¹Stem Cell Transplant Unit, University of Tokyo, Tokyo, Japan

²Department of Surgery, University of Tokyo, Tokyo, Japan

³Hematology Division, National Cancer Center Hospital, University of Tokyo, Tokyo, Japan

⁴Department of Hematology, Toranomon Hospital, University of Tokyo, Tokyo, Japan

⁵Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan

Correspondence to: Dr Y Kanda, Stem Cell Transplant Unit, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan Recevied 27 March 2001; accepted 18 July 2001

To evaluate the efficacy of long-term administration of acyclovir as prophylaxis against varicella-zoster virus (VZV) reactivation, we analyzed the medical records of 86 consecutive adult patients who obtained engraftment after allogeneic hematopoietic stem cell transplantation from January 1996 to March 2000. We started long-term low-dose (400 mg/day) oral administration of acyclovir in June 1999, and this was continued until the end of immunosuppressive therapy after transplantation. There was no breakthrough reactivation of VZV in patients receiving acyclovir. Five patients who were receiving cyclosporine or prednisolone developed VZV reactivation after discontinuing acyclovir. With this prophylaxis, the cumulative incidence of VZV reactivation at 1 year after transplantation decreased from 33% to 10% (P = 0.025). On multivariate analysis, the use of long-term acyclovir was identified as a significant independent parameter for the development of VZV reactivation. These findings suggest the efficacy of long-term prophylaxis with low-dose acyclovir. Resumption of acyclovir upon restarting immunosuppressive therapy might be important for the further prevention of VZV reactivation. The benefit of long-term low-dose acyclovir should be confirmed prospectively. Bone Marrow Transplantation (2001) 28, 689-692.

varicella-zoster virus; acyclovir; prophylaxis; hematopoietic stem cell transplantation

Varicella-zoster virus (VZV) infection is a common complication after hematopoietic stem cell transplantation (HSCT), and affects 13-55% of recipients during the first year.¹ Among adult recipients, most VZV infections have been demonstrated to be a reactivation of latent virus. A dermatomal rash is a common clinical presentation, although it may also show dissemination or visceral involvement.¹ Acyclovir has been shown to be an effective antiviral agent against VZV and is clearly beneficial for the treatment of acute herpes zoster after HSCT. However, the risk of VZV-related complications, including postherpetic neuralgia and bacterial superinfection, is high in HSCT recipients.²

Short-term acyclovir (5-43 days) is widely used as an effective prophylaxis against herpes simplex virus (HSV). However, most VZV reactivations occur 2 to 8 months (median 5 months) after HSCT.¹ Therefore, long-term administration of acyclovir at 600-3200 mg/day has been investigated. However, previous studies have failed to show a decreased cumulative incidence of VZV reactivation over a 1-year time period due to the rapid onset of VZV following the cessation of antiviral prophylaxis.^3,4,5,6,7 Therefore, we started this trial of long-term acyclovir prophylaxis at a lower dose (400 mg/day), which was continued for the duration of immunosuppressive therapy, for comparison with control patients who received short-term acyclovir.

Patients and methods

Patients

During a 4-year period (January 1996 to March 2000), 95 patients underwent allogeneic hematopoietic stem cell transplantation at the National Cancer Center Hospital. Among them, those who died before engraftment or who underwent a second allogeneic HSCT were excluded. Thus, we analyzed the data for the remaining 86 patients retrospectively by reviewing their medical records. Patient characteristics are summarized in Table 1.

Hematopoietic stem cell transplantation

The preparative regimens were classified into three groups: a total body irradiation (TBI) regimen (n = 57, mainly 120 mg/kg of cyclophosphamide and 12 Gy of TBI), a non-TBI regimen (n = 24, mainly 16 mg/kg of busulfan and 120 mg/kg of cyclophosphamide), and a reduced intensity regimen (n = 5, 0.66 mg/kg of cladribine, 8 mg/kg of busulfan, and 5 or 10 mg/kg of anti-thymocyte globulin (ATG)). Cyclosporin A was administered at a dose of 3 mg/kg/day combined with short-term methotrexate (10-15 mg/m² on day 1 and 7-10 mg/m² on days 3 and 6, and optionally on day 11) to prevent GVHD. Methyl-prednisolone (1-2 mg/kg) was added for patients who developed grade II-IV GVHD. Prophylaxis against bacterial, fungal and Pneumocystis carinii infection consisted of fluconazole, ciprofloxacin, and sulfamethoxazole/trimethoprim. All patients received CMV high-titer intravenous immunoglobulin 5 g weekly during the first 3 months after transplant. Antigenemia-guided pre-emptive therapy against CMV infection was performed as described previously.⁸

As prophylaxis against herpes simplex virus infection, acyclovir was given at a dose of 750 mg/day intravenously or 1000 mg/day orally from days -7 to 35. Beginning in June 1999, we started long-term low-dose (400 mg/day) oral administration of acyclovir as prophylaxis against VZV reactivation, which was continued until the end of immunosuppressive therapy. Acyclovir was resumed at the restart of immunosuppressive therapy for chronic GVHD at the physician's discretion.

Diagnosis and treatment of VZV reactivation

The diagnosis of VZV reactivation was established by the presence of characteristic vesicular skin lesions on an erythematous base within a dermatome or a generalized cutaneous distribution. Microbiological and/or pathological confirmation was performed only in equivocal cases. VZV reactivation was treated with intravenous acyclovir at 750-1500 mg/day in three divided doses or oral acyclovir at 4000 mg/day in five divided doses for 7-14 days.

Statistical analysis

Probabilities in two groups were compared using Fisher's exact test. The incidence of VZV reactivation was calculated by the Kaplan-Meier method and differences between groups were compared using the log-rank test. We performed multivariate analyses using a proportional hazard model to adjust the hazard ratio for patients who did not receive long-term acyclovir. The influence of chronic GVHD was evaluated only in patients who survived longer than 100 days. Patients who remained free of VZV infection after transplantation were censored at the time of their last follow-up or death from unrelated causes.

Results

VZV reactivation

Twenty-one patients developed VZV reactivation at a median of 205 (range 50-613) days after transplantation with no visceral dissemination. The cumulative incidence of VZV reactivation at 1 year after transplantation was 22.8%. All of the patients responded to a therapeutic dose of acyclovir. Possible risk factors were evaluated for their influence on the incidence of VZV reactivation, and we found that long-term acyclovir prophylaxis was the sole factor that significantly decreased the incidence of VZV reactivation (33% vs 10%, Table 2 and Figure 1). Furthermore, the use of long-term acyclovir was confirmed as a significant independent parameter in a proportional hazard model adjusted for other covariates (Table 3).

There was no breakthrough reactivation of VZV in patients who were receiving acyclovir. However, after the cessation of long-term acyclovir at a median prophylactic period of 152 days, five of 17 patients developed VZV reactivation; all of these five were receiving cyclosporine or prednisolone at the time of VZV reactivation. The actuarial incidence of VZV reactivation 1 year after the cessation of acyclovir was 29% (Figure 2). Therefore, none of the recipients had VZV reactivation after cessation of long-term acyclovir, unless immunosuppressive therapy was restarted.

Discussion

As summarized in Table 4, there has been less clinical research on long-term prophylaxis against VZV reactivation than on prophylaxis against CMV,^3,4,5,6,7 probably because it is relatively easy to cure with acyclovir after clinical observation of its reactivation. However, it has to be stressed that VZV reactivation after HSCT significantly affects the quality of life of patients, since it is frequently associated with post-herpetic neuralgia and bacterial superinfection.

Ljungman et al³ performed a randomized placebo-controlled trial of 6 months prophylaxis with acyclovir at 1200 mg/day. Although VZV reactivation was completely prevented during the prophylaxis period, VZV infection frequently recurred after discontinuation of acyclovir. Consequently, the number of VZV reactivations increased in the latter half of the first year after BMT to yield no significant ultimate clinical benefit. The VZV-specific lymphocyte proliferation response was significantly lower in the prophylaxis group at 6 months, suggesting that the administration of long-term acyclovir might delay the immune reconstitution against VZV.³ Another group tested higher-dose (3200 mg/day) long-term acyclovir for 6 months and confirmed the observation made by Ljungman et al.^4,5 A trial after autologous transplantation also failed to decrease the incidence of VZV infection during the first year.⁶

In this study, we succeeded in reducing the 1-year cumulative incidence of VZV reactivation using long-term low-dose acyclovir. Acyclovir was discontinued 6 months after transplantation in the previously published studies, whereas we continued acyclovir during immunosuppressive therapy. Continuing acyclovir in patients receiving immunosuppressants might be important, since all five of the patients who developed VZV reactivation after the cessation of long-term acyclovir were receiving resumed immunosuppressants at VZV reactivation. Another hypothesis is that the administration of very low-dose acyclovir had permitted subclinical VZV reactivation, leading to an immune recovery against VZV. It has been shown that in vivo exposure to VZV antigens due to subclinical VZV reactivation may explain the recovery of virus-specific T cell immunity.⁹

A major concern in long-term acyclovir prophylaxis is the emergence of VZV strains that are resistant to acyclovir, as demonstrated in athymic nude mice.¹⁰ However, this study, as well as previous reports, showed no breakthrough reactivation of VZV. In addition, symptomatic VZV reactivations after discontinuing acyclovir were successfully treated with a therapeutic dose of acyclovir. Therefore, we believe that the emergence of a resistant strain is not a clinically significant problem, at least with the duration of acyclovir administration in these studies. Another concern is the cost of prophylaxis. However, the expected cost in patients receiving long-term acyclovir would be almost the same as that in patients who are not receiving long-term acyclovir (120 174 yen vs 127 789 yen), assuming that patients on long-prophylaxis receive oral acyclovir at 400 mg/day for an average of 150 days and 10% of them require treatment (1500 mg/day i.v. for 10 days), whereas 33% of the patients on short-prophylaxis require treatment.

Valacyclovir and famciclovir are nucleoside analogues that also interfere with viral thymidine kinase activiry and have a safety profile similar to acyclovir.^11,12 Their advantage is more effective absorption after oral administration than acyclovir. However, they are more costly than acyclovir and have been shown not to be useful for treating VZV infections caused by acyclovir-resistant strains.¹³ Therefore, the role of these agents in HSCT recipients should be further evaluated.

In conclusion, this study showed that long-term administration of acyclovir reduced the 1-year cumulative incidence of VZV reactivation, even when a lower daily dose of 400 mg was given. Whether the concomitant resumption of acyclovir in patients who restart immunosuppressive therapy further decreases the incidence of VZV reactivation should be confirmed in a prospective study.

1 Arvin AM. Varicella-zoster virus: pathogenesis, immunity, and clinical management in hematopoietic cell transplant recipients. Biol Blood Marrow Transplant 2000; 6: 219-230, MEDLINE

2 Shepp DH, Dandliker PS, Meyers JD. Treatment of varicella-zoster virus infection in severely immunocompromised patients: a randomized comparison of acyclovir and vidarabine. New Engl J Med 1986; 314: 208-212, MEDLINE

3 Ljungman P, Wilczek H, Gahrton G et al. Long-term acyclovir prophylaxis in bone marrow transplant recipients and lymphocyte proliferation responses to herpes virus antigens in vitro. Bone Marrow Transplant 1986; 1: 185-192, MEDLINE

4 Selby PJ, Powles RL, Easton D et al. The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation. Br J Cancer 1989; 59: 434-438, MEDLINE

5 Perren TJ, Powles RL, Easton D et al. Prevention of herpes zoster in patients by long-term oral acyclovir after allogeneic bone marrow transplantation. Am J Med 1988; 85 (Suppl. 2A): 99-101, MEDLINE

6 Sempere A, Sanz GF, Senent L et al. Long-term acyclovir prophylaxis for prevention of varicella zoster virus infection after autologous blood stem cell transplantation in patients with acute leukemia. Bone Marrow Transplant 1992; 10: 495-498, MEDLINE

7 Steer CB, Szer J, Sasadeusz J et al. Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir. Bone Marrow Transplant 2000; 25: 657-664, MEDLINE

8 Kanda Y, Mineishi S, Saito T et al. Pre-emptive therapy against cytomegalovirus (CMV) diseases guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan. Bone Marrow Transplant 2001; 27: 437-444, MEDLINE

9 Wilson A, Sharp M, Koropchak CM et al. Subclinical varicella-zoster virus viremia, herpes zoster, and T-lymphocyte immunity to varicella-zoster viral antigens after bone marrow transplantation. J Infect Dis 1992; 165: 119-126, MEDLINE

10 Ellis MN, Martin JL, Lobe DC et al. Induction of acyclovir-resistant mutants of herpes simplex virus type I in athymic nude mice. J Antimicrob Chemother 1986; 18 (Suppl. B): 95-101, MEDLINE

11 Beutner KR, Friedman DJ, Forszpaniak C et al. Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995; 39: 1546-1553, MEDLINE

12 Tyring S, Barbarash RA, Nahlik JE et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia: a randomized, double-blind, placebo-controlled trial: Collaborative Famciclovir Herpes Zoster Study Group. Ann Intern Med 1995; 123: 89-96, MEDLINE

13 Balfour HH, Benson C, Baun J et al. Management of acyclovir-resistant herpes simplex and varicella-zoster infections. J Acquired Immune Defic Syndr 1994; 7: 254-260,

Figure 1 Cumulative incidence of varicella-zoster virus (VZV) reactivation after transplantation divided by the presence or absence of long-term acyclovir. Patients who remained free of VZV infection after transplantation were censored at the time of their last follow-up or death from unrelated causes.

Figure 2 Cumulative incidence of varicella-zoster virus (VZV) reactivation after the cessation of long-term acyclovir.

Table 1 Patient characteristics

Table 2 Factors evaluated for their influence on the incidence of varicella-zoster virus reactivation

Table 3 Hazard ratios for patients who did not receive long-term acyclovir adjusted for various factors in the proportional hazard model

Table 4 Summary of the results of published trials on long-term acyclovir