Listen in as Dr Marcus Pereira discusses designing cytomegalovirus (CMV) antiviral regimens for high-risk kidney transplant recipients to mitigate the impact of infection while minimizing drug toxicities.
Listen in as Dr Marcus Pereira discusses how to design cytomegalovirus (CMV) antiviral regimens for high-risk kidney transplant recipients to mitigate the impact of infection while minimizing drug toxicities. Topics include:
Presenters:
Marcus Pereira, MD, MPH, FAST
Associate Professor of Medicine
Director of Clinical Services, Division of Infectious Diseases
Medical Director, Transplant Infectious Disease Program
Columbia University Irving Medical Center
New York, New York
Link to full program:
http://bit.ly/41ejruC
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
So, what are those strategies? So there's two major categories. And then there's a new approach as well.
So, prophylaxis. What do we mean by prophylaxis? That's an antiviral drug that's given for a fixed period depending on the organ and depending on the serological status of the donor and the recipient. So, for example, for kidney transplant recipients at my center, a D+/R+ gets three months, whereas a D+/R- gets six months of prophylaxis. And that's generally what is recommended in the guidelines.
Now the second approach is preemptive therapy, or the new term is surveillance with preemptive therapy. And that's where you do not give an antiviral drug right off the bat. You actually just monitor your patient with serial PCR monitoring, usually on a weekly basis. If that becomes positive, if you achieve a certain threshold, many centers pick 1,000 IU/ml, but that's really very center-dependent. If you achieve that threshold, then you treat. You put your patient on antiviral therapy until that viral load is once again undetectable. You stop and resume monitoring.
Now there's a hybrid approach that a lot of centers to pick the best of both approaches, which is you give them antiviral prophylaxis. And then after it ends, now you survey your patient with serial PCRs. A lot of centers actually do that. We do that as well.
Comparing CMV Prevention Strategies
So, how do you compare those two strategies? They certainly get debated over and over again. As you can imagine, with antiviral prophylaxis, it is highly effective. However, there is a drug cost attached to it. Right now, you are prescribing either valganciclovir or letermovir. And there's always a cost to those drugs. There are drug toxicities related to those two medications. We will be talking about those as well.
It turns out that if you actually prevent CMV from reactivating in the first several months after transplant, what you are doing, you are protecting your patient. But in some ways, you are also delaying the reactivation of CMV for later in their transplant lives, sort of this delayed onset post prophylaxis. So, your patient will always remain at risk. Although diminished over time, there will always be a risk. That is important for you to realize that there is this post-prophylaxis CMV reactivation. The other aspect that we talked about in terms of indirect effects of CMV, prophylaxis certainly is able to prevent some of those indirect effects.
Now, what about surveillance with preemptive? Well, it does involve weekly PCR monitoring. So there is certainly a logistical issue with that. Your patient has to go to a lab once a week. Somebody has to follow those results and have the plan to enact if those results are positive. There is a logistical greater challenge with that preemptive approach. However, it does allow for low-level CMV replication, which in some ways can be controlled. In that setting, you are priming their immune system to perhaps acquire some degree of immunity to CMV that may have some benefits downstream. But, again, the logistics can be quite complicated. Which is why a lot of centers, and particularly in the US, choose more prophylaxis than preemptive therapy.
CMV Prophylaxis vs PET in Kidney Transplant Recipients: Primary Outcome
All right. So, have there been any studies for kidney transplant recipients comparing the two approaches? This is one of the few studies that compared those two approaches. This was an open-label, single-center randomized control trial with 140 kidney transplant recipients comparing a preemptive therapy with antiviral prophylaxis, which in this case was valganciclovir 900 mg PO daily for three months. Obviously, adjusted for renal insufficiency and other changes. If they were D+/R-, they would get six months as opposed to three months.
So, 47% of those patients received induction therapy. And just to say, on the preemptive therapy arm, if CMV reactivated, then they would get full-dose valganciclovir. The incidence of acute rejection, which was one of the primary outcomes, turns out that it was actually lower in the prophylaxis arm. Again, I think that that is speaking of the indirect effects of CMV. If you're suppressing CMV from reactivating, there is less of that alloreactivity and maybe concerns for rejection down the line. And in this case, it was not necessarily statistically significant for the cohort as a whole. It was 23% versus 13%, so did not achieve statistical significance. But in the subgroup of those patients who did not receive induction therapy, that was actually statistically significant in terms of valganciclovir group for prophylaxis had lower rates of rejection compared to the preemptive group. So maybe some benefit in certain categories of patients.
CMV Prophylaxis vs PET in Kidney Transplant Recipients: Other Outcomes
So, what were some of the other outcomes from that study? There was also subclinical rejection. We talked about biopsy proven. However, there is also a whole other category, which is subclinical, and that was also lower in the prophylaxis group. That was significant. 13% versus 29%. CMV DNAemia rates were higher in the preemptive therapy group. That shouldn't be any surprise. You allow those patients to reactivate. Also not surprising, neutropenia rates were also higher in the prophylaxis group. They are getting valganciclovir. That is one of the main side effects and toxicities of valganciclovir, which is bone marrow suppression, neutropenia, and thrombocytopenia. You can see here that in terms of subclinical rejection, valganciclovir did better than preemptive therapy. And there is a similar figure in terms of neutropenia, the other way around.
CMV Prevention: Antiviral Drugs
All right. Valganciclovir is no longer the only therapy or antiviral available for prophylaxis. We talked about valganciclovir is FDA-approved for CMV prevention of kidney, heart, or lung patients who are at high risk. That has been approved since 2003. It's been with us for a while. There is a whole lot of experience with us using that medication. And it is still the most commonly used drug.
And then there is letermovir. That was a new drug. It was approved actually for CMV prevention for our allogeneic stem cell transplant recipients in 2017. Based on some studies, it was approved or extended for high-risk kidney transplant recipients in 2023. Now, some of the positive aspects of letermovir are that they do not have the same side effect profile as valganciclovir. It is not associated with cytotoxicity, meaning you do not have any bone marrow suppression with letermovir, or any renal toxicity or renal adjustments. And those are important considerations. There are some reports of CMV treatment failures with letermovir. So, letermovir cannot be used for treatment. Remember, we are talking about prophylaxis only. Other drugs that we do not use for prophylaxis but are available are foscarnet, cidofovir, and maribavir. And we will not be talking about those additional drugs during this session.
Letermovir vs Valganciclovir for CMV Prophylaxis in Kidney Transplant Recipients: Primary Endpoint
All right. So the study that I alluded to was this Phase III randomized control trial in high-risk kidney transplant recipients comparing letermovir with valganciclovir for CMV prophylaxis. This included 589 D+/R- patients. They were given prophylaxis for up to 200 days. So, pretty standard duration. In a nutshell, letermovir was found to be non-inferior with the primary outcome, which was preventing CMV disease through week 52. Here you see there was a 10.4 incidence of CMV disease incidence in the letermovir arm. And valganciclovir actually had a higher rate at 11.8. But certainly within the non-inferior analyses, these drugs were quite comparable in their efficacy.
Letermovir vs Valganciclovir for CMV Prophylaxis in Kidney Transplant Recipients: Other Outcomes
What was really striking was actually the side effect profile, the treatment-related complications. In that letermovir for all the categories that are pertinent, including bone marrow suppression, leukopenia, thrombocytopenia, and so forth, letermovir did much better than valganciclovir. Again, that should not be a surprise. This is not a drug that causes bone marrow suppression. Therefore, you should not see that as a side effect. Thankfully, we did not. That in some ways had an improved safety profile compared to valganciclovir.
CMV Prevention: Monitoring Considerations for Antivirals
So, when you are choosing between valganciclovir and letermovir, what are some of the things for you to think about in your choices? Certainly, antiviral toxicities. Again, valganciclovir has this bone marrow suppression issue. Certainly, I think you are going to see neutropenia, which is not a benign side effect, thrombocytopenia, as well as the need for renal adjustments, which certainly adds a complication to valganciclovir. Letermovir, on the other hand, has some GI side effects. There are some nausea and diarrhea issues reported, and maybe some mild headache. Otherwise, no systemic side effects.
Then monitoring considerations. Renal function changes. Valganciclovir has a very narrow window when it comes to renal adjustment. You really have to stay on top of your creatinine clearance and make sure that your team is adjusting the dosage of valganciclovir. That adds its own layer of complexities, whereas letermovir does not. Drug interactions. Important to know that letermovir does increase levels of tacrolimus and sirolimus. That is important to know. You do have to consider other issues. And then role of therapeutic monitoring. I get asked a lot about that. Can you check valganciclovir against acyclovir levels? In general, there is no way to interpret those levels, so we do not. The same for letermovir. We do not measure levels or are able to interpret that.
CMV Prevention: Considerations for Antivirals
Then what are some additional considerations? Certainly, convenience and ease of administration. We have been talking about that. Both are orally administered. The frequency of doses is generally the same. Adjustments, we talked about, and drug interactions. Then last is the cost. There is a certain element of affordability that you want to keep in mind for your patients. Valganciclovir is now generic, whereas letermovir is not. So, important. However, there are certainly some downstream effects in terms of monitoring labs and adjusting your dose and keeping your team busy with keeping up with creatinine clearance and dose adjustment.
All of that is to say it is a complicated decision process. I think you want to work on what is best for your patient, and some of these patients are quite unique.