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CMV Prevention After SOT
Beware of the Troll: Preventing CMV After Solid Organ Transplantation

Released: August 30, 2023

Hannah Imlay
Hannah Imlay, MD, MS
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Key Takeaways
  • SOT recipients remain at high risk for CMV -related morbidity and mortality.
  • Further studies are needed to determine the optimal strategy for CMV prevention—prophylaxis or preemptive therapy—to prevent CMV disease in SOT recipients.


Cytomegalovirus (CMV)—sometimes referred to as the troll of transplantation—remains a major threat to solid organ transplantation (SOT) recipients. Immediately post transplantation, the risk for tissue-invasive CMV disease is high, and CMV infection is associated with detrimental downstream effects such as higher risk of allograft rejection, graft loss, opportunistic infections, and mortality. Risk for CMV varies based on the type of organ transplant, immunosuppressants used, and serologic match between the donor and recipient. Among the various serologic matches, the greatest risk for CMV replication and disease occurs when the donor is CMV seropositive and the recipient is seronegative (D+/R-). 

There are 2 strategies to prevent CMV disease in SOT recipients: universal prophylaxis and preemptive therapy.

Universal prophylaxis is a strategy in which an antiviral drug is administered for a period—typically several months following transplantation, when CMV risk is highest—until immune reconstitution occurs.

By contrast, with preemptive therapy, antivirals are not administered unless CMV is detected at a specific threshold in the bloodstream. This threshold for quantitative CMV testing, as well as the frequency of CMV monitoring (with weekly monitoring being most common), varies by site.

No clear guidance is available recommending one strategy over another for renal and liver transplant recipients. For other types of organ transplant recipients, a universal prophylaxis strategy generally is recommended in guidelines, but there are few data to address which strategy is optimal. In this commentary, I address considerations for each CMV prevention strategy.  

Universal Prophylaxis

While receiving antiviral prophylaxis, the risk for breakthrough CMV replication and disease is extremely low; universal prophylaxis typically is given during the highest-risk period immediately following transplant.

Because frequent CMV monitoring is not needed, transplant centers may find this approach easier, but additional resources may be needed to monitor for possible drug toxicities. Cytopenia (eg, leukopenia and neutropenia) is often the reason prophylaxis with valganciclovir, an antiviral commonly used for CMV prophylaxis, is stopped early.

The other limitation to universal prophylaxis is the risk of late-onset CMV replication and disease after antiviral therapy is discontinued. 

Preemptive Therapy

By virtue of frequent (eg, weekly) monitoring, the goal of the preemptive approach is to treat CMV replication prior to the development of CMV disease.

There are a few benefits to this strategy. First, not all patients will require the use of CMV-specific antivirals. In a randomized study of preemptive therapy in high-risk D+/R- liver transplant recipients, ~20% of patients did not require antiviral treatment of CMV within the first 4 weeks post-transplant. Second, patients develop CMV-specific immunity earlier from exposure to low-level viremia, which may reduce the risk for late-onset CMV disease.

On the other hand, because this approach allows for CMV replication, patients may be more susceptible to longer-term indirect effects of CMV, such as allograft rejection; it is unclear if this is different from the universal prophylaxis strategy, where CMV replication may occur, typically after antiviral prophylaxis stops. To use a preemptive strategy, transplant teams must be able to receive and respond to lab results quickly.

Comparing Approaches

Historically, most transplant centers have adopted the use of universal prophylaxis to prevent CMV disease in high-risk SOT recipients, as prior head-to-head randomized studies comparing the 2 strategies were limited to kidney transplant recipients.

It was not until 2020 that a randomized, controlled trial was performed to evaluate the difference in rates of CMV disease between the 2 approaches in high-risk D+/R- liver transplant recipients. Approximately 200 participants received either (1) universal prophylaxis with valganciclovir for 100 days or (2) preemptive therapy with weekly CMV polymerase chain reaction testing (where detection of viremia at any level triggered valganciclovir, which continued until 2 consecutive CMV polymerase chain reaction tests were negative). 

At 12 months, participants on the preemptive therapy arm had significantly lower rates of CMV disease compared with those on the prophylaxis arm (9% vs 19%; P = .04). No difference in rates of indirect CMV effects was observed between groups.

Results of this landmark study have shifted practices to consider the preemptive approach vs prophylactic therapy in high-risk liver transplant recipients. Currently, it is unclear how these results apply to other organ transplant types.

Letermovir

The debate on which strategy to use in high-risk patients has become grayer with the June 2023 approval of letermovir for CMV prophylaxis in kidney transplant recipients.

The use of letermovir was compared with valganciclovir for primary CMV prophylaxis in CMV-seronegative kidney transplant recipients in a randomized, noninferiority phase III trial. Antiviral prophylaxis was administered for up to 200 days in both study arms. Letermovir was found to be noninferior to valganciclovir in preventing CMV disease through Week 52 (10.4% vs 11.8%; stratum-adjusted difference: -1.4%; 95% CI: -6.5% to 3.8%).

Quantifiable CMV DNAemia (≥137 IU/mL) was detected in 2.1% of patients receiving letermovir vs 8.8% of patients receiving valganciclovir through Week 28. No patients (0/52) receiving letermovir and 12.1% (8/66) of patients receiving valganciclovir developed resistance-associated substitutions. Compared with those on the valganciclovir arm, participants in the letermovir arm had significantly lower rates of leukopenia (11.3% vs 37%), neutropenia (2.7% vs 16.5%), and drug discontinuation due to drug-related adverse events (2.7% vs 8.8%) through Week 28.

Clinical Application

These findings support the use of letermovir for primary CMV prevention, particularly with its favorable safety profile, considering limitations with valganciclovir and the risk of bone marrow suppression. Results from this trial help to address previous concerns for the potential of breakthrough CMV while receiving letermovir. The potential for development of resistance was another concern with letermovir that was reported in prior studies—primarily studies on CMV treatment—but this was not observed in the randomized, controlled trial.

Unanswered Questions

Although these results are promising, there are unanswered questions about letermovir. Because the specific FDA indication for letermovir was updated to include kidney transplant recipients, practical implementation in recipients of other organ transplant types remains unclear.

Learn More

To learn more about strategies to prevent CMV in SOT recipients and the potential role of letermovir, join me and a panel of experts at our live symposium at IDWeek 2023 in Boston, Massachusetts. You can participate in person or via live simulcast.

Unable to make it to the IDWeek 2023 meeting? Check out our encore virtual symposium here. 

Your Thoughts?

Which prevention strategy do you use to prevent CMV disease in your high-risk SOT recipients? Join the discussion by posting a comment.