiviral treatment is actually quite common. It occurs in
about 30 or 40% of patients and is, based on this study, linked to the underlying
immunosuppression rather than true antiviral drug resistance. So again, in the first 2 to 3 weeks in
somebody who is naive to the drug, it’s very unlikely to be due to true resistance.
So what about the rationale to give combination therapy or to continue the ganciclovir in
this particular situation? As I said, it could also be justified to simply switch to foscarnet, even
before we have the diagnostic tests, but there’s also some rationale, at least from a theoretical
point of view, to continue the ganciclovir, if it’s justifiable based on the toxicity situation in the
particular patient.
And this comes from a study done in the UK, where the investigator shows if it’s only a
single point mutation to ganciclovir, there is still some efficacy of ganciclovir. It’s not a black-
and-white situation. There’s still some efficacy that can be expected. So we sometimes actually in
severely ill patients, such as this one, we do give both drugs.
There’s been actually a tremendous amount of work done by several investigators, but
mainly some – and Chou in Portland, Oregon – of mapping the mutations that are associated with
the drug resistance. And here are shown some of these mutations of the UL97 gene. And as you
can see, there are several identified for ganciclovir and maribavir already. And there are PCR
assays that can be used to diagnose these genotypic resistance patterns.
The same has been done for the DNA polymerase gene, UL57, and this is all in your
handout and you can take it home for reference. There’s also diagnostic assays that can be done
that can tell you what the resistance pattern is.
So how do we diagnose ganciclovir and foscarnet resistance? The first hint usually comes
from an increase of viral load in a patient that is treated with an antiviral drug. Again in drug-
naive patients, resistance is unlikely, but after significant exposures, it becomes more likely. In
this case we would suggest sending a sample for direct genotypic testing of resistance if it is
suspected. And based on the drugs used, the appropriate tests need to be ordered, as listed here.
So what can be done empirically? Because these tests are typically not back within hours.
More days or up to a week. So if a patient is gravely ill, some immediate action needs to be taken.
If the patient is treated with ganciclovir at a time, one could switch to foscarnet or to cidofovir,
although less data is available on that one. And one has to make sure that there isn’t DNA
polymerase mutation that confers cross-resistance present. And in the future perhaps we can
switch to maribavir as well.
If the patient is presently treated with foscarnet, one can switch back to ganciclovir,
cidofovir, or in the future perhaps also to maribavir.
Reduction of immunosuppression if possible is always recommended. But again, often it’s
not possible.
Now often this will not work and especially infectious disease consultants are called when
there is a refractory situation that, for instance, the viral load continues to increase or there’s
clinical deterioration. In this case we would really urge to reduce immunosuppression, if at all
feasible. There’s some data that dose increase of ganciclovir could be considered. Or one could
consider combination therapy. That is, as I already mentioned, ganciclovir plus foscarnet or in the
future combination with foscarnet or cidofovir with maribavir. Based on in vitro data, a
combination of ganciclovir and maribavir is not recommended because there’s probably some
cross – some antagonism.
Then we are really turning to some more exotic options. And I was even wondering if I
should show this. But there is a number of case reports where people have tried additional heroic
things with drugs that have been very poorly evaluated, but seem to have some activity against
CMV and I list them here. These drugs are actually partially licensed, especially leflunomide, is
available in the United States, it’s an arthritis drug. And there’s also some theoretical evidence
that one potentially could switch immunosuppression to sirolimus, which decreases the risk of
CMV reactivation on a host cell level. So these are some desperate options. There’s absolutely no
systematic data on it, but sometimes we have to deal with these situations as well.
Thank you for your attention.
Dr. Limaye:
Michael, thank you very much. At this point I’d like to open it up for some panel
discussion. But before doing that, I’d like to introduce the rest of the panel to you.
Seated next to Dr. Boeckh is Dr. John Wingard, who’s Professor of Medicine and
Pediatrics and Director of the Blood and Bone Marrow Transplant Program at University of
Florida. And seated next to him is Dr. Raymund Razonable, who’s Associate Professor of
Medicine and Infectious Diseases at the Mayo Clinic. So please welcome them as well.
Your case really brought up a lot of issues and some cases that I think it might be helpful
to focus on a little bit and maybe, Dr. Wingard, you could start.
I noticed, Michael, in the patient that you presented, that the dosing of valganciclovir was
a little bit unusual. Based on the efficacy data of different doses of valganciclovir or ganciclovir
that are used, what’s the rationale in this particular patient for treating with single daily dosing of
valganciclovir? Was it related to renal failure or was there some other reason why he was on a
dose that seems different than a typical twice-daily treatment regimen?
Dr. Boeckh:
It was hard to evaluate. The patient had already been discharged from our system and was
treated in the community and we could not, from the history, really discern why this was done. I
can’t really comment on it. It was just how the patient arrived at our center. And the renal
function was normal when the patient arrived.
Dr. Limaye:
What’s the experience of Dr. Wingard or Dr. Razonable about dosing, either using BID
regimens versus single daily dosing regimens for treatment of active CMV, either in the
preemptive format or for treatment of active CMV disease?
Dr. Wingard:
Yeah, we would use the twice daily dosing. Of course, one would need to modify the dose
if they were renally impaired, but I think the standard approach would be to do it twice weekly
[sic].
I think what Michael is bringing to emphasize is that most transplant recipients leave the
center after about 2 to 3 months and they go to a local community physician, who may have a
variable skill set with how to monitor, to make clinical decisions. And sometimes they confer
with the transplant center, which we encourage. Sometimes they do not. And so, unfortunately,
we often are left with situations that are suboptimally managed.
Dr. Limaye:
Raymund, do you have any comment?
Dr. Razonable:
I agree with Dr. Wingard, that to make sure that the dosing of ganciclovir be appropriate
based on renal function because the alternative is if we create a drug-resistant virus, then the
alternative therapies are really suboptimal.
Dr. Limaye:
Now you mentioned, Michael, in the data that you presented, that overall the incidence of
resistance is less common in the setting of stem cell transplantation, compared to solid organ
transplantation. I’m just curious as to your thoughts as to why that’s the case. Is it that it’s not
really the case and that we’re actually just empirically treating people in whom we don’t make a
diagnosis virologically of resistance? What are your thoughts about that?
Dr. Boeckh:
The reason is not 100% known. I have some theories. I think there’s still, up until recently,
a lot of use of IV drug and/or – I mean, valganciclovir has a high bioavailability and the
appropriate dosing regimens are typically followed really well, so this case was, I have to say, it’s
an exception. But I think it’s a very instructive exception. And so I think people actually tend to
follow the guidelines and recommendations quite well. And overall, I can only speculate, that it’s
perhaps the preemptive approach limits the exposure to the drug, but ultimately it’s hard to say
why.
Dr. Wingard:
Could I add a comment? There is one subgroup in the hematopoietic stem cell transplant
population that does appear to be vulnerable for even early onset of resistance and that’s in the
pediatric population. Particularly those who are undergoing transplantation for immunodeficiency
syndromes. And even haploidentical recipients.
As we are becoming more adventurous with mismatch haploidentical transplants and graft
manipulations that remove immune subsets, we may encounter greater problems in the years to
come. But currently it’s the children with immunodeficiency syndromes that appear to be
particularly vulnerable.
Dr. Limaye:
Raymund, any comments?
In terms of monitoring, Michael, patients in whom there’s a suspicion of possible
ganciclovir resistance, what are the recommendations in terms of trying to make a virologic
diagnosis of resistance versus making changes in therapy? I think that’s a point that is important
clinically in terms of whether to wait until resistance has been documented or whether empiric
therapy is warranted for that possibility.
Dr. Boeckh:
I think it depends really if you have the diagnostic capability and what the turnaround time
is. Even at centers where it is available, it typically takes a few days until you have it. So I think if
somebody is severely ill, I would act empirically and then adjust, based on the results.
Dr. Limaye:
What does your laboratory current use for making a diagnosis of . . .
Dr. Boeckh:
We use genotypic resistance testing for UL97 and UL54.
Dr. Limaye:
What about at some of the other transplant centers, what’s available to you in terms of
diagnostic testing specifically to make the diagnosis?
Dr. Wingard:
We are not as fortunate as Michael and these are expensive tests and so every time I
request it, I get a lot of resistance from our laboratory directors.
But I’m just curious, Michael, because this is a frequent problem we clinicians face, is that
you start a patient on preemptive therapy, the viral load goes up, say a week later, the PCR is
higher. In that situation do you stay the course or when is it that you get nervous, that you want to
do that test?
Dr. Boeckh:
I only get nervous after two weeks. Again, an increase of a viral load, it’s also important
to see what is a true increase. Even the best PCR, quantitative PCR assay, has quite a bit of
variability and the coefficient of variation is – even in the low level, sometimes 10, 15%. So we
really would like to see that the viral load goes up half a log 10, which is three times baseline,
before we make the determination that this is really a true increase that requires a change. If this
continues for more than 2 weeks, I think it’s probably justified to switch to an alternative drug.
Dr. Razonable:
There is actually data out there, especially with pp65 antigenemia, that when you start
therapy, there are cases wherein the number of pp65 antigens actually rise during the first 2 to 3
weeks. So it basically needs to be interpreted in the context of the clinical patient. If the patient is
doing well, then I would not really be that much concerned.
Dr. Limaye:
You described, the particular case that you described, Michael, was a patient who had
obviously very severe symptoms and multiple things going on. You described some of the
alternative options in terms of combined therapy and so on. What are your thoughts in terms of
the possibility of using immunotherapy, for example, in the setting of stem cell transplantation? Is
that even an option in 2008? Will it likely be an option in 2009 or later? What else could you
offer this patient if other options didn’t appear to be working?
Dr. Boeckh:
I think it’s not a general option. Some centers that have specific research focus on
generating CMV-specific T cells, may be able to do this. These T cells are typically donor-
derived, so there’s the access to donor-derived T cells. Donor has to be CMV seropositive. And
the T cells need to be generated within a short period of time. This is very much restricted to a
few centers that have this capability. It’s not a general tool yet. But I think in the future it might
be and then, of course, this is a situation, maybe could use it.
Dr. Limaye:
Have there been any instances, John, in your institution, where there are protocols that
might allow for immunotherapy in selected situations?
Dr. Wingard:
No. We do know what the relevant protective immune response is, the cytotoxic T-cell
responses, natural killer responses, and as Michael has said, there are several pilot studies that
show that you can confer really robust protection if you give CD4 and CD8 cells that are CMV-
specific. The issue is that this is very expensive technology, it’s not easy to export, it takes
considerable effort to mount it.
Michael, do you want to comment on CMV? I mean, a vaccine strategy?
Dr. Boeckh:
Vaccine strategy is perhaps something to be done in the future. In an acute case like this, I
can’t really see how it would play a role. But for just in general, let’s go back to the particular
patient where the disease occurred in the late setting. That is something where we would like to
have a strategy to long-term boosting the immune response and there are several efforts now
ongoing to do this by vaccination strategies. So sometime in the future we are perhaps there,
hopefully, but at this point we are not yet.
In an acute situation like this, where actually somebody presents with disease, I think we
need to go in with an antiviral approach.
Dr. Limaye:
Good. Now I’d like to, if we could, discuss this a little bit further, but I’ll save some of the
issues to discuss at the end when the audience participates.
Now let’s go ahead and move on to the second case. Dr. Wingard is going to present the
case of CMV in a hematopoietic stem cell transplant patient.
Dr. Wingard:
Thank you.
This is another case of a CMV infection in a patient undergoing hematopoietic stem cell
transplantation.
You can see my conflicts of interest here and in your handbook.
This is a 47-year-old man who underwent a matched unrelated donor hematopoietic cell
transplant 5 months earlier for acute myelogenous leukemia, receiving cyclophosphamide and
total body irradiation, is the conditioning regimen.
Tacrolimus plus a short course of methotrexate was given as graft-versus-host disease
prophylaxis. The patient then grafted on day 20. Valacyclovir, trimethoprim-sulfa prophylaxis
were given.
On day 38 he developed cutaneous and gastrointestinal graft-versus-host disease.
Prednisone was initiated at a dose of 2 milligrams per kilogram per day. The GVHD did respond
and he had clinical improvement. And the prednisone was tapered weekly by 0.5 milligrams per
kilogram per day, and eventually discontinued altogether on day 70.
Weekly CMV was assessed, using a quantitative PCR assay, and on day 54 the PCR was
positive. He was initiated with valganciclovir that was given for 2 weeks. The PCR became
negative quite promptly and on consecutive testing was negative and thus the valganciclovir was
stopped.
On day 100 the patient had no active infections, no active graft-versus-host disease. The
tacrolimus was on a slow taper. And accordingly, he was discharged to his local community
setting with monthly follow-up back at the transplant center.
On day 120, 20 days later, he developed a rash and dry mouth. This is the rash that was
evident, showing erythematous macular rash that was diffusely situated. And there were oral
lichenoid changes seen here on the hard palate, but also in the buccal mucosa.
A skin biopsy was performed that showed histologic evidence of lichenoid chronic graft-
versus-host disease. Again prednisone was reinitiated at a dose of a milligram per kilogram per
day and this was gradually tapered to an alternate day regimen at 1 milligram per kilogram on
alternate days.
On day 140 he developed a low-grade fever, a dry cough, dyspnea on exertion. On
examination there were scattered rales noted and a chest radiograph was performed.
This is the radiograph that showed a diffuse infiltrate, mixed alveolar-interstitial infiltrate
bilaterally.
So the first question posed to you is as follows. This is a true-or-false question. And you
are asked, is this unlikely to be CMV pneumonia because most CMV pneumonias occur before
day 100 in the hematopoietic stem cell transplant situation?
So 90% of you believe this to be false, 10% believe this to be true. In fact this is false.
And listed here on this slide are some of the major shifts in the epidemiology of CMV over the
last two decades.
Historically the true response would have been correct. When I was a fellow, 90% of
CMV pneumonias occurred before day 100 with a median time of onset of day 50. But what we
have witnessed over those ensuing decades is a rising rate of late onset disease. We’ve always
broached the subject of resistance that Michael presented and we’ll hear more in the subsequent
discussions of this evening’s symposium. And there are new oral agents. This patient received
valganciclovir, so too did Michael’s patient, and in the ensuing months hopefully we’ll see
another oral agent, maribavir, which is undergoing clinical trials currently.
Now various published series have shown a variable incidence of late onset CMV
occurring in 3 to 17%. It’s likely that this variability is different because of different explanations
in these various series. Different case mixes; the denominator, whether the denominator was all
patients who were transplanted or merely those that survived to 3 months and were thus at risk for
that. And we know that different stem cell sources, mismatched versus unrelated versus sibling
matched donors, cord blood versus bone marrow versus peripheral blood, and, of course, the
duration of follow-up and how vigorous the clinicians and transplant team were in establishing
the diagnosis, particularly if the patient was not present at the transplant center. So all these
factors probably contributed to this variability.
Now when one considers the etiology of a case such as illustrated in this patient, there are
both non-infectious and as well as infectious etiologies. The non-infectious include things such as
idiopathic pneumonitis, felt to be related to pro-inflammatory cytokines such as TNF, IL6, and
other inflammatory cytokines, and their immunomodulatory effects, and bronchiolitis obliterans
with organizing pneumonia, a syndrome quite similar to rejection episodes following lung
transplantation, and felt to be a manifestation of graft-versus-host disease. And there are a variety
of infectious etiologies as well. Michael has pointed out several of these. These include PCP,
CMV, the subject of this symposium, the community respiratory viruses such as influenza,
parainfluenza, RSV, adenovirus could be a culprit, and certainly Legionella could also be.
So this patient had several tests performed. A plasma PCR for CMV was performed and it
was positive. A bronchoscopy was also performed with both bronchoalveolar lavage and
transbronchial biopsy. Shell vial cultures demonstrated CMV, and the patient was started on
ganciclovir.
So the second question posed to you are, did this infection occur out of serendipity, just
bad luck, or were there certain things that should have given us clues to this likely to be
happening? So you are asked to respond to the following. Risk factors for late CMV pneumonia
are A, acute GVHD occurring before day 100; early CMV infection before day 100; the use of
ganciclovir prophylaxis, which was not done in this patient; D, all of the above; or E, none of the
above, all patients are equally at risk. So if you could use your response keyboard.
71% of you believe that it should be all of the above and a few of you thought that acute
GVHD or the use of ganciclovir prophylactically were risk factors.
Well, the correct response is really all of the above. And I hope to convince you in this
slide. Here you can see by these three panels. If you first look at the panel to your left you can see
the declining rate of early CMV, that is before day 100, by the yellow curves, and the relentless
climb in late-onset CMV by that greenish-blue curve. And in the right panel you can see from
data published by Michael, the risk and the contribution of the early onset of CMV infection as
illustrated by pp65, and also the role of graft-versus-host disease. And you can see by the cartoon
graph below that there has been a gradual shift to the right in the occurrence of CMV pneumonia.
Whereas the immediate onset used to be day 50, today it’s closer to 4 to 6 months. But today,
roughly 80 to 90% do occur within the first 9 months after transplant. And it is a more protracted
period of time that we need to be vigilant for the occurrence of this.
This illustrates the effect of the CMV strategy. Both ganciclovir prophylaxis and intensive
surveillance with preemptive ganciclovir have been shown to be effective in randomized
strategies. But you can see the effect of which strategy you choose on the likelihood of CMV
pneumonia occurring after day 100. So prophylaxis is very good in preventing early onset, but
then you are shifting the curve to a later onset, as shown in the second column. Whereas the
preemptive strategy, there may be more earlier CMV pneumonias, but fewer – but still some
somewhat a sobering incidence of CMV pneumonia beyond day 100.
So who should be monitored for late onset CMV? Certainly allogeneic transplant
recipients is where the money is. It’s a rare even in the autotransplant setting, although that may
be changing with the use of purine analogues during the period of time prior to patients coming to
autotransplant. And certainly more monoclonal antibodies, they’ve had anti-B cell and anti-T cell
activity, may give rise to a new population of people with prolonged deficiencies of both B- and
T-cell immunity.
Patients who are seropositive prior to transplant are at greatest risk. But patients who are
seronegative and yet receive a graft from a donor who is seropositive are also at risk. And as
we’ve mentioned, either the use of ganciclovir or valganciclovir prophylactically, particularly in
the recipient seropositive patient, is at higher risk.
Those are viral events. But if you add in addition host immunodeficiency events, such as
the occurrence of graft-versus-host disease, the use of high doses of corticosteroids for whatever
reason, a graft that has been manipulated to remove T cells, and the use of donor lymphocyte to
bolster the graft-versus-tumor effect, all of these may be associated with greater
immunodeficiency that may be more prolonged and make the patient vulnerable for a greater risk
period.
Now a survey of transplant centers worldwide, in the 400 centers that report data to the
Center for International Blood and Marrow Transplant Research, indicate that roughly two thirds
of all transplant centers do have a strategy in place to monitor for a late-onset CMV. That’s the
good news. The bad news is about a third still do not. And the vast majority of these centers that
do have a program in place are monitoring their patients with a preemptive approach. Very few
are giving prophylaxis during this late period of time.
And, of course, the other issue is well, how long should we monitor these patients? Well, I
mentioned to you that most of the infections do occur within the first 9 months, so you could
arbitrarily choose that as a delimiter. But in fact really it’s the host immune status that is the most
telling feature. And thus if one had measures of CMV-specific T-cell function, which most of us
do not, but if the patient has now come off of immunosuppressive therapy or is on very low doses
of immunosuppression, they are probably at very low risk. If one could measure lymphocyte
counts, CD4 counts, those would be candidates for discontinuing. And those who are not on other
anti–T-cell agents. And those not receiving donor lymphocyte infusions. These would be
candidates for removal of the surveillance program. But one should do this cautiously in patients
who are continuing to receive immunosuppressive therapy or have refractory chronic forms of
graft-versus-host disease.
Now the first case illustrates one of the issues that is the biggest challenge to us with late-
onset CMV, and that is that many of these patients no longer are being followed primarily at the
transplant center. They’re in local communities. Clinicians may not be well experienced or versed
in what tests to order, how to interpret them, what drugs to use, how to monitor the adverse events
of these drugs. And the availability of the testing, the cost, the adherence, all these are particularly
important issues.
Moreover, what we have noted in a number of series is that patients who are seropositive
before transplant, when matched for all other risk factors for outcomes, that there is about 10%
lower survival rate. Even today with preemptive therapy or ganciclovir prophylaxis, this has not
been overcome. Clearly there are indirect effects, presumably immunomodulatory effects, that we
are not accounting for. And prophylaxis may or may not reduce some of these effects.
And of course, when one looks at the agents that one would use, valganciclovir as used in
both of these patients, is one option. There is no data for valacyclovir for the late setting in
contrast to early situation. Cidofovir has a number of challenges, both myelosuppression and
nephrotoxicity. And for inexperienced clinicians this would not be a good choice. And perhaps in
the future a drug such as maribavir may have a role.
Thank you.
Dr. Limaye:
Alright, I’d like to open this now to the rest of the panel. Anyone have any particular
comments, Michael, on the presentation?
Dr. Boeckh:
No.
Dr. Limaye:
Okay, I’d like to start by asking you just a little bit about valacyclovir, John. You
mentioned that there are not many data particularly with regard to its use in late-onset disease.
And maybe we could step back just a little bit. Here’s a compound, acyclovir, that in vitro shows
essentially no activity against CMV, yet there are data in the setting of stem cell transplantation
that there might be at least some impact, both on CMV infection, and at least even in some
studies, potentially on survival. So I wanted to get your perspective on what does this mean for a
compound, that at least when we test by standard virologic means, has essentially no in vitro
activity?
Dr. Wingard:
Well, it’s a good question and it’s a puzzling question. Acyclovir and valacyclovir have a
clear-cut role in these individuals. They are very effective in the prevention of herpes simplex 1
and 2, which occurs at a median onset of about 8 days after transplant, and should be routinely
used in patients who are HSV seropositive. It also has an effective role in prevention of Varicella
zoster infection, where the median onset is 140 days after transplant. And Michael has shown in
data at their center that continuation of acyclovir for a year after transplant is associated with
substantial protection and without late reactivation, which was a problem in other studies where it
was continued just for 6 months.
With respect to CMV, you rightly point out human CMV does not encode for a viral-
specified thymidine kinase. In vitro shows very minimal activity. And yet Grant Premiss led a
multicenter trial in Europe some years ago, published in 2002 in Lancet, where they demonstrated
that high-dose IV acyclovir given prior to engraftment and continued for a prolonged period of
time as high-dose oral acyclovir, 800 milligrams four times a day, did not do much to prevent
CMV events, viremia and disease, but was associated with a survival advantage that approached
19%. This was a bit puzzling, but I was talking with Michael prior to the symposium, you know
we mentioned some of the indirect effects, and in that trial there were few deaths due to bacterial
and fungal infections. And so there may have been some effect on the indirect deleterious effects
on CMV.
Interestingly enough, a follow-up study that was done by Pierre Lumen that compared
valacyclovir with acyclovir, that did show a reduction in viremia in favor of the valacyclovir.
There was no difference in survival. But that antiviral benefit was mostly in the less
immunocompromised patients. So it’s rather modest.
So the sum of all of this is that, you know, about half of transplant centers in Europe do
use either acyclovir or valacyclovir, about a quarter of the centers in the United States do this for
a CMV effect, but I think that the biggest impact of this is really on herpes simplex and for
Varicella zoster. And I’m still not clear as to whether there’s a role.
Dr. Limaye:
Michael, what are your comments about the use of valacyclovir specifically as an agent
for prophylaxis or prevention of CMV? Are there any specific settings in the stem cell transplant
patient that you would consider using valacyclovir or high-dose acyclovir, specifically directed
against CMV?
Dr. Boeckh:
Well, it does have some effect, a moderate effect. It’s not that it can be totally ignored. We
have chosen not to use it routinely, in favor of preemptive strategy. But I can see the rationale to
use it in some extremely immunosuppressed patient as an adjunct. I think that in at least reduction
of CMV viremia, when IV acyclovir is followed up by valacyclovir in high doses, that has some
effect. I mean, it’s not really one that allows you to not do diagnostic and use ganciclovir as you
would like to do with an effective prophylactic strategy, but it may be an adjunct in some
situations where the CMV is a major problem, such as some centers I know do it in cord bloods or
in severely immunosuppressed haploidentical transplant recipients. I think it’s not completely
irrational to do it. Most people are not doing it these days.
Dr. Limaye:
Raymund, do you have any comments in the solid organ transplant setting?
Dr. Razonable:
Yes, I’d like to extend the data – that the protection against CMV with valacyclovir
extends into the kidney transplant population. There is this data way back, published in 1999,
saying that valacyclovir compared to placebo, reduced the incidence of CMV infection and CMV
disease, even in the high-risk D plus, R minus patients. And in addition, there was reduction in
allograft rejection, findings that actually was not observed with the later drugs such as oral
ganciclovir or valganciclovir. The mechanism is puzzling.
Dr. Limaye:
Interesting. So despite its – there seems to be a discordance between what’s present in
terms of in vitro activity compared with what’s been seen at least in some clinical studies in terms
of prevention of either CMV infection or some of the indirect . . .
Dr. Razonable:
Right. And I may add as well that smaller studies that looked into heart transplants and
liver transplants, didn’t see those events. So it was specific to the kidney transplant population.
Dr. Limaye:
Dr. Wingard, if I could ask you a little bit about the use of agents such as valganciclovir in
patients with severe graft-versus-host disease, particularly involving the GI tract, what are the
data about the absorption and tolerability of this agent in that particular setting? I noticed that in
your case that patient actually received it and we can’t really measure ganciclovir levels very
easily, so when do you feel comfortable, what are the specific clinical settings in which you’re
comfortable using that, as opposed to intravenous therapy?
Dr. Wingard:
Well, there are studies that have actually looked at the bioavailability of oral ganciclovir in
patients with gut GVHD and, more recently, Drew Winston looked at oral valganciclovir and
published in 2006 in Biology of Blood and Marrow Transplantation an interesting crossover
study. So patients had gut GVHD and they were randomly assigned to one dose of IV ganciclovir,
five per kilo, or oral valganciclovir, 900 milligrams. They evaluated the area under the curve and
then after a washout of 2 to 7 days, they got the opposite drug. So each patient served as their own
control. And what they found was that the area under the curve was quite similar with the oral and
the IV drug.
Now the caveat is that the patients had to have stable gut GVHD during that interval. So
by the selection, obviously those people were not severely ill. Did not have severe diarrhea. And
so in a patient with uncontrolled diarrhea or acute, I think the better part of valor would be to give
it intravenously until the patient stabilizes. But once the patient has stabilized and the clinical
situation appears favorable, then I think one could, with good sensibility, switch to the oral agent
and feel comfortable that you’re getting good control.
Dr. Limaye:
Raymund, your thoughts from a solid organ transplant perspective about when
valganciclovir might make sense?
Dr. Razonable:
Our practice, we try to avoid it in cases of severe CMV disease, especially those with
severe gastrointestinal CMV disease, wherein there is massive amounts of stool volume. But I am
aware of what Dr. Wingard’s data – that he was alluding to, that in stable cases of GVHD, that it
gets absorbed.
Dr. Wingard:
May I just make sure that I’m not misunderstood? I was thinking of it in the preemptive
strategy. If somebody had overt disease, I would give an IV drug. No matter what one feels about
. . .
Dr. Limaye:
As opposed to the solid organ transplant setting, where there are now good data from a
randomized controlled trial that use of valganciclovir might be reasonable for the treatment of
selected patients with CMV disease, active symptomatic CMV infection.
Dr. Wingard:
Correct.
Dr. Limaye:
Good. You alluded, John, to some of the problems with regard to the monitoring and
logistics for dealing with late-onset CMV disease in the stem cell transplant setting. Does your
program have any specific protocols or algorithms in place in terms of who specifically should be
monitored, by what methodology, and what should be done in the event of a positive monitoring
test? Because you have a large referral center where patients are sent from quite some distance.
So can you comment on that for us, please?
Dr. Wingard:
Yeah, so we went over the risk factors for late CMV disease and I think you have to
individualize it according to the resources in the local community that one goes back. Whether or
not they have access to getting the tests done and you have good communications with the doctor
to not result in the situation that Michael was faced, and also – so that’s one thing that you have to
be concerned. But also does the doctor know how to administer the drug and monitor
myelosuppression and what to do in that situation as well.
Although, Michael, you may want to – because you could give valganciclovir
prophylactically, and Michael actually has led a trial to do a randomized comparison between two
strategies. One, to give valganciclovir prophylactically, and the other would be intensive
monitoring and preemptive therapy. Do you want to make a comment?
Dr. Boeckh:
We presented the trial, so it’s not really secret any more. Because at least logistic
difficulties of getting the test done, which is sometimes not feasible, we wanted to test if 6 months
of valganciclovir at 900 milligrams per kilogram is an alternative. And we actually thought it was
going to be better, but that was not the case. But it also didn’t look worse. And interestingly
enough, the toxicity, in any way we looked at it, was not worse than what we saw with the
preemptive approach. So I think that is an alternative, giving prophylaxis – however, one will
have to check for hematologic and renal toxicity and adjust the doses accordingly. So there isn’t
really any approach that completely avoids monitoring. But sometimes it’s easier to do a CBC
and diff and creatinine in a community. That is sometimes even done office-based. As opposed to
a quantitative PCR for CMV.
Dr. Limaye:
Thank you. Alright, we should keep on schedule, so I’d like to introduce Dr. Raymund
Razonable, who’s going to give us a case on CMV in solid organ transplantation.
Dr. Razonable:
Switching gears now to the solid organ transplant patient population.
That’s my conflict of interest.
And the case I’m presenting is that of a 55-year-old Caucasian woman, who is originally
from Las Vegas, Nevada, and I am from Minnesota, so the distance is an issue.
She had a past medical history of astrocytoma associated with seizures. She had some
lipid disorders, diabetes. But the reason why she was being evaluated for transplantation is that
she is diagnosed with idiopathic pulmonary fibrosis.
She eventually received a right single-lung transplant in October of 2005. Our usual
protocol is to give induction therapy with OKT3 and they get maintained on a triple
immunosuppressive regimen consisting of cyclosporine, azathioprine and prednisone.
The patient, incidentally, was a CMV mismatch. But she did have a very uncomplicated
early posttransplant course. She received the usual perioperative cefotaxime prophylaxis for 48
hours. The cultures of the donor bronchus as well as the culture of the recipient bronchus at the
time of lung transplantation were O negative for any bacterial or fungal pathogens. And she got
initiated on itraconazole antifungal prophylaxis and prophylaxis with trimethoprim-
sulfamethoxazole against Pneumocystis jeroveci infection.
The next question is, what about CMV?
This is a slide that basically summarizes the two major strategies to prevent CMV
infection after solid organ transplantation. It’s basically similar to what the stem cell transplant is,
but in contrast with stem cell transplant, population who are in preemptive therapy is the more
preferred approach. In solid organs, most centers, at least in a survey that was conducted in the
United States, do use prophylaxis over preemptive therapy.
When we say prophylaxis, this is basically giving the antiviral drug to all patients at risk.
It’s been shown to reduce the direct effects of CMV as well as the indirect effects of CMV. I
alluded to earlier about the reduction in acute rejection in patients, in kidney transplant recipients,
who receive valacyclovir compared to placebo.
But a problem with antiviral prophylaxis is the risk of late onset CMV disease, which
happens usually during the first 3 months after you stop the prophylaxis. And we’re going to
discuss about certain risk factors in the next several slides.
In contrast, preemptive therapy means that you need to give the drug only when there is
evidence of CMV replication in the blood, meaning we monitor the blood usually with PCR assay
or antigenemia assay. Most commonly every week and once we detect the presence of CMV,
that’s the time that we give antiviral therapy in order to prevent the progression of CMV
replication and reactivation to full-blown CMV clinical disease.
The advantage for this approach is it minimizes drug exposure. Not everybody will get the
drug. And there will be probably the majority of patients who will not receive antiviral therapy.
The problem with this approach is that some episodes may escape detection, particularly in the
high-risk patient population, D plus, R minus, wherein the rate of viral replication is so rapid, that
we may not be able to detect it before the onset of clinical symptoms.
And there are data to suggest that preemptive therapy does not really eliminate the indirect
effects associated with CMV.
There’s been collective data out there, summarized here in these slides, which
demonstrated that preemptive therapy really is very effective in preventing CMV disease in solid
organ transplantation. Studies by Hodson, Kalil, and Small all allude to the significant reductions
in the incidence of CMV disease among patients who receive preemptive therapy, with the
reduction as high as 70%. However, there is no effect on all-cause mortality with the use of
preemptive therapy.
What about prophylaxis? This is the data that currently drives the current practice of
prophylaxis in solid organ transplantation, other than lung transplants, which happened to be our
patient. This was the data that was presented about 4 or 5 years ago now, demonstrating the
incidence of CMV disease in patients who received oral ganciclovir prophylaxis versus
valganciclovir prophylaxis. And there was basically no significant difference. Whether this was
on the protocol definition or on the investigator-treated disease. But when you look at the
subgroup analysis, what comes out that’s really remarkable in this study is that valganciclovir
appears to be associated with a higher incidence of tissue-invasive CMV disease in the liver
transplant population and hence the US FDA did not approve its use for prophylaxis against high-
risk D plus, R minus liver transplant patient population. But nonetheless, in a survey that was
published probably about a year or two ago, suggests that even in the US valganciclovir is used as
off-label for the prevention of CMV disease in liver transplant patient population.
Similar group of investigators, Hodson, Kalil and Small, looked at the effect of antiviral
prophylaxis compared to placebo, in several meta-analyses published over the past 3 years,
suggesting that prophylaxis reduces the incidence of CMV disease by as high as 80%. This
basically is around 60 to 80%, depending on the study that you look into.
What distinguishes this compared to preemptive therapy is that if you look at the study of
Hodson and Kalil, there was also reduction in all-cause mortality associated with antiviral
prophylaxis, a finding that was not observed by the third study by Small.
So going back to our case, the patient was a high-risk transplant patient population. She
was a recipient of a lung, which is basically the organ with the highest risk of CMV disease
among the solid organ transplant patient population. She was a CMV mismatch. And she got
induction therapy with OKT3. All of which has been associated with CMV disease in one way or
another.
Our program uses 1 year of prophylaxis and I’ll be interested to know what other centers
are using in preventing CMV disease in lung transplant population.
So she ended her valganciclovir prophylaxis around October of 2006. At that time she was
on stable immunosuppressive regimen using cyclosporine, azathioprine, and prednisone. Review
of her records did not suggest any evidence of prior opportunistic infections or prior evidence of
rejection episodes during the past year. Six weeks after her first-year anniversary, she presented to
her local physician, complaining of an upper respiratory infection. Low-grade fever, some cough,
weakness, predominantly in the lower extremities. And she had some runny nose and shortness of
breath on exertion. Remember this is November of 2006 and the start of the flu season.
The local physician, who I assume is not familiar with the care of transplant recipients,
prescribed empiric course of amoxicillin-clavulanic acid and actually increased the dose of
prednisone, resulting with no clinical response.
Because of that, the Augmentin® was switched to levofloxacin. A week later she
developed high-grade temperature, as high as 104 degrees Fahrenheit, requiring hospitalization to
his local community in Nevada. Wherein the chest X-ray was read as left-sided pneumonia.
If you look back, she did not get transplanted on the left. She got transplanted on the right
lung and what they were seeing was actually the fibrosis associated with idiopathic pulmonary
fibrosis.
Cultures of the blood and sputum both for fungi and bacteria were all negative. And she
got several courses of linezolid, moxifloxacin, cefepime, and oseltamivir, over the concern that
maybe she had flu. At that time she was getting trimethoprim-sulfamethoxazole and itraconazole
prophylaxis, which makes the diagnosis of fungal pneumonia probably less likely, although not
completely eliminated. It also makes the diagnosis of Pneumocystis pneumonia less likely, since
the patient is on trimethoprim-sulfamethoxazole. But because she was not getting better and there
was no definite diagnosis, they finally flew her in to Minnesota and transferred to our transplant
center.
On examination she was requiring oxygen by nasal cannula and when you removed it she
basically desaturates. She was ill-looking, she had crackles in her left lung as well as in the right
base, as well as mild right upper quadrant tenderness and she was basically generally weak in
both lower extremities. The initial laboratory examination indicates a white count of 5.2. She was
anemic. So hemoglobin of 8.6. And the platelet was low at 99. There was also some elevation in
AST as well as LDH.
Her x-ray looks liked this. The left is the normal or – the left is her lung and the right is
her lung allograft. Showing that there are some interstitial infiltrates really beginning, not really
very florid.
And this is her chest CT scan. And she eventually got into the bronchoscopy suite and
underwent bronchoscopic evaluation, wherein we ruled out the diagnosis of Pneumocystis,
Aspergillus, and other opportunistic infections. What is notable here is the cytomegalic inclusion
cell present in there, consistent with the diagnosis of CMV pneumonia. The blood PCR was
224,000 copies per mL. And the shell vial culture from the BAL fluid was with CMV and the
histopathology showed acute CMV disease, CMV pneumonitis.
This illustrates basically the thing that we’re seeing now, just like in the stem cell
transplant patient population, we’re also seeing CMV disease now at the late onset in solid organ
transplantation and this has basically been delayed with the use of antiviral prophylaxis, most
commonly with valganciclovir.
This is the data from the PV16000 trial, indicating that when the patients received the
drug, which is during the first 3 months, you rarely see CMV disease occurring. But once you
stop it, that’s when it comes and it usually occurs during the first 3 months after you stop the
drug.
And this has been observed whether you use valacyclovir in kidney transplant population,
whether you use oral ganciclovir or whether you use valganciclovir, it’s basically the same
phenomenon.
The distribution is mostly CMV syndrome in 60%. But it is tissue-invasive disease in
roughly about 40%. And among the tissue- invasive disease cases, they are predominantly
gastrointestinal.
Several risk factors have been associated with late-onset CMV disease. What has been
consistent among all studies is that this is a disease of the mismatch patient population. The donor
positive, recipient negative, who receive antiviral prophylaxis.
But the question is, who among the CMV D plus, R minus will develop disease? If you
look at the data, roughly maybe about one out of four or one out of five of the D plus, R minus
will develop CMV disease at late onset, while the other four will not. So what distinguishes those
who develop it and those who don’t develop it?
And there are several studies that have been done, including allograft rejection, data from
us about maybe 7 years ago. The role of blood group A and female gender has been raised in
some studies. The role of low creatinine clearance has also been raised in one of the trials.
Possibly because there are some patients who are, for example, kidney transplant recipients, they
don’t have normally functioning kidneys after transplant, they got started with low dose of
valganciclovir and once the renal function gets better, people forget to adjust the dosing. And
that’s also risk for resistance.
But what is also striking in recent data that we have is the association of late CMV disease
with the use of higher doses of immunosuppression at the time that you stop the drug. Meaning
that the overall net state of immunosuppression, if it’s still augmented and intensified, is a risk
factor for developing late-onset CMV disease.
We also have data suggesting that the presence of bacterial infections, invasive fungal
infections during the first 3 months after transplantation increases the risk of patients developing
late CMV disease when they stop prophylaxis.
So how do we treat late-onset CMV disease in solid organ transplant population? The
preferred drug is IV ganciclovir, although just like what Dr. Limaye had alluded to, there is now
data on the use of valganciclovir in selected nonsevere cases of CMV disease in solid organ
transplantation population. The duration should be individualized. The last AST guidelines
suggest at least 2 to 4 weeks, but this should be guided by molecular diagnostic testing, make sure
that CMV is eliminated from the blood before you stop therapy. And as always, reduction in the
degree of immunosuppression, should always be a component of the treatment.
Going back to our case, the patient was given intravenous ganciclovir because of her
severe illness with pneumonia. The patient also was given CMV Ig at that time because of the
severity of her illness, although the data around CMV Ig is somewhat controversial. And this led
to a really significant decline in the viral load over the ensuing weeks. This was switched
eventually to valganciclovir induction dosing, roughly about 2 months after the diagnosis. It took
that long for the viral load to really completely go back, go down to zero. And when we switched
to valganciclovir that was actually a blip there between February and March 2007, and sometimes
we get worried, are we dealing now with drug-resistant CMV disease in cases like this. But we
basically held the course, continued the valganciclovir treatment, eventually leading to viral
suppression and clinical resolution of symptoms.
This is the data that we’ve been alluding to about the role of valganciclovir for the
treatment of CMV disease in solid organ transplant recipients. Slightly over 300 patients were
randomized to receive IV ganciclovir for 21 days or valganciclovir at treatment doses for 21 days,
followed by maintenance dosing with valganciclovir once daily until day 49. And what this figure
shows is the rate of viral load eradication at day 21 and day 49 are similar or not statistically
significantly different between IV ganciclovir and valganciclovir. And the clinical resolution of
symptoms also was similar between the two drugs.
So going back to the case, the CMV pneumonia resolved. She had persistent bilateral leg
weakness, which we think probably is a possible CMV polyradiculopathy. She got switched to
valganciclovir secondary prophylaxis mainly because she was persistently CMV IgG-
seronegative, despite receiving CMV Ig up front. And even at 1 year she has not really fully
seroconverted in terms of IgG, although the patient was IgM seropositive at that time.
Question. My questions are actually at the last two slides, so you’d better get this right,
otherwise I’m going to repeat my presentation.
Question number 1. What is the optimal duration of antiviral prophylaxis after solid organ
transplantation? A, 1 month. B, 3 months. C, 6 months. D, 12 months. E, indefinite duration.
Okay. There is actually no correct answer on this one because we really don’t know what
the optimal duration of treatment is. All we know is 1 month probably is not sufficient. And
indefinite probably is too long. So the 1% who chose 1 month and the 21% who said indefinite
duration, please approach me after the presentation.
The current standard is actually 3 months, but the answer is supposed to be it depends on
the organ, it depends on the serostatus. But the current duration is 3 months in general and that’s
actually what was supposed to be the answer, but I do modify that answer.
There is an ongoing trial now because of the significant incidence of CMV disease, even
with 3 months of prophylaxis in D plus, R minus patient population. There is an ongoing trial
comparing 3 months versus 6 months prophylaxis in CMV donor positive, recipient negative
kidney transplant patient population. And we think the data will reflect a single center trial
published about 2 years ago, there will be significant reduction in the incidence of CMV disease
in 6 months. Although we have not yet adapted that guideline, so that’s the answer.
And at 12 months in our cases, because the patient was lung, so I’d like to point out that
there is actually a study performed – a single-center study performed in Colorado, who compared
a different duration of prophylaxis in lung transplant population and the treatment duration should
be at least 6 months. And in our case we used 1 year because of a mismatch patient population.
But then again, as illustrated by this case, it’s probably not optimal. We really need to look at the
overall patient scenario and whether the patient still has augmented immunosuppression at that
time.
Question number 2. Which of the following statements is true? A, preemptive therapy is
preferred approach for the prevention of primary CMV disease after solid organ transplantation.
B, treatment of CMV disease after solid organ transplantation is for a fixed duration of 3 weeks.
C, antiviral prophylaxis is complicated by the occurrence of late-onset CMV disease. D,
valganciclovir is a proven effective oral option for the treatment of all cases of CMV disease after
solid organ transplantation.
Good. Now I don’t have to repeat my presentation. Preemptive therapy is really not the
preferred. You can do it, but antiviral prophylaxis is equally as effective as well. At least in the
small comparative trials that’s been performed. Treatment for CMV disease, just like what I said,
should be guided by molecular testing and should not be for a fixed duration of period. And
valganciclovir is proven effective in mild-to-moderate cases of CMV disease in solid organ
transplantation. Cases of severe disease, it’s really not been studied in that patient population.
And the answer is C.
Thank you.
Dr. Limaye:
Thanks very much. Raymund, thank you. I want to ask you to follow up a couple of issues
you raised with regard to preemptive therapy versus prophylaxis. I think based on the data that
you showed, that the vast majority of centers in the US are using the strategy of antiviral
prophylaxis, typically given for about a 3 months. Yet with the use of that strategy we see a
substantial onset of late-onset CMV disease that now I think we have good data suggesting it’s
independently associated with bad clinical outcomes in terms of mortality. So given that, along
with the risk factors that you showed, what does your center do, how do you manage patients who
you know after completion of 3 months of prophylaxis, are at a substantially increased risk of
disease, at least among the D plus, R minus patients?
Dr. Razonable:
We use 3 months of prophylaxis in the non-lung solid organ transplantation population,
but we do extend that for 3 extra months after a treatment for rejection. For example, if a D plus,
R minus solid organ transplant recipient developed rejection at month 2, then the duration of
prophylaxis gets extended for 3 extra months after that. That’s the only clinical variable that is
currently influencing our management on how long to give the prophylaxis, beyond what is
standard.
We also have tried to do preemptive therapy approach after prophylaxis in our kidney and
liver transplant patientpopulation, but the main issue of that is the logistic difficulty of getting
blood samples in patients who are doing well. They are out of the transplant center, already back
in their community in Nevada or even internationally, and it’s really difficult to do PCR
monitoring for preemptive therapy when they’re out of the transplant center.
Dr. Limaye:
Although you described a number of the risk factors for late-onset CMV disease, these are
really relative risks for people who either had or did not have the risk factor. But how good really
is the sensitivity and specificity of those specific risk factors? Because even if they are very
significant in a statistical analysis, when you’re dealing with individual patients, what you really
need to consider is what’s the negative predictive value or the positive predictive value and in
whom would you want to consider additional strategies to reduce the risk?
Dr. Razonable:
Unfortunately those types of studies have not been performed. So it’s basically just an
individual case management that if you think this patient is of high risk mainly because he’s not
doing well, he’s had multiple rejection episodes, the amount of immunosuppression that you’re
providing, at the time that you’re supposed to stop prophylaxis is still very high, then it’s more
likely that if the virus reactivates in that patient, that patient will not be able to mount an immune
response because he just got bombarded with thymoglobulin, for example, or the dose of
prednisone is so high to prevent rejection. So that’s how we manage currently those patients.
Dr. Limaye:
Great. This brings us to the final presentation and I’m going to present the second case on
CMV in solid organ transplantation.
So this is a patient that actually Michael and I both cared for. This was a few years ago
and I chose this case in particular, even though it’s a couple of years old, because I think in many
ways it really highlights and illustrates some of the key concepts about antiviral resistance in
patients who’ve received a solid organ transplant.
A 45-year-old man received a cadaveric kidney/pancreas transplant. He was CMV
seronegative and the donor was CMV seropositive. He received standard immunosuppression as
shown there. Given that he was at high risk for developing CMV disease, he received a strategy of
prophylaxis, in this case with oral ganciclovir for 3 months after transplant. He did develop an
episode of rejection 1 month posttransplant, for which he was treated with methylprednisone
pulses times 3. And then at 4.5 months after transplant, he developed signs and symptoms
compatible with CMV pneumonia, which was confirmed on bronchoscopy and transbronchial
biopsy. For this episode of CMV pneumonia, he was treated with IV ganciclovir, combined with
immunoglobulin for 3 weeks and then treated in addition with a 3-month course of oral
ganciclovir, but this time a secondary prophylaxis, given that he would have been predicted to
have between a 10 and 20% chance of relapse.
Shortly after completing this secondary prophylaxis, the patient returned at 9 months
posttransplant with fevers, myalgias, was found to have leukopenia and elevated transaminases
and was found to have very elevated pp65 antigen levels in his blood, although his viral cultures
from his blood remained negative.
He was treated again with IV ganciclovir, but it was noted that he had a very slow and
unexpectedly slow clinical response and his viral load, instead of being decreased, was actually
increasing.
In addition he had some mild radiographic abnormalities on his chest x-ray when he was
admitted. During this time of treatment he actually developed pulmonary symptoms and his chest
x-ray now progressed to show bilateral infiltrates as shown here.
There was a concern about a possible superimposed opportunistic infection versus just
progression of CMV and so he underwent a bronchoscopy with transbronchial biopsies and as in
some of the previous cases, there was evidence of CMV pneumonitis on the biopsy.
So now we have a patient who despite receiving full-dose antiviral therapy is having
clinical progression, virologic progression, in a patient who’s been heavily pretreated with
ganciclovir, so there was obviously a concern that this could be due to a ganciclovir-resistant
strain of CMV. And so his therapy now was switched to a combination of IV foscarnet and
ganciclovir. CMV hyperimmune globulin was added and he developed known complications of
nephrotoxicity and electrolyte abnormalities related to his foscarnet. And unfortunately, despite
maximal medical support, ventilatory support, the patient ultimately died unfortunately of
progressive respiratory failure. And even at autopsy 2 weeks later, there was evidence of CMV
pneumonia and no other pathogens were isolated by histopathology or culture. And the always
helpful laboratory 2 weeks – and I can say that as the Associate Director of the clinical
microbiology laboratory at the U – 2 weeks after the patient died, unfortunately, was the first
laboratory evidence that we had confirming that in fact this patient’s isolate was ganciclovir-
resistant.
So this case really illustrates and raises a number of very important issues about
ganciclovir resistance in the solid organ transplant setting.
What is the incidence, how common is it and what are the risk factors? Might we have
predicted that this particular patient was at an increased risk based on certain epidemiologic
variables? And I’ll argue that yes, there are several features about this patient’s case that would
have put him at increased risk and we’ll talk just very briefly about how those risk factors are
thought to be important in the pathogenesis of the development of ganciclovir resistance in this
setting.
Clearly, diagnostic tools are limited. They’re much better and I’m going to just point out a
few places where I think we have significant new improvements, but a take-home point will be in
a patient in whom resistance is suspected, one must treat empirically and not wait until laboratory
confirmation is received.
And then finally, what are some of the treatment options that are available and again,
much of this is based on clinical experience rather than any evidence-guided recommendations.
So let’s start with a question now, sort of a pre-test before I give you the answers in a few
slides. Which of the following is considered the most important risk factor for development of
ganciclovir-resistant CMV in solid organ transplant patients? Is it female gender? Is it recipient
CMV seropositive status? Is it the receipt of a liver transplant as opposed to an organ – another
type of organ transplant? Or is it donor positive, recipient negative CMV serostatus? Or is it
specifically the use of cyclosporine? Please put in your answer now.
Okay, good, that’s great, 69% of you got what I consider to be the correct answer, which
is donor positive, recipient CMV seronegative status. And in fact, in solid organ transplant
patients, except perhaps for lung patients, which might be a little exception, virtually every patient
reported to date in the literature who’s had virologically confirmed ganciclovir resistance has
been a seronegative patient who has developed a primary infection, either from blood transfusion
or from the allograft itself.
Liver transplant patients actually have somewhat lower rates of resistance compared to
other organ transplant types and seropositive patients, these two are mutually exclusive, so for the
betters in here that guessed correctly, you were right here.
Female gender to my knowledge has never been shown to be a risk factor for resistance.
And cyclosporine or any particular agent, except perhaps antilymphocyte antibodies, are the only
immunosuppression-related factors that might portend an increased risk.
So now a more detailed question based on Michael’s data that he had presented. Which of
the following statements regarding the mechanism of ganciclovir resistance in CMV is correct?
So which of the following statements is correct? Mutations in the UL97 phosphotransferase are
the most common mechanism underlying ganciclovir resistance. B, resistant strains are not
capable of causing tissue-invasive disease. C, assessment of the IC50 by phenotypic testing is the
preferred diagnostic method to confirm resistance. Or D, mutations in UL97 confer cross-
resistance to foscarnet and cidofovir. Please consider those choices and put in your vote now.
Good, that’s excellent. So the majority of you, 80% of you got the correct choice there,
which is mutations in UL97 are the most common mechanism. Although there are differences in
terms of the replicative potential of resistant versus susceptible strains, as in this patient’s case
and in many other previous case reports, resistant strains appear to be fully pathogenic when
compared to susceptible strains.
Although this had been the gold standard method for confirming resistance, waiting for
the isolate to actually – to have a clinical isolate, which can take 2 to 4 weeks in the microbiology
lab, is much too slow to be clinically useful. And so we’ll talk specifically about what tests are
available to help you on a clinical basis in a patient in whom resistance is suspected.
And finally, mutations in UL97 are quite different than the mutations that occur in UL54
or the DNA polymerase. And in fact it’s only mutations that occur in UL54 that can lead to cross-
resistance between various antivirals.
So what is the overall incidence of ganciclovir resistance and why is it that it seems much
higher in certain reports rather than others?
Well, if we look first in abdominal organs and split it out according to transplant type, the
overall incidence of resistance is quite low. And these numbers you might argue why are we
making mountains out of molehills here, those are very low numbers. But I think there are a
couple of important caveats here.
First, resistance occurs only in patients or virtually only in patients who are seronegative
recipients of an organ from a seropositive donor. And those patients typically comprise
approximately 20 to 25% of the whole transplant population, so these numbers really need to be
multiplied by a minimum of 5-fold.
Second, as we’ve done a better job of preventing CMV infection with the use of various
strategies such as preemptive therapy and prophylaxis, the number of patients in whom infection
even develops and therefore even have CMV that’s resistant to ganciclovir is relatively low. And
so if one looks at this in terms of the number of patients overall who develop CMV disease, there
are at least a couple of cohort studies suggesting that approximately 10 to 20% of patients who
develop infection or disease have disease due to resistant strains.
The incidence in thoracic organ recipients is somewhat higher. And in fact, among all the
organ transplant recipients, it’s lung transplant patients who are well documented to have the
highest incidence of resistance in the solid organ transplant setting.
So what are the risk factors? Many of which this particular patient had. And I think it’s
important to remember in order for clinically resistant, ganciclovir-resistant CMV disease to
develop, a number of factors probably have to come together in an individual patient, otherwise
the resistance that we would see or the rates that we would see would be much higher than are
actually presently observed. And central to this story is the fact that I have mentioned already,
that virtually all patients have been seronegative recipients of an organ from a seropositive patient
or a donor.
And these are the patients who tend to have very high viral loads and even with antiviral
therapy can have prolonged periods of subclinical reactivation. And in the setting of highly potent
immunosuppression, particularly antilymphocyte antibodies, and prolonged exposure to drug, that
provides a situation in which resistant strains are most likely to emerge. And this patient, as you’ll
recall, had received antilymphocyte antibodies, had been D plus, R minus, had previous episodes
of CMV disease for which he received prolonged courses of antiviral therapy, and so he really
had all of the risk factors that are known to predispose to ganciclovir resistance.
In terms of diagnosis, we used to rely on phenotypic methods, which relied on growing
CMV from a clinical specimen, growing that cultured strain in the presence or absence of drug,
and then comparing it to a known wild-type strain and looking for differences. But this can take
months and is simply not feasible in order to get a result that’s available in clinical time. And so
genotypic methods have really come to the forefront for diagnosis of antiviral resistance and
ganciclovir resistance in particular.
And mutations in this UL97 and UL54 are the most common mutations. And instead of
relying on or waiting for an actual clinical isolate to be present, these genotypic methods for
either mutations in UL97 or UL54 can be done directly on clinical specimens and these are now
commercially available and by several commercial laboratories and can be extremely helpful in
confirming resistance in a suspected case.
So Michael had already showed this slide. This is just to emphasize that in the UL97 open
reading frame, there really are a few specific hot spots where ganciclovir-resistant mutations seem
to occur preferentially. And this is what’s really opened up the opportunity to develop clinical
assays to document resistant isolates. And shown here on the bottom are the changes in the
ganciclovir IC50, based on what the actual specific mutation is. And this is work published many
years ago by Sun-Wen Chou.
So what can we say about UL97 mutations? Overall these tend to be either point mutations
or deletions and the net effect, regardless of what the specific mutation is, is that there’s a
decrease in the level of the activated form of ganciclovir in CMV-infected cells. And in effect,
viral replication can continue because there is no longer inhibition that’s occurring.
The mutations at three specific codons account for the majority of clinical ganciclovir-
resistant isolates. And mutations that occur in UL97 do not confer resistance to any of the other
antivirals that are currently FDA approved. Although Michael did bring up the issue about
mutations in UL97 and what importance they may have with other agents, for example, such as
maribavir.
The current antiviral options, these are based really on more on opinion and clinical
experience rather than any evidence-guided recommendations based on clinical trials. There are
many strains that show only slightly increased IC50s to ganciclovir and here there are several case
reports suggesting that using higher than standard doses of ganciclovir might be clinically helpful
when combined with reduction and immunosuppression and other strategies.
Foscarnet either used alone or in combination has been used and there at least are some in
vitro data suggesting that perhaps the combination might have synergy and might potentially be
more useful than switching to foscarnet alone.
Other interventions that I think are important are reduction in immunosuppression, and
although there are no compelling data, the use of hyperimmune globulin might also be a
reasonable strategy, particularly in a patient who’s severely ill.
There are a number of interesting compounds that have shown various in vitro activities
and there are anecdotes about the use of these as Michael had mentioned in his talk and I won’t go
into them any further, other than to say that they look interesting, they will need to be
systematically evaluated before they can actually be recommended.
So what should be your clinical approach? So this is at least what I like to go over with
with the trainees at the University of Washington who are rotating on the solid organ transplant
service, in terms of how to approach a patient in whom resistance is suspected.
So in a patient who has either clinical failure or virologic failure defined as no clinical
improvement at 2 weeks or no reduction in viral load at 2 weeks, specifically to account for the
fact that some people will have increases in viral load, but it’s typically not due to resistance at
earlier time points. Then you need to consider, has that patient been exposed to drug for any
significant length of time? Even if a patient is clinically or having virologic failure, if they have
not had prior drug exposure, drug resistance is a very unlikely explanation as to why they’re
clinically or virologically failing. And I think you really need to focus on host factors, drug
dosing, other factors that might be important into explaining why it is that that patient isn’t
responding. So it’s really – there’s a very strong association between prior drug exposure and then
the likelihood of resistance. So if they haven’t had drug exposure, look elsewhere. If they’ve had
drug exposure and are failing, then do they have other risk factors for resistance? Are they a D
plus, R minus patient? If they’re not, then the overwhelming likelihood is there’s some other
explanation in all likelihood to explain their clinical or virologic failure.
If they have risk factors and they’ve had prolonged drug exposure, then there is a
significant risk and it’s probable that drug resistance is explaining their virologic failure and then
one should pursue confirmatory laboratory testing. But in the meanwhile certainly treat for the
presumptive diagnosis of ganciclovir-resistant CMV.
In a patient who doesn’t have other risk factors, but has had prolonged antiviral drug
exposure, here I really like to classify patients and distinguish patients from having significant
disease versus those who might have asymptomatic viremia that’s not responding. And in those
who are very sick, I think you can’t wait, you have to presume that they might be resistant, not
wait until you get laboratory confirmation, and treat similar to what’s shown here.
In patients who do not have life-threatening disease or just have asymptomatic viremia, I
think there it’s reasonable to perform genotypic testing and perhaps make some other
interventions and then only switch therapy as long as they remain clinically stable, until
laboratory confirmation is received.
Alright, so with that I’ll end and we will open it up for panel discussion followed by
questions from the audience. Thank you.
So Raymund, in this particular case, what did we do wrong, what would you have done
differently?
Dr. Razonable:
I don’t know if you did something wrong.
Dr. Ajit:
Okay, good, I feel a little bit better. Was this patient – do you think his exposure,
prolonged exposure to oral ganciclovir, for example, something that now – this was a case that
was several years ago when we didn’t have those other oral options – do you think that might
have made a difference in this particular case?
Dr. Razonable:
Correct. Most of the data resistance out there has happened in the context of prolonged
oral ganciclovir exposure. There’s also data that happens with the use of valganciclovir as well,
although in many of those cases who used valganciclovir, that’s on patients who are receiving
suboptimal dosing, such as maybe just 450 milligrams once a day, on the patient with normal
renal function. And some data out there suggests that if you’ve been exposed to at least 73 days of
suboptimal ganciclovir levels, then your risk of getting resistance is increased.
Dr. Limaye:
Michael, do you have any comments on the case?
Dr. Boeckh:
Well, one option that one has in the kidney transplant patient is, of course, to sacrifice the
kidney. It’s the one organ transplant – that’s theoretically at least possible, and stop all
immunosuppression cold turkey. It’s a very difficult decision to make and everyone involved is
always very reluctant to do it, but there is something that can be done. If you do it and we
ultimately did suggest it, there’s still some lag time until the immunity that you theoretically gain
recovers. But it is something to keep in mind if somebody is really that gravely ill. That’s
possible.
Dr. Limaye:
In this particular case I think we had considered that the patient was dead against having
his immunosuppression reduced because he said anything would be better than being back on
dialysis again. So you’re dealing with sometimes very, very difficult issues as we dealt with in
this particular case.
So let me just briefly – yes, John, please.
Dr. Wingard:
I wonder what the various members of the panel would say, is there a role for oral
ganciclovir in either the stem cell transplant or solid organ transplant today? What do folks think?
Dr. Razonable:
Well, it’s the one that’s approved in liver transplants, that’s for sure. Although just like
what I said earlier, valganciclovir is the most commonly used drug off-label in the liver transplant
population. Patients with renal dysfunctions who happen to have other organ transplants, oral
ganciclovir is still the one that’s being used. But other than those two, valganciclovir is the drug
of choice currently.
Can I go back to the other question you had earlier? About the refusal to give up
immunosuppression. That also becomes an issue in actually living-related donor transplants in
kidneys because of the gratitude a recipient has to a living donor, especially if they are relatives,
they would not want to pursue and get the kidney failed because of some gratitude experience by
them.
Dr. Limaye:
My take on the oral ganciclovir, John, is really that in the setting of liver transplantations,
as Raymund points out, in a head-to-head randomized controlled trial, some people don’t believe
the results. There was an increased incidence of tissue-invasive disease with valganciclovir
compared to oral ganciclovir and so it doesn’t have an FDA indication for that, so I think people
are leery of those data and that might be one situation specifically that it might be considered.
And then the other issue I think has to do with something as trivial, if you will, as the
tablets for ganciclovir. Valganciclovir comes as 450-milligram tablets and in patients with rapidly
changing renal function, oftentimes you’re left with a decision of relative underdosing or relative
overdosing. And so sometimes it’s more convenient to use oral ganciclovir with smaller dosages,
so that we can more fine-tune and provide what we think might be an appropriate oral dose. So
those are two situations that I’ve dealt with when that becomes an issue.
Dr. Wingard:
What about stem cell transplant, Michael?
Dr. Boeckh:
I haven’t used it in many years.
Dr. Wingard:
I’ve always thought of it as being a bad idea. I spent 5 years in the laboratory generating
resistant CMV isolates. That’s exactly the way you do it in the laboratory. Low doses, gradually
escalating, long time, and no immune defenses.
Dr. Limaye:
Let me just turn briefly to the issue of diagnostic testing. That’s an area that’s on one of
the learning objectives that we haven’t really covered. I’d like to hear from each of you what your
center does in terms of laboratory testing for routine monitoring of patients for disease. Raymund,
can you please tell us what you do?
Dr. Razonable:
We do have quantitative PCR assay that’s based on the light cycler format. And it’s
something that’s available and offered every day, 7 days a week, so you really get the results
really quickly. And that’s what we use for patients who are undergoing preemptive approach and
for those for diagnosis as well.
Dr. Limaye:
John?
Dr. Wingard:
In our stem cell transplant we use intensive monitoring, quantitative PCR. When we
switched from the pp65 to the quantitative PCR, we actually did both assays. We could get a good
sense, we clinicians, as well as the laboratory, could get a sense as to what was equavalent.
Basically it looked like the antigen test was positive when our value was about 1,000, but
realistically between 500 and 1,000 was the gray area. So if we see it positive, but it’s less than
1,000, we check this once weekly. If it’s low and particularly if the patient is on high doses of
immunosuppression, we’ll repeat it a couple of days later and if it’s rising, we’ll go ahead and
start. And the threshold of when you start a patient I think depends on how immunosuppressed
they are. And so you have to weigh both of those.
Dr. Boeckh:
Yeah, we do something very similar. We also have a quantitative PCR and plasma basis
in-house tag method and we also use for low levels of valdynamics, how quickly increases to
determine when to start. I have to say, though, in the highest risk patients such as the cord blood
transplant, we are more aggressive and would take even very low levels very seriously and
probably go in – but that’s a small group of patients and all the others we use a similar approach.
Dr. Limaye:
So all of you are monitoring specifically for the presence of virus, either viral DNA or
antigen and so on. I’m curious whether any of you have experience with using immune
monitoring tests. We have certain situations where, for example, in D plus, R minus solid organ
transplant patients where infection is virtually ubiquitous, and if we used the preemptive strategy
in that setting we’d literally be treating all patients because they’ll all be positive at relatively high
viral loads, yet we know that only a smaller proportion of them actually go on to develop disease.
So immune monitoring seems to me to be a logical approach to maybe fine tune who it is that
actually requires antiviral therapy. Do you have any availability or experience, Raymund, with
that sort of an approach?
Dr. Razonable:
We do have the ability to measure CMV-specific CD8 T cells and this is available in the
clinical laboratory, although the data is really difficult – it’s still at the early stages of its use.
There is data presented at the American Transplant Congress earlier this year, showing that the
presence of or generation or CMV-specific T cells in a mismatched donor positive, recipient
negative solid organ transplant population will predict who will be protected from developing
CMV disease, although that is just a single study that needs to be validated in the future. Probably
multicenter collaboration would be something that’s needed in that regard.
Dr. Limaye:
John, what’s your experience in the stem cell transplant setting?
Dr. Wingard:
No, we have no experience, we don’t have the availability. It’s sensible, it makes all the
sense in the world.
Dr. Limaye:
Is it ready for prime time, Michael?
Dr. Boeckh:
Well, there is no really an approved assay. But we have one available and individual
cases, mainly those that have one episode of reactivation after the other, we sometimes look at
what their T-cell situation is. And if they even still need treatment very late after transplant, and
sometimes when we find this – because sometimes we are pushed to the wall with toxicity at
some point, with toxicity and/or resistance. So that has in some cases saved some people, where
to be a bit more relaxed in terms of the threshold, basically let them go with certain low-grade
viral load. But it’s not really generally accepted strategy.
Dr. Limaye:
Is it something that you think will likely be an accepted strategy once assays are
commercialized and developed?
Dr. Boeckh:
I think it’s possible. I think it’s very intriguing, but for using it very early after transplant
where you conceivably could use this test to withhold preemptive therapy, I think it does require a
randomized trial because there are some safety issues early after transplant. Because if you are
wrong, it could be a devastating outcome with some case of pneumonia, which you simply can’t
treat them any more. So yes, I think in theory and conceptually it’s really cool even, but I’d like to
see a trial really proving that. Although a pilot study has been reported from Sweden, where they
did this in a cohort and it seemed to work. So I think we’re getting there.
Dr. Limaye:
Great, thank you.
Let’s move to some questions from the audience, if there are any. I noticed we have a
couple of questions posed by people who are involved, viewing this as a Webcast. We want to see
one of those questions, please.
Dr. Wingard:
While we’re waiting for the Webcast question, I have a question for all of us. I’ve always
been intrigued by the difference between stem cell transplant and solid organ. So with the stem
cell transplant, it’s the patients who are sero – the recipient seropositive, so these are reactivation
infections we think of mostly. Yes, the donor has a contribution, but it’s less powerful. With the
solid organ transplant, it’s primary infection since you’re donor positive, recipient negative. I’m
curious, any thoughts as to why that seems to be?
Dr. Limaye:
I think at least one interpretation is, as is true for many viral infections, that the primary
infection particularly that occurs in the context of a limited host immune response, is just less
likely to be able to control primary infection. We know that there appears to be an increased risk,
even among seropositive patients and seropositive patients who receive an organ from a
seropositive donor, so the situation that the patient is donor positive, recipient positive, seems to
confer a slightly higher risk than donor negative, recipient positive. And so that seems to argue
that perhaps there’s incomplete immunity across strains, different genotypes, etc. So I think that’s
my understanding of the increased risk for CMV specifically in the context of a primary infection
with an impaired primary response.
Raymund, do you have comments?
Dr. Razonable:
Yeah, I kind of agree with that. It makes you think that maybe there is some incomplete
protection against other strains of CMV because if you look at the literature and data that’s been
published on what reactivates in CMV-seropositive recipient, for the most part it’s actually donor-
derived virus and not from the recipient.
Dr. Boeckh:
I think one interesting thing is that the D plus, R minus setting after stem cell seems to be
for some reason a quite inefficient way of transmission of the virus, although in theory at least
there should be latent virus in some of the stem cell fractions. We see only 25 to about 30% of
transmission even with these massive amounts of cells. So I think that’s probably the difference,
that it’s perhaps just an inoculum effect. But nobody has really proved that.
Dr. Limaye:
So let’s go to our first question that’s posed by someone participating in the Webcast and
I’ll open this up to the panel. What data are there to support the use of double antiviral therapy for
CMV disease in transplant patients? Michael, do you want to tackle that one?
Dr. Boeckh:
Well, there aren’t any good data, to my knowledge, that really proves that that’s effective.
It’s more based on some theoretical and in vitro data, so there is an additive effect with some
combinations, not a synergistic effect. There is some data from the early HIV days where we saw
some beneficial effect by combining full-dose ganciclovir, for instance, with half-dose foscarnet
or vice versa. And so I think it’s more circumstantial evidence than anything and this is more, I
have to admit, in my opinion, desperation treatment in many cases. Because in the case that we
had in front of us, my first case, and this looked really like pretty severe situation and we just
hoped that more is better.
Dr. Limaye:
John, do you have any comments?
Dr. Wingard:
No, I generally look at the patient that you guys struggled with as a host failure more than
an antiviral failure. Where Bob here, he would echo that and say it in spades.
Dr. Limaye:
Raymund?
Dr. Razonable:
They have similar mechanisms of action, right?
Dr. Limaye:
They do, but I think as Michael alludes to, there are some data back from the HIV era,
where patients who were failing ganciclovir therapy for CMV retinitis in the setting of advanced
HIV infection, that people who were randomized either to switch to foscarnet or the addition of
foscarnet, while maintaining ganciclovir, actually had some clinically significant outcomes in
terms of progression of retinitis and even survival. So we’re . . .
Dr. Razonable:
Were we dealing with ganciclovir-resistant strains and that’s where the foscarnet was
effective? There’s also data out there on – actually used as a preemptive therapy – of halfdose
foscarnet and half-dose ganciclovir in solid organ transplant patient population. And there was no
significant additional benefit and actually it was more side effects that were observed with
nephrotoxicity and electrolyte imbalance.
Dr. Limaye:
Good. Can we have any audience members who have any questions, to please come to the
microphone? Please state your name and your affiliation and then your question.
Audience:
My name is Israel L. from Medarex. I have a question on the theme of the immune status
of the patients with regard to CMV. So the first question is the difference between stem cell
transplant patients and solid organ transplant patients, is it that the extent of immunosuppression
is greater in the stem cell transplants, that might play a role in that? That’s part one. And part two
is given that there seems to be a difference potentially between CMV-specific CD8 T cells, has
anybody ever entertained the thought of doing a CMV-specific T-cell infusion in the patients who
are deficient in that and are having active CMV disease, who have that background?
Dr. Limaye:
Thank you for your question. So just to summarize very briefly, you’re wondering
whether there are systematic differences in the degree of immunosuppression that a stem cell
transplant patient might receive, compared to a solid organ transplant patient. And the second part
of your question was the question I posed earlier about the use of infusing, adoptive T-cell
immunotherapy, for example, as a potential treatment. Michael, do you want to start and comment
on that, about the differences in immunosuppression used for a stem cell transplant patient
compared to a solid organ transplant recipient?
Dr. Boeckh:
Well, I think it’s a question that’s difficult to answer because there is not one
immunosuppressive regimen either for stem cell and for solid organ transplant. In each category
there’s a spectrum, a wide spectrum of immunosuppression within the solid organ that is in part
organ-specific and center-specific, what type of cocktails people use. And the same is true in stem
cell transplantation, whereas allogeneic, autologous , non-myeloablative transplantation, where
it’s very minimal upfront dose of chemotherapy, but then quite a substantial immunosuppression
to prevent graft-versus-host disease.
If I had to make an estimate, I think the most immunosuppressed stem cell transplant
patient is, I would say, perhaps a bit more immunosuppressed than the average solid organ
transplant, but even that is kind of difficult to decide. I’d be interested what other people . . .
Dr. Wingard:
I would say among the stem cell transplant is the haplomismatched transplants. Then T-
cell–depleted transplants. Then cord blood. Then probably the least immunosuppressed is the
autotransplant and then the sibling matched. And so there’s a hierarchy, as you point out.
And yes, there is a role for adoptive immunotherapy of either clone CMV-specific T cells
or expanded CMV-specific and they do have protective benefits, but again these are very small
pilot studies. And it’s technologically very intensive, very expensive. The technology is not easy
to export. So there are a lot of logistic – it just hasn’t made it practical.
Dr. Boeckh:
I might add something about the T cells. Most of the studies have actually been done in
the refractory viremia. In overt disease I’m not aware of many, if any case – I think the concern . .
.
Dr. Wingard:
It’s probably too late.
Dr. Boeckh:
Either too late or you just wonder what these T cells do or inflamed tissues, if they might
aggravate the symptomatology. So yeah, I think in the case of – there are several cases, very
compelling cases of refractory viremia, even with drug resistance, where the viral load then nicely
came down, that’s been reported, yeah. It’s clearly something that needs advancing.
Dr. Razonable:
I don’t think you really can compare head-to-head stem cell and solid organ transplant
patient population because those are just two different patient populations and it depends on what
immunosuppressive drugs are given. Having cared for both groups of patients, I usually tend to
consider the stem cells as the sicker ones, compared to the solid organs. But both of them are
really – both groups are immunosuppressed. It depends on what immunosuppressive therapy are
used and that kind of determines the level of immunosuppression.
Dr. Limaye:
And one of the difficulties is obviously how does one objectively measure the degree of
immunosuppression. In a given patient, a level of a given – for example, calcineurine inhibitor
might have very different effects in terms of immune dysfunction than the same level in another
patient. So they’re really – sort of the Holy Grail of transplantation is being able to have some
objective marker that might tell you how immunosuppressed a given patient is and that’s simply
not available yet.
Are there other questions, please, from the audience?
Audience:
I’m Bob from Fargo, North Dakota. What would be the role for measuring serum
ganciclovir levels in people being treated with valci?
Dr. Limaye:
I’m sorry, could you state the question again?
Audience:
What would be the role for measuring serum ganciclovir levels in people being treated
with valci?
Dr. Limaye:
Okay, alright. So the question is the role of ganciclovir levels in a patient being treated
orally with valganciclovir.
Dr. Wingard:
It’s not easy to get and so if you’re faced with a patient where you’re asking yourself that
question, switch to IV ganciclovir.
Dr. Limaye:
Yeah, I’m not aware of commercial laboratories that we have used to get an answer in a
clinical real time, a ganciclovir level. I don’t know whether there is experience with anyone else.
Raymund, have you?
Dr. Razonable:
We do have the assay available at our center, of measuring ganciclovir levels. And I
actually used it just recently because of a viral load that’s not declining, in a patient who is having
CMV reactivation disease. And the question is, is she absorbing good enough levels? And it
turned out that her renal function does not coincide with the actual level that was being given with
the drug dose, so even with renally adjusted valganciclovir dosing, the level was really low,
compared to what was supposed to be expected. That’s a situation I would use . . .
Dr. Limaye:
And are there good enough pharmacodynamic data that link levels of ganciclovir, peak
and trough, with what you might expect to see . . .
Dr. Razonable:
Not necessarily. We were just basing it, based on the PK data that was available with the
PV16000 trial.
Dr. Boeckh:
I’ve been involved in a number of cases where even the patients treated with IV
ganciclovir, where there was an apparent disconnect with something that should have worked and
simply didn’t, and then we just bumped up the dose and that was empirically – or the people that I
worked with, they were even up to doubling the dose. And then when the levels were finally
measured, they only then came back with what you would expect. So I think there is still, with IV
ganciclovir, some unpredictable pharmacokinetics in some people. And I’ve also noticed this in
children sometimes that way. But this is where we simply not canautomatically translate all the
adult dosing guidelines to children because I think there hasn’t really been, until recently, any
pharmacokinetic evaluation in the very small children. Yeah, it would be great if you had this
assay more readily available. Sometimes it’s helpful, I guess.
Audience:
I’ve got two fairly specific questions and should be easy to answer. So the first one is with
the prophylactic dose of valganciclovir orally, what do you use? Do you use 900 milligrams twice
daily or 900 milligrams daily? And my second question relates to increased dose of ganciclovir
with ganciclovir resistance, how much do you actually use?
Dr. Limaye:
Okay, so I just want to restate your questions to make sure that I have them. What I heard
was what is the appropriate dose of valganciclovir for prophylaxis? And then your second
question was related to the dosing of IV ganciclovir in a patient with presumed resistance.
Audience:
I think someone mentioned increased dose, so higher doses than you would normally use,
so what’s that dose?
Dr. Limaye:
Okay, those are excellent questions. Let’s hear from the panel. Raymund, what would you
recommend if you had to use valganciclovir as prophylaxis, what dosage would you recommend?
Dr. Razonable:
In a patient with normal renal function the dose is 900 milligrams once a day. And the
other question is?
Dr. Limaye:
Is the dosing of IV ganciclovir in a patient who might potentially have ganciclovir-
resistant CMV.
Dr. Razonable:
And in the patient with that scenario with normal renal function, I’ve used as high as
double the usual dose, which is 5 milligrams per kilo is the usual, I can go as high as 10.
Dr. Limaye:
I would agree with those recommendations. I think even though lower doses have been
used in some studies, in observational studies for valgan, at least in the controlled trials that have
been done using valganciclovir for prophylaxis, the doses that have been formally studied are 900
once a day in a person with normal renal function. And I agree, my clinical experience, Raymund,
for treating occasional patients with non–life-threatening disease with suspected ganciclovir-
resistant strains in whom there was a contraindication or some other reason why we didn’t switch
or add foscarnet, we’ve used pretty much what Raymund has described, using up to 20 mgs per
kg per day in two doses of ganciclovir. Now obviously there’s going to be significant bone
marrow toxicity, so we try and hold their other marrow-toxic medications. We would provide
them with growth factors to try and support their neutrophil count during this, but it has been
done and it’s been reported in the literature, at least anecdotally, to successfully treat what was
ultimately diagnosed as a ganciclovir-resistant CMV infection.
Yes, please.
Audience:
I’m Mina Gim from Asam Medical Center in Seoul,Korea. My question is in the case of
pneumonia after transplantation, if we found CMV and PCP together, from a lung specimen,
would you treat CMV in addition to PCP? Or what condition will you treat, if you find both CMV
and PCP?
Dr. Limaye:
If you found CMV and Pneumocystis together, I’m sorry?
Audience:
Will you treat CMV or what condition?
Dr. Limaye:
Interesting, okay. Would this be in the setting of solid organ transplantation or stem cell
transplant? Either?
Audience:
Either.
Dr. Limaye:
You want to tackle that, Michael, what would you do?
Dr. Boeckh:
Can you restate the question?
Dr. Limaye:
Sure, I’m sorry. So the question was related to if you found both Pneumocystis together
with CMV in a BAL specimen of a patient, would you treat both or only presumably the
Pneumocystis? In other words, what is the role of CMV found in a BAL? That’s a good question.
Dr. Boeckh:
I would treat both. I think it brings up the general question if you found copathogen – we
see it more often than with PCP with Aspergillus – what is really – are these both equally
important pathogens at the time, with a causative role in the event – to my knowledge there is no
simple test and way to be sure that one of them is not. So I always opt for treating them both.
Dr. Limaye:
John, your comments?
Dr. Wingard:
Yeah, I would definitely treat them both in the stem cell transplant population. The
sensitivity and specificity of those predicting disease is more than 90% for both organisms.
Back in the early days of HIV, you got a patient with PCP and CMV, you treated the PCP
and you got the CMV, the patient got better. Very different situation with the stem cell transplant.
I can’t comment on the solid organ.
Dr. Limaye:
Raymund, what are your comments?
Dr. Razonable:
How was the CMV identified?
Audience:
By culture, culture from BAL.
Dr. Razonable:
They usually do biopsies as well, so that’s one thing that would argue for or against
whether there is a shedding or a true disease. But in the absence of that, I would probably tend to
treat both, especially if the patient is severely ill in the ICU.
Audience:
Thank you.
Dr. Limaye:
Please?
Audience:
Katherine from University of California San Francisco. Question I have is regarding the
prolonged antiviral exposure as a risk factor for a resistant CMV. Is there any data on the median
duration of antiviral therapy in terms of a risk for resistant CMV? Is there any specific data on
what’s the earliest time frame at which you might expect to see resistant CMV?
Dr. Limaye:
So, interesting question. So the questions were is there data about the actual duration of
antiviral exposure as a risk factor for developing ganciclovir-resistant CMV and then also what’s
sort of the earliest time frame that one might develop ganciclovir resistance? Are you referring
specifically to solid organ transplant or stem cell transplant, either/or? Okay, so, Michael, can you
tackle the stem cell portion of that question?
Dr. Boeckh:
I think there isn’t, to my knowledge, a single magic threshold. But I think after several
months I would say 2 to 3 months of ganciclovir exposure cumulatively, I think it becomes much
more likely. John pointed out some exceptional situations in children with immunodeficiency,
which may have been pre-exposed to ganciclovir or foscarnet prior to transplant, those are special
situations. And there’s also other small reports from the pediatric literature where some early
mutations have been seen in some children. But we have never seen this in adults. And I can’t
recall having ever seen somebody having significant ganciclovir resistance during the first 100
days with a preemptive approach in stem cell transplant, I might add.
Dr. Wingard:
I would agree.
Dr. Limaye:
Raymund?
Dr. Razonable:
In the solids there’s at least one report there that had demonstrated maybe as short as even
73 days of oral ganciclovir prophylaxis. In our experience, the cases that we’ve seen are actually
kidney-pancreas wherein they get kidney, they were mismatched, they get 90 days of prophylaxis,
then they get pancreas later on, they are still a mismatch, they get another 90 days of prophylaxis.
So it’s really a prolonged course of ganciclovir exposure.
Dr. Limaye:
And I can share with you data that we have looked at specifically in the setting of both
abdominal organ transplant recipients compared to thoracic recipients and what we found was that
typically resistance in abdominal organ transplantations developed after a minimum of 2 months
or more of prior drug exposure. Whereas at least in lung transplant setting with D plus, R minus
patients, resistance has been documented, was statistically quite a bit earlier than it was for
nonthoracic patients and there’s a couple of specific references that look at that data and describe
those differences in CMV onset or ganciclovir-resistant CMV onset, between thoracic versus non-
thoracic organ transplant patients.
Alright, we have a question here from Dr. Yen-Lieberman from Cleveland Clinic. Hi,
Belinda. Does anyone use the Cylex T-cell function assay to monitor patients’ immune status, i.e.,
ATP in nanograms per mL. Raymund, do you want to tackle that one?
Dr. Razonable:
We do have the machine, but we are not using it.
Dr. Limaye:
So you just bought the machine, but decided not to use it.
Dr. Razonable:
Yes.
Dr. Limaye:
Is that used in the setting of stem cell transplantation, John, at all at your center?
Dr. Wingard:
?? at University of Arkansas is trying to organize a study to look at this prospectively. He
had some data that suggests it can be predictive of opportunistic infections. Hasn’t been looked at
as extensively in the allogeneic as to whether it can predict GVH and other sorts of things. But it’s
interesting, but I don’t have personal experience.
Dr. Limaye:
We currently do offer that assay in our clinical laboratory and I think some of the renal
transplant patients use it to evaluate patients for risk of rejection when they’re going to perform a
biopsy or whether to perform a biopsy. But other than that I haven’t seen compelling data of how
those results can necessarily be incorporated into clinical practice.
I will tell you parenthetically, however, in patients with ganciclovir-resistant CMV in
whom I feel that a reduction in immunosuppression is absolutely necessary as part of their
treatment, and the transplanters are, for whatever reason, very reluctant to use or to reduce
immunosuppression, I’ve used that assay and pretty much been batting 100%, finding that at least
by that assay that patients appear to be immunosuppressed by low ATP levels, so I’ve used it in
that situation only.
The evening is late. I’d like to wrap up things now. The faculty will stay for just a couple
of minutes to answer any final questions. We’d like to thank everyone for attending the
symposium today. We hope that the information that’s been presented has been useful for you.
I’d like to thank all the members of the panel for participating as well.
Please remember to fill out your evaluations, which are required to receive the continuing
education credit. And if you joined us on the Web, please make sure to download the forms and to
fax them to the number listed in order to get continuing education credit.
Again, thank you and goodnight, and we hope you enjoy the rest of your IDSA meeting.
Goodnight.
END
Top Related