Available online 22 April 2024, 105678

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Valacyclovir is an effective anti-viral prophylaxis for CMV after adult and pediatric kidney transplant

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Valacyclovir is better tolerated with less dose-limiting leucopenia, particularly in pediatrics

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Valacyclovir is not an effective anti-viral prophylaxis for EBV after adult and pediatric kidney transplant

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In kidney recipients with inability to tolerate valganciclovir due to dose-limiting side effects, valacyclovir is a viable option

ABSTRACTBackground

Valganciclovir (valG), a cytomegalovirus (CMV) prophylactic agent, has dose-limiting side effects. The tolerability and effectiveness of valacyclovir (valA) as CMV prophylaxis is unknown.

Methods

We conducted a randomized, open-label, single-center trial of valA versus valG for all posttransplant CMV prophylaxis in adult and pediatric kidney recipients. Participants were randomly assigned to receive valA or valG. Primary endpoints were the incidence of CMV viremia and side-effect related drug reduction with secondary assessment of incidence of EBV viremia.

Results

Of the 137 sequential kidney transplant recipients enrolled, 26% were positive and negative for CMV antibody in donor and recipient respectively. The incidence of CMV viremia (4 of 71 [6%]; 8 of 67 [12%] P=0.23), time to viremia (P= 0.16) and area under CMV viral load time curve (P=0.19) were not significantly different. ValG participants were significantly more likely to require side-effect related dose reduction (15/71 [21%] versus 1/66 [2%] P=0.0003). Leukopenia was the most common reason for valG dose reduction and granulocyte-colony stimulating factor was utilized for leukopenia recovery more frequently (25% in valG vs 5% in valA: P=0.0007). Incidence of EBV viremia was not significantly different.

Conclusions

ValA has significantly less dose-limiting side effects than valG. In our study population, a significant increase in CMV viremia was not observed, in adults and children after kidney transplant, compared to valG.

Trial Registration Number

NCT01329185

Section snippetsINTRODUCTION

Prevention of cytomegalovirus (CMV) has been a critical development in the field of kidney transplant, saving numerous lives. [1,2] Despite valganciclovir (valG), having breakthrough infections, dose-limiting side effects, and a black box warning of teratogenicity, it remains the primary CMV prophylaxis to prevent poor graft and patient outcomes.[3,4]

ValA has been demonstrated to reduce the incidence and delay the onset of CMV disease in CMV seronegative (P<0.001) and seropositive participants

Trial Design and Oversight

A trial advisory board consisting of 3 transplant recipients and the parents of 2 pediatric participants was created. Participants met quarterly to advise on protocol creation and implementation. A 3-physician and 1 statistician Data Safety and Monitoring Board reviewed the study every 6 months until study conclusion. We randomly assigned participants in a 1:1 ratio to receive either valA or standard of care valG within 5 days of kidney transplantation. Study drug was assigned before discharge

Participants

Of the 41 pediatric and 96 adult recipients included; 66 began treatment in the valA group and 71 in the standard of care valG group (Fig. 1). Study enrollment was May 5th, 2015, to December 27th, 2020. In the valA group, 6 participants were switched to valG due to CMV viremia. In the valG group, 1 participant was switched to valA due to neutropenia.

The clinical characteristics (Table 2) of the participants were similar for age of recipients (Fig. 2) with majority White and male participants.

DISCUSSION

In this randomized, controlled, single-center clinical trial, we demonstrate no statistically significant differences regarding CMV infection or CMV disease (P > 0.10) in adult and pediatric kidney recipients administered valA for CMV prophylaxis. The hazard ratios of CMV viremia in valG compared to valA were 0.44 (95% CI 0.13–1.45), 0.41 (0.12–1.36), and 0.35 (0.06–1.93) in all, in all but D-R-, and in D+R- only, respectively. Our study is the largest of its kind with a substantial portion of

CONCLUSION

ValA has significantly less dose-limiting side effects than valG without significant increase in CMV viremia in adults and children after kidney transplantation. Studies powered for non-inferiority are critical to confirm these findings.

Author contributions

Priya S. Verghese: conceptualization, data curation, formal analysis, project administration, original draft preparation, manuscript revisions and edits. Michael D. Evans: conceptualization, formal analysis, original draft preparation and revisions. Amy Hanson: project administration and data curation. Justina Hathi: original manuscript revisions and edits. Srinath Chinnakotla: conceptualization, manuscript revisions and edits. Arthur Matas: conceptualization, manuscript revisions, project

Disclosure

This study was presented in part at the American Transplant Congress, Boston, MA, June 5, 2022.

Uncited References

[12]

CRediT authorship contribution statement

Priya S. Verghese: Writing – review & editing, Writing – original draft, Validation, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Michael D. Evans: Formal analysis, Validation. Amy Hanson: Data curation, Project administration. Justina Hathi: Writing – review & editing. Srinath Chinnakotla: Conceptualization, Writing – review & editing. Arthur Matas: Conceptualization, Funding acquisition, Resources, Writing – review & editing. Henry H. Balfour:

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This research was supported by the National Institutes of Health's National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's National Center for Advancing Translational Sciences.

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