Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation--a randomized double-blind placebo-controlled study

Abstract

Varicella-zoster virus (VZV) disease occurs in 30% of allogeneic hematopoietic cell transplant recipients who had a history of VZV infection. A safe and effective prevention strategy has not been established. In a double-blind controlled trial, 77 hematopoietic cell transplant recipients at risk for VZV reactivation were randomized to acyclovir 800 mg twice daily or placebo given from 1 to 2 months until 1 year after transplantation. VZV disease at 1 year was the primary end point; VZV disease after discontinuation of prophylaxis, VZV-specific T-cell immunity, herpes simplex virus (HSV) infection, cytomegalovirus (CMV) disease, survival, and safety were secondary end points. Acyclovir significantly reduced VZV infections at 1 year after transplantation (HR, 0.16; 95% CI, 0.035-0.74; P = .006). In the post-intervention observation period, this difference was not statistically significant (2 years: HR, 0.52; 95% CI, 0.21-1.3; 5 years: HR, 0.76; 95% CI, 0.36-1.6). There was no statistically significant difference in reconstitution of VZV-specific T-helper cell responses, HSV infections, CMV disease, chronic graft-versus-host disease, and overall survival between the groups. Acyclovir was well tolerated. Post-study VZV disease predominantly occurred in patients with continued need for systemic immunosuppression. In conclusion, acyclovir effectively and safely prevents VZV disease during the first year after hematopoietic cell transplantation. Periods of prophylaxis longer than 12 months may be beneficial for those hematopoietic cell transplant recipients on continued immune suppression.

Figure 1.

Study flow diagram.

Figure 2.

Time to first VZV disease in the modified intent-to-treat population. Acyclovir prophylaxis significantly reduced VZV disease at the end of the active treatment period (1 year) (Table 2). The vertical dotted line indicates 1 year after transplantation (note: patients were randomized approximately 2 months after transplantation).

Figure 3.

Risk of late VZV disease relative to use of immunosuppression. Cumulative incidence of VZV disease after 1 year in all patients and those who are still on systemic immunosuppression or received a transplant from an unrelated or HLA-mismatched donor versus patients not on immunosuppression or with an HLA-matched related donor.

Figure 4.

VZV- and HSV-specific T-cell reconstitution at start of study drug and at 1 year after transplantation or VZV disease (whichever occurred first). A positive result was defined as a stimulation index of 3 or greater. Shown is the proportion of patients with a positive response. None of the differences are statistically significant. Phytohemagglutinin (PHA) responses were present in all but one patient in both study arms.