Use of Valacyclovir for the Treatment of Cytomegalovirus Antigenemia after Hematopoietic Stem Cell Transplantation
Authors: Ong Shin-Yeu , Truong Ha Thi Thu , Ho Aloysius Y , Linn Yeh Ching , Goh Yeow-Tee YT , Diong Colin Phipps , Loh Yvonne , Hwang William YK 
Published: October 2019

Abstract
Background: Cytomegalovirus (CMV) infection remains a cause of morbidity and mortality in patients who have undergone allogeneic hematopoietic cell transplantation (HSCT) despite pre-emptive antiviral therapy. Available treatments have clinically significant toxic effects. Valacyclovir is well tolerated, and limited evidence suggests that Valacyclovir is effective in preventing CMV disease when given as prophylactic treatment. We investigated the efficacy and safety of high dose Valacyclovir compared with Valganciclovir or Foscarnet in the pre-emptive therapy of CMV antigenemia.
Methods: In a retrospective single-center study, 61 allogeneic HSCT recipients with an initial episode of CMV antigenemia received pre-emptive therapy with either Valacyclovir (n=15), Valganciclovir (n=16), or Foscarnet (n=30). Patients were treated with either Valacyclovir at 2 g twice-daily, Valganciclovir at 900 mg twice-daily, or Foscarnet at 90 mg/kg twice-daily, with appropriate renal dose adjustments for each drug. Patients were assessed weekly using the pp65 antigenemia assay. Endpoints analyzed include viremia clearance at day 14 and 28, and rates of recurrent antigenemia. Neutrophil counts and creatinine levels were monitored during treatment.
Results: Overall, 60/61 (98%) of cases achieved CMV antigenemia clearance by day 28, and no patient developed CMV disease. Valacyclovir achieved similar clearance of CMV viremia compared to Valganciclovir and Foscarnet, at rates of 93.3%, 77.5%, and 79.5% respectively at 14 days (p=0.054; log rank test). After adjusting for age, sex, CMV serological status, donor type, CMV antigen level, GVHD therapy, and conditioning regimen, there were no significant differences in the odds of viral clearance at day 14 in patients who received Valganciclovir (odds ratio (OR) 0.16, 95% confidence interval (CI) 0.01 to 2.14, p=0.17) and Foscarnet (OR 0.21, 95% CI 0.02 to 2.39, p=0.21), compared to Valacyclovir (assigned OR 1.00). Recurrent CMV antigenemia by day 180 after clearance of the initial episode occurred in 34/61 (56%) of patients. Use of Acyclovir was not associated with an increased odds of CMV recurrence, compared to Valganciclovir or Foscarnet, after adjusting for the same covariates in logistic regression models. Foscarnet significantly increased creatinine levels (p=0.009), while Valganciclovir significantly reduced neutrophil counts (p=0.012). Laboratory evaluation revealed no hematopoietic or renal toxicity in patients on Valacyclovir treatment.
Conclusion: Pre-emptive treatment with Valganciclovir, Foscarnet and Valacyclovir led to similar clearance of CMV antigenemia and rates of recurrence. High dose Valacyclovir is a potential alternative for pre-emptive CMV treatment in allogeneic HSCT recipients, with an acceptable safety profile. Table 1.Response to preemptive cytomegalovirus therapyAll(n=61)Valacyclovir(n=15)Valganciclovir(n=16)Foscarnet(n=30)P Median viral load (No. of CMV positive cells per million leukocytes, range)3 (1-750)3 (1-140)3 (2-181)3.5 (1-750)0.772 Clearance, N (%)0.054Cleared by day 735 (58.3)12 (80.0)11 (68.8)12 (41.4)Cleared by day 1414 (23.3)2 (13.3)2 (12.5)10 (34.5)Cleared by day 218 (13.3)1 (6.7)3 (18.8)4 (13.3)Cleared by day 283 (5.0)0 (0)0 (0)3 (10.3) Recurrent antigenemia, N (%)34 (55.8)7 (46.7)11 (68.8)16 (53.3)0.434 Median days to recurrence43.5 (11-173)59 (27-173)42 (14-94)38 (11-163)0.081

Disclosures
Off Label Use: Valacyclovir use for CMV pre-emptive therapy in allogeneic HSCT recipients. Goh:Novartis Pte Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceuticals Inc: Research Funding; Bristol-Myres Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hospira Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees.