The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation

Abstract

Summary Eighty-two patients were randomly allocated to receive intravenous acyclovir 5 mg kg 1t.d.s. for 23 days followed by oral acyclovir 800mg 6-hourly for 6 months or matching placebos after allogeneic bone marrow transplantation. Herpes simplex and varicella zoster virus infections were significantly reduced during the period of administration of acyclovir. No reduction in cytomegalovirus infection was demonstrated. The drug was not toxic.The introduction of acyclovir into clinical practice was a useful development in the management of herpesvirus infections (Selby et al., 1979). The drug has been proved to be a highly effective treatment for herpes simplex (HSV) and varicella zoster virus (VZV) infections both in immune compromised and immune competent patients (Meyers et al., 1982;Balfour et al., 1983;Prober et al., 1982; reviewed by Fiddian & Grant, 1985;Prentice & Hann, 1985;Strauss, 1985;Gore & Selby, 1987). The efficacy and lack of toxicity of acyclovir has led to its use to prevent reactivation of herpesvirus infections. It is effective in the prophylaxis of HSV reactivation both in the immune competent patient with, for instance, recurrent genital herpes simplex and in the immune compromised patient, after, for instance, allogeneic bone marrow transplantation (Saral et al., 1981;Gluckman et al., 1983;Wade, 1984; Fiddian & Grant, 1985;Prentice & Hann, 1985; Straus, 1985;Gore & Selby, 1987). However, information about the prophylaxis of VZV infection is much less complete.The concentrations of acyclovir that are required to inhibit VZV in vitro are much higher than those required to inhibit HSV. This observation, together with the limited absorption of acyclovir when given by the oral route (Brigden & Whiteman, 1985), led to doubt about the effectiveness of acyclovir for the oral treatment or prophylaxis of VZV. However, it has been shown that oral acyclovir in high doses is effective in shortening the duration of VZV infections in immune competent patients (Peterslund, 1985;McKendrick et al., 1986).Reactivation of both HSV and VZV after bone marrow transplantation are a common source of morbidity. Up to 70% of patients who are seropositive for HSV infection develop reactivations and 40% of patients get herpes zoster or varicella (Saral et al., 1981;Locksley et al., 1985). However, evidence that long-term oral acyclovir will prevent the development of VZV was inconclusive. We have therefore carried out a prospective randomised double blind trial of intravenous acyclovir given for 23 days followed by oral acyclovir for 6 months in patients following allogeneic bone marrow transplantation. (Freedman & White, 1976).Acyclovir or placebo was administered to adults at a dose of 5mg kg-1 in 100 ml of normal saline infused over 1 h, given 8-hourly starting on the day before transplantation and continuing for 23 days. At that point adults received 800mg tablets 6-hourly for 6 months. Children less than 12 years of age received 250 mg m-2 acyclovir intravenously followed by 400mg orally 6-hourly. Patients wer...

Long-term low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation

“…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 lowdose acyclovir.…”

“…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.…”

“…6 months 31% at 6 months Selby 4 Allogeneic 3200 mg p.o. 6 months 45% at 6 months Sempere 6 Autologous 1200 mg p.o.…”

“…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.…”

Reimmunization after blood or marrow stem cell transplantation

“…This delays reconstitution of VZV-specific immunity resulting in delayed reactivation after acyclovir is stopped. 72 Data on the usefulness of varicella vaccination after transplantation are limited. 73,74 Sauerbrei et al 73 administered a live attenuated VZV vaccine to 15 patients 12-23 months after BMT.…”