Low‐dose acyclovir prophylaxis for bortezomib‐induced herpes zoster in multiple myeloma patients

Treatment of multiple myeloma (MM) with bortezomib results in the induction of high overall response rates. However, there is evidence of an increased incidence of herpes zoster during bortezomib treatment (Richardson et al, 2005; Kropff et al, 2007; Chanan-Khan et al, 2008; San Miguel et al, 2008). The occurence of herpes zoster is mostly managable, although it might delay or interrupt proper chemotherapy or even become dose-limiting. On the other hand, herpetic infections are easily preventable. Long term administration of acyclovir to all patients receiving bortezomib in clinical trials lead to eradication of this unfavourable condition (Mateos et al, 2006). Some recent papers have reported successful prevention, even with lower doses of acyclovir (Pour et al, 2009; Vickrey et al, 2009; Kim et al, 2011; Swaika et al, 2012). To date, however, there has not been a consensus on an appropriate prophylactic dose of acyclovir. We carried out a retrospective analysis of 169 patients treated with bortezomib-based regimens between June 2003 and January 2012 at the Department of Internal Medicine III of the University Hospital in Olomouc. Patients were included only if the course of bortezomib lasted at least three cycles, with proper follow-up. The incidence of herpes zoster was analysed in patients receiving or not receiving 200 mg acyclovir. There were 78 patients not receiving any antiviral prophylaxis (46%), and 92 patients (54%) who received prophylactic acyclovir 200 mg/day for the whole course of bortezomib treatment and stopped with the last dose of bortezomib. Basic characteristics of the study group is summarised in Table 1. In the cohort not receiving prophylaxis (N = 78), 21 patients were diagnosed with herpes zoster infection after bortezomib administration (27%). A subgroup analysis of patients with herpes history showed even higher incidence of herpes zoster reactivation (33%). In the group of patients with acyclovir 200 mg prophylaxis (N = 92) we observed only one case of herpetic infection for the whole duration of bortezomib treatment and in the follow-up (1%), Fig 1. Later inspection revealed that the patient had poor adherence to the treatment, and the reactivation was caused by skipped medication. Of the 22 patients with diagnosed herpes zoster during bortezomib treatment, herpes zoster occured after cycle 1 in seven patients (32%), after cycle 2 in five patients (23%), after cycle 3 in five patients (23%), and after cycle 4 in three patients (13%). The infection occurred after cycle 5 in one patient and after cycle 7 in one patient (9%). Patients treated with acyclovir 200 mg (n = 92) did not have any grade 2, 3 or 4 adverse effects. There were no significant differences in the occurence of herpes reactivation regarding age, gender, line of therapy or regimen used. The nature of herpes zoster reactivation in patients treated with bortezomib is poorly understood. Former theories of induction of deeper immunodefficiency in bortezomib-based regimens do not correspond to low herpes incidence in other polychemotherapeutic regimens which induce similar or even deeper post-treatment immunodefficiency. Indeed, the connexion lies very likely in the mechanism of bortezomib action, i.e. the inhibition of proteasome. One theory points to the fact that herpes viruses are thought to express transcripts during latency, which are actively suppressed by immunoproteasome (Swaika et al, 2012). Short term inhibition of the proteasome by bortezomib creates a sufficient window for the reactivation of the virus. Another possible mechanism is common to both bortezomib-induced neuropathy and herpes zoster reactivation. Bortezomib is thought to affect dorsal root ganglia which in turn are known to be the reservoirs of latent varicella-zoster virus (Argyriou et al, 2008). Due to the insignificant initial occurence of herpes zoster infections in patients treated with bortezomib at our department we did not initially use prophylactic acyclovir, and many patients had no prophylaxis for the whole course of their treatment. Based on alarming data from clinical trials we started treatment with low doses of prophylactic acyclovir, 200 mg daily (standard dose in one pill) to all patients. The rationale for such low dose was not supported by standard prophylactic recommendations but was based on concerns about possible drug interactions. There were no available reports on interactions of acyclovir with bortezomib but both the drugs were reported to be substrates for several cytochrome P450 isoenzymes. Concerns about possible reduction of bortezomib effect lead to a rather conservative dosing schedule, which proved to be sufficient. All patients with proper prophylaxis did not have herpes zoster reactivation. On the other hand, patients treated with bortezomib without any prophylaxis were at substantial risk of the infection, particularly those with herpes zoster history. The occurence of herpetic infection was not dose-dependent. Most of the patients experienced herpes reactivation within the first three cycles (78%) with decreasing incidence in later cycles. Reactivation after cycle 5 or 7 in some patients implies the necessity of acyclovir prophylaxis throughout the whole therapy with bortezomib, and there is probably no need to prolong acyclovir administration after the last cycle of bortezomib as no herpes zoster reactivation was observed after the patients stopped bortezomib and acyclovir treatment. Prophylaxis with acyclovir 200 mg/day was effective regardless of type of therapy administered, both during initial treatment as well as in relapsed setting. As our study was retrospective, and did not compare different dosing regimens of acyclovir we cannot proclaim that lower doses are superior to standard dosing. Further studies are therefore needed to confirm our observation. We conclude that the treatment of MM with bortezomib-based regimens is accompanied by higher risk of herpes zoster reactivation, regardless of regimen administered, total dose of bortezomib, and may occur in any phase of the treatment. Patients with previous history of herpes zoster are at particular risk. Lower doses of acyclovir, such as 200 mg/day, are safe and sufficient for adequate prophylaxis, and should be maintained for the duration of bortezomib therapy. The paper was supported by the grant IGA CR NT 12451/5 and IGA MZ CR NT 12215-4/2011. JM designed the study, collected the data and wrote the paper, TP and JB revised the data and critically revised the paper, KL analysed the data, VS critically revised the paper.