Trial tested approach against antiviral prophylaxis in CMV-seronegative recipients
Using preemptive therapy led to a lower incidence of cytomegalovirus (CMV) disease over 12 months in CMV-seronegative liver transplant recipients with seropositive donors, researchers reported.
Compared with antiviral prophylaxis, the incidence of CMV disease — and delayed-onset disease in particular — was significantly lower with preemptive therapy (9% versus 19%) in 205 patients, for a 10% difference (95% CI 0.5%-19.6%, P=0.04), according to Nina Singh, MD, of the University of Pittsburgh, and co-authors.
In addition, the incidence of allograft rejection, opportunistic infections, graft loss, and neutropenia did not differ significantly for preemptive therapy versus antiviral prophylaxis, they wrote in JAMA.
But the authors warned that “CMV-specific immune responses were exploratory end points and, therefore, all findings should be considered tentative and, at best, hypothesis-generating,” and “adherence to monitoring and timely initiation of antiviral therapy are important components of preemptive therapy that might not be feasible for all transplant programs.”
In an editor’s note accompanying the study, Angel N. Desai, MD, MPH, and Preeti N. Malani, MD, MSJ, both of the University of Michigan in Ann Arbor, acknowledged that “these results provide some clarity regarding the use of preemptive therapy,” but they also urged cautious interpretation.
Desai and Malani pointed out that weekly serum PCR monitoring must be done for preemptive therapy, with immediate start of antivirals when indicated. “Transplant centers may differ in their capacity to support such frequent measures, and some patients may find these requirements costly, and logistically burdensome, especially if this specialized test is not easily available locally,” they wrote.
Ultimately, the choice to use preemptive therapy will depend on an institution’s capacity and resources, Desai and Malani noted in agreement with Singh and co-authors. Limitations aside, “preemptive therapy may be a viable option for preventing CMV infection among selected high-risk patients following liver transplant,” they concluded.
In preemptive therapy, patients are monitored for early replication — viremia by polymerase chain reaction [(PCR) — and an antiviral drug is given only when CMV replication is detected to prevent its progression to higher-grade viremia and CMV disease, the authors explained.
For the trial, patients in the preemptive therapy group underwent weekly testing for CMV viremia for 100 days using a “highly sensitive real-time plasma CMV PCR assay” with a limit of detection of 20 IU/mL. Tests were performed at a central lab.
If any level of viremia was detected, valganciclovir (Valcyte) at 900 mg was given orally twice daily until patients had two consecutive negative tests at 1 week apart. Also, in the preemptive therapy group, recurrent viremia within 100 days was treated similarly, Singh’s group stated.
Patients assigned to antiviral prophylaxis received valganciclovir (900 mg) orally once daily for 100 days initiated within 10 days of transplant.
In order to meet trial inclusion criteria, adult patients had to have first orthotopic liver transplant (deceased or live CMV-seropositive donor) within 10 days prior, be CMV-seronegative, and have an absolute neutrophil count >1,000/μL at randomization. Eligible patients were randomized within 10 days of transplant in a 1:1 ratio to preemptive therapy or antiviral prophylaxis.
The trial was conducted at six U.S. academic transplant centers from Oct. 2012 to June 2017, with last follow-up in June 2018. The authors reported that 100% of the enrolled patients (mean age 55 years; 30% women) completed the trial.
Singh’s group found that the lower incidence of CMV disease at 12 months was driven primarily by a reduction in delayed-onset disease (beyond day 100) at 6% for the preemptive group versus 17% for the antiviral prophylaxis group for an 11% difference (95% CI, 2.4%-19.9%, P=0.01).
For the secondary outcomes, the authors reported the following incidence:
- Allograft rejection: 28% for preemptive therapy versus 25% for antiviral prophylaxis (3% difference, 95% CI −9% to 15%])
- Opportunistic infections: 25% versus 27% (2% difference, 95% CI −14% to 10%)
- Graft loss: 2% versus 2% (<1% difference, 95% CI −4% to 4%)
- Neutropenia: 13% versus 10% (3% difference, 95% CI −5% to 12%)
All-cause mortality at last follow-up was 15% in the preemptive therapy versus 19% in the antiviral prophylaxis group for a 4% difference (95% CI −14% to 6%, P=0.46).
As for adverse events (AEs), protocol-specified AEs occurred in 2% of patients in the preemptive therapy group (one case of pericardial effusion and one case of kidney stones) while no patients in the antiviral prophylaxis group experienced AEs.
The authors noted that another study limitation was that “given the known low rates [about 2.5%] of breakthrough viremia during valganciclovir prophylaxis, CMV viremia was not assessed during antiviral prophylaxis (compatible with current guidelines), so a direct comparison of the relationship between viremia and immune responses was not feasible for the prophylaxis group.”
But they also highlighted that “preemptive therapy has been the dominant strategy and standard of care for CMV prevention for approximately 30 years in hematopoietic cell transplant recipients who are much sicker than organ transplant patients and published data demonstrate feasibility of preemptive therapy in organ transplant recipients in clinical nonresearch settings as well” (such as in an earlier study by Singh and colleagues).
The use of antiviral preemptive therapy with valganciclovir resulted in lower incidence of cytomegalovirus (CMV) over 12 months compared with antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors.
Adherence to monitoring and timely initiation of preemptive therapy are important and may not be possible in all transplant programs.
The study was supported by the National Institute of Allergy and Infectious Diseases.
Singh reported funding from the NIH. Co-authors reported support from, and/or relationships, with Merk, Chimerix, Shire, Gilead, Oxford Immunotech, Novartis, Takeda Pharmaceutical, the NIH, Shire, Qiagen, Astellas, Vir Bio, GlaxoSmithKline, Allovir, Helocyte, Moderna, and Artemis.
Desai reported being a Fishbein Fellow at JAMA. Malani reported being a JAMA associate editor.
Cat ID: 633
Topic ID: 630,633,633,636,473,190,192,925
Singh N, et al “Effect of preemptive therapy vs antiviral prophylaxis on cytomegalovirus disease in seronegative liver transplant recipients with seropositive donors: A randomized clinical trial” JAMA 2020; 323(14):1378-1387.
Desai AN, Malani PN “Preventing cytomegalovirus infection after liver transplant: An evolving approach” JAMA 2020; 323(14):1388.