High Dose Valacyclovir Is Highly Effective to Prevent Cytomegalovirus and Other Herpes Viruses Viremia After Allogeneic Stem Cell Transplantation.

Cytomegalovirus (CMV) remains the most significant viral pathogen following allogeneic hematopoietic stem cell transplantation. Pre-emptive therapy has now become the most commonly used strategy to prevent CMV disease. However, the use of a very effective anti-viral agent could theoretically minimize the risk of disease caused by CMV and other herpesviridae as well as abrogate prospective surveillance after allogeneic transplant. Valacyclovir, the L-valyl ester oral pro-drug of acyclovir, has excellent bioavailability, resulting in high plasma exposures similar to those following IV acyclovir administration. This property confers to valacyclovir antiviral activity against CMV and other herpesviridae. We hypothesized that universal prophylaxis with valacyclovir until day +100 after allogeneic transplant in recipients at high risk of CMV reactivation would lead to a decreased incidence of CMV viremia.

Between 2003 and 2005, we conducted a prospective, randomized study in two allogeneic transplant centers in the Province of Quebec, Canada. Eligibility criteria included therapy with allogeneic blood or marrow transplantation, recipient CMV seropositivity, ability to follow protocol and give informed consent. One group was randomized to receive high dose acyclovir (500 mg/m² iv TID from day -1 till oral intake was resumed followed by valacyclovir 2000 mg QID until day +100 after transplant (n=32), while the control group was followed using a PCR-based (Cobas system, Amplicor Monitor CMV test, Roche) preemptive approach (n=23). Valacyclovir doses were adjusted according to renal function. In addition, weekly specimens, from before initiation of conditioning regimen until day +100, were also collected in both groups of patients in order to compare incidences of other herpes viruses viremia (HSV, EBV) by real-time PCR. All patients with a positive CMV viremia were immediately treated with ganciclovir 5 mg/kg BID until disappearance of positive signal (minimum of 2 weeks) followed by 2 additional weeks. Recurrences were treated as inititial episodes. Primary end point was incidence of CMV viremia by day +100.

Both groups of patients were similar regarding age, type of transplant (sibling vs unrelated donor), HLA compatibility, conditioning regimen (myeloablative vs reduced intensity), GVHD prophylaxis, graft nature and content and acute or chronic GVHD incidence. Valacyclovir was highly effective to reduce the incidence of CMV viremia. In the Valacyclovir group, CMV viremia occurred in 6 patients (6/31;19%) compared to 12 (12/23;63%) in the control group. Cox regression demonstrates a protective effect with valacyclovir (HR, 0.28; 95% CI: 0.10-0.74; p=0.01). Time to CMV viremia was identical in both groups (day +39 vs +36); however, the median viral load was lower in the valacyclovir group (748 vs 8043) although this difference did not reach statistical difference. Similar to CMV, both incidences of EBV and HSV viremia were significantly lower in the valacyclovir group (EBV: 4% vs 28%, p=0.005; HSV: 4% vs 30%, p=0.002). Day +100 mortality and at last follow-up are similar in both groups. Valacyclovir use was safe and well tolerated by most allogeneic transplant recipients but required frequent dose modification according to creatinine level.

Valacyclovir prophylaxis until day +100 is effective to prevent CMV, HSV and EBV reactivation after allogeneic hematopoietic transplantation. Further studies in larger numbers of patients are needed to precise the optimal use of valacyclovir in this patient population.

Off Label Use: Valacyclovir was used to prevent CMV reactivation following allogeneic transplantation under an experimental protocol approved by our IRB.