Use of Valacyclovir for the Treatment of Cytomegalovirus Antigenemia after Hematopoietic Stem Cell Transplantation

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.

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“…IDO is an immunosubversive factor and will increase Treg cell number in GBM and contribute to other issues in GBM [17][18]. Valacyclovir also has some activity against cytomegalovirus [19].…”

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“…El ACV y el VACV tienen un perfil de seguridad adecuado para su uso durante el embarazo (categoría B de la FDA), con una tasa de malformaciones fetales equivalente a la de la población general 76 . Según la experiencia in vitro 75 e in vivo del uso de dosis altas de ACV/VACV para el tratamiento de la infección por CMV en otras poblaciones 77 , se realizó un estudio doble ciego, aleatorizado, controlado con placebo, que utilizó en 45 mujeres embarazadas VACV a dosis de 8 g al día (8 cápsulas de 500 mg cada 12 h) con el objetivo de prevenir la transmisión materno-fetal en caso de que se documentara una seroconversión durante el período periconcepcional o en el primer trimestre de gestación. Desde ese momento se iniciaba el tratamiento y se mantenía hasta la amniocentesis diagnóstica (aproximadamente a las 21 semanas de gestación).…”