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Antiviral prophylaxis for preventing herpes zoster in hematopoietic stem cell transplant recipients: A systematic review and meta-analysis
Antiviral Research 140 (2017) 106e115
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Antiviral Research journal homepage: www.elsevier.com/locate/antiviral
Antiviral prophylaxis for preventing herpes zoster in hematopoietic stem cell transplant recipients: A systematic review and meta-analysis Hyun-Min Seo a, Yoon Seob Kim a, Chul Hwan Bang a, Ji Hyun Lee a, Jun Young Lee a, Dong-Gun Lee b, Young Min Park a, * a
Department of Dermatology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Division of Infectious Diseases, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 December 2016 Received in revised form 8 January 2017 Accepted 11 January 2017 Available online 26 January 2017
The optimal duration of prophylaxis for the varicella-zoster virus following hematopoietic stem cell transplantation (HSCT) remains unclear. The purpose of this study was to systematically review the available literature to determine the optimal duration of antiviral prophylaxis for preventing herpes zoster (HZ) in allogeneic and autologous HSCT recipients. The MEDLINE and EMBASE databases were searched to identify relevant studies. The relative risk (RR) of HZ was calculated using fixed effects or random effects models depending on heterogeneity across the included studies. We analyzed six observational studies comprising a total of 3420 patients. In all HSCT recipients, the overall incidence of HZ in the prophylaxis group and the control group was 7.8% and 25.6%, respectively, with a pooled RR of 0.31 (95% CI, 0.26e0.37). The incidence of HZ in the subgroup wherein prophylaxis was given for at least 1 year and in the subgroup wherein prophylaxis was given for less than 1 year was 2.1% and 15.4%, respectively, with a pooled RR of 0.23 (95% CI, 0.04e1.39). Taken together, our results demonstrate that antiviral prophylaxis can significantly reduce HZ in HSCT recipients, and suggests that long-term prophylaxis given for at least 1 year may be recommended for better preventive effects. © 2017 Elsevier B.V. All rights reserved.
Keywords: Acyclovir Allogeneic Autologous Hematopoietic stem cell transplantation Herpes zoster Valacyclovir
Contents 1. 2.
3.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 2.1. Data sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 2.2. Data extraction and study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 2.3. Prophylaxis and outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 2.4. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 2.5. Statistical analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 3.1. Search results and characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 3.2. Description of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 3.3. Influence of antiviral prophylaxis on the incidence of HZ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 3.4. Assessment of publication bias and risk of bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 Authorship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Conflict-of-interest disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
* Corresponding author. Department of Dermatology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea. E-mail address: [email protected] (Y.M. Park). http://dx.doi.org/10.1016/j.antiviral.2017.01.011 0166-3542/© 2017 Elsevier B.V. All rights reserved.
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1. Introduction Herpes zoster (HZ) is caused by the varicella-zoster virus (VZV) and is a common complication following hematopoietic stem cell transplantation (HSCT), occurring in approximately 17e50% of allogeneic transplant recipients and 14e28% of autologous transplant recipients (Schuchter et al., 1989; Truong et al., 2014). According to a large retrospective cohort study, most cases of HZ occur during the first year following both types of HSCT, at a median duration of 6 months after allogeneic HSCT and 5 months after autologous HSCT (Erard et al., 2007). In addition to the risk of a more severe and prolonged local disease in this immunecompromised population, transplant patients are at risk for developing dissemination. Disseminated HZ can manifest as a cutaneous disease with erythematous papules, vesicles, pustules, or crusts appearing outside the primary dermatome, and with more severe systemic organ involvement, including encephalitis, pneumonia, hepatitis, and even death (Koc et al., 2000; Gnann, 2002). The 2016 National Comprehensive Cancer Network (NCCN) Guidelines® in Oncology currently recommend prolonged antiviral prophylaxis in hematopoietic stem cell transplant patients for the prevention of HZ with a duration of at least 6e12 months following autologous HSCT, and with a duration of at least 12 months following allogeneic HSCT (Baden et al., 2016). However, there is a lack of evidence on the optimal duration of VZV prophylaxis. Moreover, following discontinuation of antiviral prophylaxis, there is always some concern about the possible disproportionate increase of HZ in patients. When this occurs (with this and other disorders), the phenomenon is often termed a “rebound” disease (Erard et al., 2007). The aim of this study is to systematically evaluate the optimal duration of antiviral prophylaxis for preventing HZ in allogeneic and autologous HSCT recipients. Because our database search yielded only two randomized controlled trials with small numbers of patients (Boeckh et al., 2006; Klein et al., 2011), we included six observational studies for the meta-analysis herein. The analysis compares preventive effects between an antiviral prophylaxis group and a control group (i.e., no prophylaxis) on the development of HZ in HSCT recipients.
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and duration of follow up. The investigators resolved any disagreement by consensus. Included for analysis were studies that evaluated the effectiveness of antiviral prophylaxis in HSCT recipients. Recipients of all ages were included, irrespective of VZV serologic status prior to HSCT (allogeneic or autologous). Recipients of solid organ transplants were excluded. Because there was heterogeneity in the duration of follow up across the studies, we gathered data for the longest period possible for analyses in each study. 2.3. Prophylaxis and outcome measures Prophylaxis involved antiviral agents, including acyclovir, famciclovir, and valacyclovir. Because the majority of participants in the included studies received antiviral prophylaxis to prevent cytomegalovirus or the herpes simplex virus for durations of several days before transplant to about 1 month following HSCT, these antiviral prophylaxes were regarded as co-prophylaxis. We considered prophylaxis as the antiviral prophylaxis following coprophylaxis. Comparisons were made between groups undergoing prophylaxis for the prevention of HZ and a control. Primary outcome measures were the overall incidence of HZ between prophylaxis and control groups in all HSCT recipients. Secondary outcome measures were the incidence of HZ between prophylaxis and control groups in the recipients of each type of HSCT (allogeneic or autologous). The definition of HZ was as defined by the investigators of the included studies (Truong et al., 2014; Erard et al., 2007; Kanda et al., 2001; Asano-Mori et al., 2008; Kim et al., 2008a; Kawamura et al., 2015). Typically, this definition involved the presence of characteristic grouped vesicles on an erythematous base along a dermatome, a generalized cutaneous distribution, or microbiological and/or pathological confirmation. 2.4. Quality assessment
This systematic review was performed in accordance with the recommendations of the Meta-analysis of Observational Studies in Epidemiology Group and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (Stroup et al., 2000; Moher et al., 2009).
Two authors (H. M. Seo and C. H. Bang) independently evaluated the quality of the studies without blinding to authorship or to the journal of publication. The risk of bias in the observational studies included was assessed by the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS), which assesses the selection of participants, confounding variables, measurement of exposure, blinding of outcome assessments, incomplete outcome data, and selective outcome reporting. All parameters were categorized as having a low, unclear, or high risk of bias (Kim et al., 2013). In the case of disagreement between the two investigators, consensus was reached after discussion.
2.1. Data sources
2.5. Statistical analyses
Discrete literature searches were independently conducted by two reviewers (H.M. Seo and Y. S. Kim). The MEDLINE and EMBASE databases were searched from inception through May 1, 2016. Observational studies were identified using the following search terms: “herpes zoster” (Medical Subject Headings, MeSH) and “hematopoietic stem cell transplantation” (MeSH). All published articles written in English, limited to human studies, were included.
We have presented dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs). Heterogeneity was assessed using c2 tests and I2 statistics, with p < 0.1 for the c2 tests and with I2 > 50% used as a threshold to indicate moderate heterogeneity. We pooled the data using a Mantel-Haenszel method to calculate a summary estimate of effect (Mantel and Haenszel, 1959). If moderate heterogeneity was seen, then the results of a random effects model were reported after exploring the causes of heterogeneity. Otherwise the results of the fixed effects model were reported. All treatment regimens were combined for comparison, regardless of the kind or dosage of various antiviral agents. Subgroup analyses were conducted according to HSCT type and the duration of antiviral prophylaxis. The meta-analysis was performed with RevMan software, version 5.3 (Cochrane Collaboration, Copenhagen, Denmark).
2. Methods
2.2. Data extraction and study selection Two investigators (H. M. Seo and Y. S. Kim) independently reviewed the eligible reports in detail, and abstracted relevant information using a standard extraction sheet that covers study design, country, number and demographics of subjects, type of HSCT and antiviral prophylaxis, duration of antiviral prophylaxis,
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Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram of study flow. VZV, varicella-zoster virus.
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3. Results 3.1. Search results and characteristics of included studies Our literature search yielded a total of 498 articles. Twenty-nine articles remained after the screening of titles and abstracts by the
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two independent reviewers (Fig. 1). A total of 29 full-text articles were assessed for eligibility, 23 of which were excluded for the following reasons: (1) no VZV prophylaxis (n ¼ 9) (Blennow et al., 2014; Berman et al., 2006; Offidani et al., 2001; Onozawa et al., ski et al., 2015; Su et al., 2006; Srinivasan et al., 2014; Styczyn 2011; van der Beek et al., 2013; Verdeguer et al., 2011), (2) no
Table 1 Characteristics of studies included in review HZ, Herpes zoster. Study
Country Study design
Participants Transplantation Regimen of antiviral prophylaxis type
AsanoMori et al. (2008)
Japan
Treatment group Number: 137 Age: NS Sex (M/F): NS Control group Number: 105 Age: NS Sex (M/F): NS Treatment group A Number: 586 Age: 47 (0 e73), median (range) Sex (M/F): 358/228 Treatment group B Number: 1117 Age: 45 (1 e74), median (range) Sex (M/F): 576/541 Control group Number: 932 Age: 42 (1 e68), median (range) Sex (M/F): 487/445 Treatment group Number: 45 Age: NS Sex (M/F): NS Control group Number: 41 Age: NS Sex (M/F): NS Treatment group A Number: 7 Age: NS Sex (M/F): NS
Erard et al. USA (2007)
Kanda et al. Japan (2001)
Kawamura Japan et al. (2015)
Single center/ Retrospective cohort
Single center/ Retrospective cohort
Single center/ Retrospective cohort
Single center/ Retrospective cohort
Allogeneic HSCT Prophylaxis group Acyclovir 200 mg/d at least 1 year after HSCT Control group No treatment
Follow up duration Mean 486 days (range, 37e4209 days)
Co-prophylaxis Acyclovir given at 750 mg/day intravenously or at 1000 mg/ day orally from days 7e35 after HSCT
Allogeneic/ autologous HSCT
Prophylaxis group A 2 years Prophylaxis against HZ over 1 year after HSCT (acyclovir 250 mg/m2 intravenously followed by 800 mg orally or valacyclovir 500 mg orally, all drugs given twice per day; valacyclovir was preferred for patients who received 0.5 mg/ kg per day of steroids) Prophylaxis group B Prophylaxis against HZ for 1 year after HSCT (same regimen prescribed for prophylaxis A) Control group No treatment
Co-prophylaxis Not receiving acyclovir for HZ prevention; herpes simplex virus (HSV)epositive recipients were given acyclovir, 250 mg/m2 twice per day, from day 7 until engraftment and resolution of mucositis
Allogeneic HSCT/PBSCT
12 months Prophylaxis group Long-term low-dose (400 mg/day) oral administration of acyclovir as prophylaxis against HZ, which was continued until the end of immunosuppressive therapy (median 152 days)
Control group No treatment Co-prophylaxis 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 7e35 Autologous HSCT
2 years Prophylaxis group A Acyclovir was continued at 200 mg at the discretion of the attending physicians (1 year) Prophylaxis Group B Acyclovir was continued at 200 mg at the discretion of the attending physicians (36 days to 1 year) (continued on next page)
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Table 1 (continued ) Study
Country Study design
Kim et al. Canada/ Multi(2008a) Korea center/ Retrospective cohort
Truong et al. (2014)
USA
Single center/ Retrospective cohort
Participants Transplantation Regimen of antiviral prophylaxis type Treatment group B Number: 14 Age: NS Sex (M/F): NS Control group Number: 41 Age: NS Sex (M/F): NS Treatment group A Number: 27 Age: 49 (22 e69), median (range) Sex (M/F): 13/14 Treatment group B Number: 73 Age: 36 (16 e60), median (range) Sex (M/F): 45/28 Control group Number: 166 Age: 51 (17 e71), median (range) Sex (M/F): 96/70 Treatment group A Number: 40 Age: 55 (26 e70), median (range) Sex (M/F): 27/13 Treatment group B Number: 12 Age: 52 (22 e72), median (range) Sex (M/F): 9/3 Control group Number: 77 Age: 54 (16 e72), median (range) Sex (M/F): 49/28
Follow up duration
Control group No treatment
Co-prophylaxis Oral acyclovir at 200 mg once or five times daily from day 7 to engraftment (35 days)
Allogeneic PBSCT
Prophylaxis group A Long-term (more than 3 months) low-dose acyclovir prophylaxis (200 mg twice daily orally) Prophylaxis group B Oral acyclovir prophylaxis (400 mg twice daily) given routinely until immunosuppressive therapy was discontinued
Median 26.5 months (range, 2e77)
Control group No treatment
Co-prophylaxis Acyclovir was used intravenously at 160 mg daily in divided doses or orally at 400 mg orally for 28 d for herpes simplex virus (HSV) prophylaxis in group A, and 800 mg orally per day in group B and control
Autologous HSCT
Prophylaxis group A Median 23 (range 6e24) months for group Antiviral prophylaxis 12 months (±60 days) post-auto-HCT A, 13 (range 4e19) months for group B, 13 Prophylaxis group B (range 7e13) months for control Antiviral prophylaxis for 6 months (±60 days)
Control group Antiviral prophylaxis until neutrophil recovery to 500/ mm3 from post-HCT nadir
Co-prophylaxis Acyclovir 400 mg orally or intravenously twice daily or valacyclovir 500 mg orally/day starting at the initiation of preparatory chemotherapy for transplant
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Fig. 2. Forest plot estimating the risk of herpes zoster with antiviral prophylaxis in all HSCT recipients. A, Antiviral prophylaxis versus control. B, Antiviral prophylaxis given for at least one year versus control. C, Antiviral prophylaxis given for less than one year versus control. D, Antiviral prophylaxis given for at least one year versus antiviral prophylaxis given for less than one year. HSCT, hematopoietic stem cell transplantation.
control of VZV prophylaxis (n ¼ 5) (Aytac et al., 2011; Oshima et al., 2010; Rogers et al., 2011; Uchiyama et al., 2010; Steer et al., 2000), (3) not written in English (n ¼ 3) (Akiyama et al., 2000; Karasuno and Hiraoka, 2006; Li et al., 2011), (4) inadequate evidence of VZV reactivation (n ¼ 2) (Toze et al., 2012; Pergam et al., 2012), (5) randomized controlled studies comprising a small number of patients (n ¼ 2) (Boeckh et al., 2006; Klein et al., 2011), (6) antiviral prophylaxis at the discretion of attending physicians (n ¼ 1) (Leung et al., 2002), and (7) patients were also included in a previous trial (n ¼ 1) (Kim et al., 2008b). Finally, six observational studies met the inclusion criteria and were included in this review (Truong et al., 2014; Erard et al., 2007; Kanda et al., 2001; Asano-Mori et al., 2008; Kim et al., 2008a; Kawamura et al., 2015). 3.2. Description of included studies A total of 3420 patients from the six studies were available for analysis. Among them, 2058 patients received prophylactic antiviral prophylaxis, and 1362 were included as a control.
Five studies were single-center (Truong et al., 2014; Erard et al., 2007; Kanda et al., 2001; Asano-Mori et al., 2008; Kawamura et al., 2015) studies and one was a multi-center study (Kim et al., 2008a). Three studies were conducted in Japan (Kanda et al., 2001; AsanoMori et al., 2008; Kawamura et al., 2015), two studies were conducted in the United States (Truong et al., 2014; Erard et al., 2007), and the other included study was conducted in Canada/Korea (Kim et al., 2008a). The six studies were commonly designed as retrospective cohort studies. Most participants received antiviral prophylaxis for durations of at least 3 months. The number of participants receiving prophylaxis for a duration of at least 1 year was 1887 (91.7%) in the included studies (Truong et al., 2014; Erard et al., 2007; Asano-Mori et al., 2008; Kawamura et al., 2015). The dosages of acyclovir and valacyclovir used in the included studies ranged from 200 to 1600 mg/day and 500e1000 mg/day, respectively. The duration of follow up ranged from 12 months to a median of 26.5 months. The recipients of allogeneic HSCT were available for analyses in four studies (Erard et al., 2007; Kanda et al., 2001; Asano-Mori et al., 2008; Kim et al., 2008a) and recipients of
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autologous HSCT were available for analyses in three studies (Truong et al., 2014; Erard et al., 2007; Kawamura et al., 2015). Antiviral agents used for prophylaxis were only acyclovir in four studies (Kanda et al., 2001; Asano-Mori et al., 2008; Kim et al., 2008a; Kawamura et al., 2015) and acyclovir/valacyclovir in two studies (Truong et al., 2014; Erard et al., 2007). The use of VZV antiviral prophylaxis for a duration of at least 1 year was identified in four studies (Truong et al., 2014; Erard et al., 2007; Asano-Mori et al., 2008; Kawamura et al., 2015), and prophylaxis given for less than 1 year was identified in four studies (Truong et al., 2014; Kanda et al., 2001; Kim et al., 2008a; Kawamura et al., 2015). Detailed characteristics of the six included studies are presented in Table 1.
bias might exist. Thus we assessed publication bias using funnel plots. Possible asymmetry could not be found with visual examination. Accordingly, the plots were not suggestive of any publication bias (Fig. 4). Regarding the risk of bias, the selection of participants was considered inadequate in all but two studies. The most frequent reason whereby studies were designated as having a “high” risk of bias was a definition of control groups that were selected from different population groups (historical control). The results are summarized in Fig. 5. The graph provides an overview of the authors’ judgments about each risk of bias item using the RoBANS, presented as percentages across all included studies. Fig. 6 presents the risk of bias summary of the six observational studies included in our meta-analysis.
3.3. Influence of antiviral prophylaxis on the incidence of HZ In all HSCT recipients, the overall incidence of HZ in the prophylaxis group and control group was 7.8% and 25.6%, respectively, with a pooled RR of 0.31 (95% CI, 0.26e0.37). There was no heterogeneity across studies (p ¼ 0.92, I2 ¼ 0%) (Fig. 2A). Both prophylactic groups (i.e., prophylaxis given for at least 1 year and prophylaxis given for less than 1 year) had a lower risk of HZ events in comparison to the control group (RR, 0.30; 95% CI, 0.24e0.36 and RR, 0.41; 95% CI, 0.25e0.66, respectively) (Fig. 2B and C). The incidence of HZ in the subgroup wherein prophylaxis was given for at least 1 year and in the subgroup wherein prophylaxis was given for less than 1 year was 2.1% and 15.4%, respectively, with a pooled RR of 0.23 (95% CI, 0.04e1.39) (Fig. 2D). Subgroup analysis according to HSCT type revealed that both allogeneic and autologous HSCT groups with antiviral prophylaxis had a lower risk of HZ events in comparison to the control group (RR, 0.29; 95% CI, 0.24e0.36 and RR, 0.36; 95% CI, 0.25e0.54, respectively) (Fig. 3A and B). However, there were no significant differences in prophylactic effects on the development of HZ between allogeneic and autologous HSCT recipients. 3.4. Assessment of publication bias and risk of bias Given the tendency to publish only studies that show the prophylactic effects of antiviral prophylaxis on HZ, we were aware that
4. Discussion To our knowledge, this is the largest systematic review of existing literature and the first meta-analysis for preventing HZ in 3420 HSCT recipients. The analysis demonstrates two important findings, as follows. First, antiviral prophylaxis may significantly reduce HZ development in HSCT recipients. Second, long-term prophylaxis given for at least 1 year following HSCT demonstrates much better HZ preventive effects, irrespective of HSCT type. Recently, the 2016 NCCN guidelines recommended prolonged antiviral prophylaxis for the prevention of HZ with a duration of at least 6e12 months following autologous HSCT and with a duration of at least 12 months following allogeneic HSCT (Baden et al., 2016). In contrast, our analysis demonstrates that the incidence of HZ with antiviral prophylaxis given for at least 1 year was lower than the incidence of HZ with antiviral prophylaxis given for less than 1 year (2.1% and 15.4, respectively). Similarly, the work of Truong et al. reports that there might be suboptimal VZV-specific immunereconstitution at 6 months of antiviral prophylaxis versus a 12month period of antiviral prophylaxis following autologous HSCT (Truong et al., 2014). Thus it might be assumed that long-term antiviral prophylaxis given for at least 1 year is more suitable for preventing HZ, irrespective of HSCT type. Within the studies included in our meta-analysis, there was a lack of consensus about the proper dosage of antiviral agents to
Fig. 3. Forest plot estimating the risk of herpes zoster with antiviral prophylaxis according to each type of HSCT. Antiviral prophylaxis versus control in allogeneic (A) and autologous HSCT (B) HSCT, hematopoietic stem cell transplantation.
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Fig. 4. Funnel plot of comparison. Antiviral prophylaxis versus control in both groups (A), in allogeneic (B), and in autologous HSCT (C). Antiviral prophylaxis given for at least one year in both groups versus control (D). Antiviral prophylaxis given for less than one year versus control (E). Antiviral prophylaxis given for at least one year versus antiviral prophylaxis given for less than one year (F). HSCT, hematopoietic stem cell transplantation.
prevent HZ in HSCT recipients. The most frequently reported agent was acyclovir in HSCT recipients with a wide range of 200e3200 mg/day (Truong et al., 2014; Erard et al., 2007; Boeckh et al., 2006; Kanda et al., 2001; Asano-Mori et al., 2008; Kim et al., 2008a; Kawamura et al., 2015; Oshima et al., 2010; Steer et al., 2000; Selby et al., 1989). In the studies included in our metaanalysis, the long-term administration of acyclovir at a relatively low dosage of 200e1600 mg/day was shown to be effective in preventing HZ (Truong et al., 2014; Erard et al., 2007; Kanda et al., 2001; Asano-Mori et al., 2008; Kim et al., 2008a; Kawamura et al., 2015; Steer et al., 2000). Although the dosage of antiviral agents varied among the included studies, the RRs of each study were similar. Regarding valacyclovir, there were a few studies with long-
term prophylaxis for the prevention of HZ with valacyclovir at dosages ranging from 500 to 2000 mg/day, which showed comparable effects and safety profiles in the prevention of HZ in HSCT recipients (Truong et al., 2014; Erard et al., 2007; Klein et al., 2011; Asano-Mori et al., 2008). One pharmacokinetics study shows that 500 mg/day of valacyclovir has comparable efficacy to a dose of 400 mg/day of acyclovir (Koc et al., 2000). There were no included studies in which famciclovir was used as the prophylactic agent for preventing HZ in HSCT recipients. To prevent development of HZ, acyclovir and valacyclovir are recommended with dosages of 200e1600 mg/day and 500e2000 mg/day, respectively. There is concern about the rebound of HZ after discontinuation of antiviral prophylaxis in HSCT recipients. A previous randomized
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Fig. 5. Risk of bias graph of included observational studies. Authors' judgments about each risk of bias item presented as percentages across all included studies.
Fig. 6. Risk of bias summary of included observational studies. Authors' judgments about each risk of bias item for each included study.
trial reports that HZ episodes occurred in 2 of 13 recipients, at 3 and 8 months after discontinuation of 24 months of antiviral prophylaxis. Even if the numbers of patients are too small to draw any conclusions, antiviral prophylaxis might not allow sufficient immune reconstitution in some HSCT recipients (Klein et al., 2011). On the other hand, another randomized trial shows that antiviral prophylaxis in allogeneic HSCT recipients in fact allowed VZVspecific immune reconstitution (Boeckh et al., 2006). In addition, antiviral prophylaxis with acyclovir or valacyclovir given for at least 1 year in a large cohort shows persistent benefits after drug discontinuation, and shows no evidence of rebound effects in groups of patients that underwent both types of HSCT (Erard et al.,
2007). Despite some conflicting results, based on our review, longterm antiviral prophylaxis given for at least 1 year may have longterm benefits for the prevention of HZ. The emergence of resistant herpes simplex virus (HSV) type I has been demonstrated in a study with athymic nude mice (Ellis et al., 1986). In several existing reports, however, no breakthrough of antiviral-resistant HSV or VZV was observed, and symptomatic HZ events following discontinuation of antiviral prophylaxis were well treated with typical therapeutic doses of antiviral agents (Kanda et al., 2001; Kawamura et al., 2015). In addition, the work of Erard et al., reports that certain dosages of acyclovir or valacyclovir have been shown to also effectively prevent wild-type and drug-resistant HSV diseases in HSVseropositive recipients (Erard et al., 2007). According to our systematic review, the emergence of resistant HSV or VZV may not be a serious problem. Nonetheless, we should be careful not to overlook the emergence of antiviral-resistant HSV or VZV strains. Another concern is the tolerability of long-term use of antiviral agents. One study using acyclovir in a dose of 1600 mg/day for 1 year shows long-term use to be well tolerable except for mild gastrointestinal adverse effects (Boeckh et al., 2006). Another study using valacyclovir in a dose of 2000 mg/day for 2 years also reports the prophylactic regimen to be well tolerable (Klein et al., 2011). Thus long-term prophylaxis with antiviral agents in usual dosages is safe and well-tolerable in HSCT recipients. Our meta-analysis has some limitations. First, our results are based on a small number of studies. Second, there is too much heterogeneity in the duration, kind, and dosage of antiviral agents used in the studies to determine an optimal prophylactic regimen in preventing HZ in HSCT recipients. Third, there was a selection bias in participants across the studies due to the retrospective nature of the studies. Further studies are necessary to establish the optimal dosage of antiviral agents for the prevention of HZ in HSCT recipients. In conclusion, our results demonstrate that antiviral prophylaxis can reduce HZ development in recipients of both types of HSCT. Moreover, long-term prophylaxis given for at least 1 year may be recommended to get better preventive effects, irrespective of HSCT type. Authorship Contribution: H.M.S. developed the protocol, conducted the literature search, assessed the methodological quality, performed data extraction, conducted the statistical analysis, and wrote the
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manuscript; Y.S.K. conducted the literature search and performed data extraction; C.H.B. assessed methodological quality; J.H.L. reviewed the analysis and protocol; J.Y.L. and D.G.L. reviewed the protocol and the manuscript; Y.M.P. developed the protocol and reviewed the protocol and the manuscript. All the authors approved the final version of the manuscript. Conflict-of-interest disclosure The authors have no conflict of interest to declare. References Akiyama, H., Inoue, T., Okoshi, Y., Mori, S., Ohashi, K., Maeda, Y., et al., 2000. Varicella-zoster virus infection after hematopoietic stem cell transplantation. Rinsho ketsueki 41 (1), 20e24. Asano-Mori, Y., Kanda, Y., Oshima, K., Kako, S., Shinohara, A., Nakasone, H., et al., 2008. Long-term ultra-low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Am. J. Hematol. 83 (6), 472e476. Aytac, S., Yalcin, S.S., Kucukbayrak, O., Cetin, M., Uckan, D., 2011. Dynamics in children and adolescents who experience varicella zoster virus infections after haematopoietic stem cell transplantation: a case-control study. Epidemiol. Infect. 139 (11), 1701e1709. Baden, L.R., Swaminathan, S., Angarone, M., Blouin, G., Camins, B.C., Casper, C., et al., 2016. Prevention and Treatment of Cancer-Related Infections, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J. Nat. Compr. Canc. Netw. 14 (7), 882e913. Berman, J.N., Wang, M., Berry, W., Neuberg, D.S., Guinan, E.C., 2006. Herpes zoster infection in the post-hematopoietic stem cell transplant pediatric population may be preceded by transaminitis: an institutional experience. Bone marrow Transplant. 37 (1), 73e80. Blennow, O., Fjaertoft, G., Winiarski, J., Ljungman, P., Mattsson, J., Remberger, M., 2014. Varicella-zoster reactivation after allogeneic stem cell transplantation without routine prophylaxisethe incidence remains high. Biol. blood marrow Transplant. 20 (10), 1646e1649. Boeckh, M., Kim, H.W., Flowers, M.E., Meyers, J.D., Bowden, R.A., 2006. Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantationea randomized double-blind placebocontrolled study. Blood 107 (5), 1800e1805. Ellis, M.N., Martin, J.L., Lobe, D.C., Johnsrude, J.D., Barry, D.W., 1986. Induction of acyclovir-resistant mutants of herpes simplex virus type I in athymic nude mice. J. Antimicrob. Chemother. 18 (Suppl. B), 95e101. Erard, V., Guthrie, K.A., Varley, C., Heugel, J., Wald, A., Flowers, M.E., et al., 2007. One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicellazoster virus disease after drug discontinuation. Blood 110 (8), 3071e3077. Gnann Jr., J.W., 2002. Varicella-zoster virus: atypical presentations and unusual complications. J. Infect. Dis. 186 (Suppl. 1), S91eS98. Kanda, Y., Mineishi, S., Saito, T., Saito, A., Yamada, S., Ohnishi, M., et al., 2001. Longterm low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Bone marrow Transplant. 28 (7), 689e692. Karasuno, T., Hiraoka, A., 2006. Herpesvirus infections in hematological diseases. Nihon rinsho. 64 (Suppl. 3), 73e76. Kawamura, K., Hayakawa, J., Akahoshi, Y., Harada, N., Nakano, H., Kameda, K., et al., 2015. Low-dose acyclovir prophylaxis for the prevention of herpes simplex virus and varicella zoster virus diseases after autologous hematopoietic stem cell transplantation. Int. J. Hematol. 102 (2), 230e237. Kim, D.H., Kumar, D., Messner, H.A., Minden, M., Gupta, V., Kuruvilla, J., et al., 2008a. Clinical efficacy of prophylactic strategy of long-term low-dose acyclovir for Varicella-Zoster virus infection after allogeneic peripheral blood stem cell transplantation. Clin. Transplant. 22 (6), 770e779. Kim, D.H., Messner, H., Minden, M., Gupta, V., Kuruvilla, J., Wright, J., et al., 2008b. Factors influencing varicella zoster virus infection after allogeneic peripheral blood stem cell transplantation: low-dose acyclovir prophylaxis and pretransplant diagnosis of lymphoproliferative disorders. Transpl. Infect. Dis. 10 (2), 90e98. Kim, S.Y., Park, J.E., Lee, Y.J., Seo, H.J., Sheen, S.S., Hahn, S., et al., 2013. Testing a tool for assessing the risk of bias for nonrandomized studies showed moderate reliability and promising validity. J. Clin. Epidemiol. 66 (4), 408e414. Klein, A., Miller, K.B., Sprague, K., DesJardin, J.A., Snydman, D.R., 2011. A randomized, double-blind, placebo-controlled trial of valacyclovir prophylaxis to prevent zoster recurrence from months 4 to 24 after BMT. Bone Marrow Transplant. 46 (2), 294e299. Koc, Y., Miller, K.B., Schenkein, D.P., Griffith, J., Akhtar, M., DesJardin, J., et al., 2000. Varicella zoster virus infections following allogeneic bone marrow
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A predictive model of varicella-zoster virus infection after autologous peripheral blood progenitor cell transplantation. Clin. Infect. Dis. Off. Publ. Infect. Dis. 32 (10), 1414e1422. http://dx.doi.org/10.1086/320157 e-pub ahead of print 2001/04/24. Onozawa, M., Hashino, S., Takahata, M., Fujisawa, F., Kawamura, T., Nakagawa, M., et al., 2006. Relationship between preexisting anti-varicella-zoster virus (VZV) antibody and clinical VZV reactivation in hematopoietic stem cell transplantation recipients. J. Clin. Microbiol. 44 (12), 4441e4443. Oshima, K., Takahashi, T., Mori, T., Matsuyama, T., Usuki, K., Asano-Mori, Y., et al., 2010. One-year low-dose valacyclovir as prophylaxis for varicella zoster virus disease after allogeneic hematopoietic stem cell transplantation. A prospective study of the Japan Hematology and Oncology Clinical Study Group. Transpl. Infect. Dis. 12 (5), 421e427. Pergam, S.A., Xie, H., Sandhu, R., Pollack, M., Smith, J., Stevens-Ayers, T., et al., 2012. Efficiency and risk factors for CMV transmission in seronegative hematopoietic stem cell recipients. Biol. blood marrow Transplant. 18 (9), 1391e1400. Rogers, J.E., Cumpston, A., Newton, M., Craig, M., 2011. Onset and complications of varicella zoster reactivation in the autologous hematopoietic cell transplant population. Transpl. Infect. Dis. 13 (5), 480e484. Schuchter, L.M., Wingard, J.R., Piantadosi, S., Burns, W.H., Santos, G.W., Saral, R., 1989. Herpes zoster infection after autologous bone marrow transplantation. Blood 74 (4), 1424e1427. Selby, P.J., Powles, R.L., Easton, D., Perren, T.J., Stolle, K., Jameson, B., et al., 1989. The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation. Br. J. cancer 59 (3), 434e438. Srinivasan, A., McLaughlin, L., Wang, C., Srivastava, D.K., Shook, D.R., Leung, W., et al., 2014. Early infections after autologous hematopoietic stem cell transplantation in children and adolescents: the St. Jude experience. Transpl. Infect. Dis. 16 (1), 90e97. Steer, C.B., Szer, J., Sasadeusz, J., Matthews, J.P., Beresford, J.A., Grigg, A., 2000. Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir. Bone marrow Transplant. 25 (6), 657e664. http://dx.doi.org/10.1038/sj.bmt.1702190 e-pub ahead of print 2000/03/29. Stroup, D.F., Berlin, J.A., Morton, S.C., Olkin, I., Williamson, G.D., Rennie, D., et al., 2000. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA 283 (15), 2008e2012. ski, J., Czyzewski, K., Siewiera, K., Fra˛czkiewicz, J., Zaja˛ c-Spychała, O., Styczyn Go zdzik, J., et al., 2015. Viral infections in children undergoing hematopoietic stem cell transplantation. Acta Haematol. Pol. 46 (4), 312e317. Su, S.H., Martel-Laferriere, V., Labbe, A.C., Snydman, D.R., Kent, D., Laverdiere, M., et al., 2011. High incidence of herpes zoster in nonmyeloablative hematopoietic stem cell transplantation. Biol. blood marrow Transplant. 17 (7), 1012e1017. http://dx.doi.org/10.1016/j.bbmt.2010.10.025 e-pub ahead of print 2010/10/28. Toze, C.L., Dalal, C.B., Nevill, T.J., Gillan, T.L., Abou Mourad, Y.R., Barnett, M.J., et al., 2012. Allogeneic haematopoietic stem cell transplantation for chronic lymphocytic leukaemia: outcome in a 20-year cohort. Br. J. Haematol. 158 (2), 174e185. Truong, Q., Veltri, L., Kanate, A.S., Hu, Y., Craig, M., Hamadani, M., et al., 2014. Impact of the duration of antiviral prophylaxis on rates of varicella-zoster virus reactivation disease in autologous hematopoietic cell transplantation recipients. Ann. Hematol. 93 (4), 677e682. Uchiyama, M., Tamai, Y., Ikeda, T., 2010. Low-dose acyclovir against reactivation of varicella zoster virus after unrelated cord blood transplantation. Int. J. Infect. Dis. 14 (5), e451e452. van der Beek, M.T., Vermont, C.L., Bredius, R.G., Marijt, E.W., van der Blij-de Brouwer, C.S., Kroes, A.C., et al., 2013. Persistence and antiviral resistance of varicella zoster virus in hematological patients. Clin. Infect. Dis. 56 (3), 335e343. lez, M., Martínez, A.M., Fern Verdeguer, A., De Heredia, C.D., Gonza andezrez-Hurtado, J.M., et al., 2011. Observational prospective study Navarro, J.M., Pe of viral infections in children undergoing allogeneic hematopoietic cell transplantation: a 3-year GETMON experience. Bone Marrow Transplant. 46 (1), 119e124.
Contents lists available at ScienceDirect
Antiviral Research journal homepage: www.elsevier.com/locate/antiviral
Antiviral prophylaxis for preventing herpes zoster in hematopoietic stem cell transplant recipients: A systematic review and meta-analysis Hyun-Min Seo a, Yoon Seob Kim a, Chul Hwan Bang a, Ji Hyun Lee a, Jun Young Lee a, Dong-Gun Lee b, Young Min Park a, * a
Department of Dermatology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Division of Infectious Diseases, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 December 2016 Received in revised form 8 January 2017 Accepted 11 January 2017 Available online 26 January 2017
The optimal duration of prophylaxis for the varicella-zoster virus following hematopoietic stem cell transplantation (HSCT) remains unclear. The purpose of this study was to systematically review the available literature to determine the optimal duration of antiviral prophylaxis for preventing herpes zoster (HZ) in allogeneic and autologous HSCT recipients. The MEDLINE and EMBASE databases were searched to identify relevant studies. The relative risk (RR) of HZ was calculated using fixed effects or random effects models depending on heterogeneity across the included studies. We analyzed six observational studies comprising a total of 3420 patients. In all HSCT recipients, the overall incidence of HZ in the prophylaxis group and the control group was 7.8% and 25.6%, respectively, with a pooled RR of 0.31 (95% CI, 0.26e0.37). The incidence of HZ in the subgroup wherein prophylaxis was given for at least 1 year and in the subgroup wherein prophylaxis was given for less than 1 year was 2.1% and 15.4%, respectively, with a pooled RR of 0.23 (95% CI, 0.04e1.39). Taken together, our results demonstrate that antiviral prophylaxis can significantly reduce HZ in HSCT recipients, and suggests that long-term prophylaxis given for at least 1 year may be recommended for better preventive effects. © 2017 Elsevier B.V. All rights reserved.
Keywords: Acyclovir Allogeneic Autologous Hematopoietic stem cell transplantation Herpes zoster Valacyclovir
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 2.1. Data sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 2.2. Data extraction and study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 2.3. Prophylaxis and outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 2.4. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 2.5. Statistical analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 3.1. Search results and characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 3.2. Description of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 3.3. Influence of antiviral prophylaxis on the incidence of HZ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 3.4. Assessment of publication bias and risk of bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 Authorship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Conflict-of-interest disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
* Corresponding author. Department of Dermatology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea. E-mail address: [email protected] (Y.M. Park). http://dx.doi.org/10.1016/j.antiviral.2017.01.011 0166-3542/© 2017 Elsevier B.V. All rights reserved.
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1. Introduction Herpes zoster (HZ) is caused by the varicella-zoster virus (VZV) and is a common complication following hematopoietic stem cell transplantation (HSCT), occurring in approximately 17e50% of allogeneic transplant recipients and 14e28% of autologous transplant recipients (Schuchter et al., 1989; Truong et al., 2014). According to a large retrospective cohort study, most cases of HZ occur during the first year following both types of HSCT, at a median duration of 6 months after allogeneic HSCT and 5 months after autologous HSCT (Erard et al., 2007). In addition to the risk of a more severe and prolonged local disease in this immunecompromised population, transplant patients are at risk for developing dissemination. Disseminated HZ can manifest as a cutaneous disease with erythematous papules, vesicles, pustules, or crusts appearing outside the primary dermatome, and with more severe systemic organ involvement, including encephalitis, pneumonia, hepatitis, and even death (Koc et al., 2000; Gnann, 2002). The 2016 National Comprehensive Cancer Network (NCCN) Guidelines® in Oncology currently recommend prolonged antiviral prophylaxis in hematopoietic stem cell transplant patients for the prevention of HZ with a duration of at least 6e12 months following autologous HSCT, and with a duration of at least 12 months following allogeneic HSCT (Baden et al., 2016). However, there is a lack of evidence on the optimal duration of VZV prophylaxis. Moreover, following discontinuation of antiviral prophylaxis, there is always some concern about the possible disproportionate increase of HZ in patients. When this occurs (with this and other disorders), the phenomenon is often termed a “rebound” disease (Erard et al., 2007). The aim of this study is to systematically evaluate the optimal duration of antiviral prophylaxis for preventing HZ in allogeneic and autologous HSCT recipients. Because our database search yielded only two randomized controlled trials with small numbers of patients (Boeckh et al., 2006; Klein et al., 2011), we included six observational studies for the meta-analysis herein. The analysis compares preventive effects between an antiviral prophylaxis group and a control group (i.e., no prophylaxis) on the development of HZ in HSCT recipients.
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and duration of follow up. The investigators resolved any disagreement by consensus. Included for analysis were studies that evaluated the effectiveness of antiviral prophylaxis in HSCT recipients. Recipients of all ages were included, irrespective of VZV serologic status prior to HSCT (allogeneic or autologous). Recipients of solid organ transplants were excluded. Because there was heterogeneity in the duration of follow up across the studies, we gathered data for the longest period possible for analyses in each study. 2.3. Prophylaxis and outcome measures Prophylaxis involved antiviral agents, including acyclovir, famciclovir, and valacyclovir. Because the majority of participants in the included studies received antiviral prophylaxis to prevent cytomegalovirus or the herpes simplex virus for durations of several days before transplant to about 1 month following HSCT, these antiviral prophylaxes were regarded as co-prophylaxis. We considered prophylaxis as the antiviral prophylaxis following coprophylaxis. Comparisons were made between groups undergoing prophylaxis for the prevention of HZ and a control. Primary outcome measures were the overall incidence of HZ between prophylaxis and control groups in all HSCT recipients. Secondary outcome measures were the incidence of HZ between prophylaxis and control groups in the recipients of each type of HSCT (allogeneic or autologous). The definition of HZ was as defined by the investigators of the included studies (Truong et al., 2014; Erard et al., 2007; Kanda et al., 2001; Asano-Mori et al., 2008; Kim et al., 2008a; Kawamura et al., 2015). Typically, this definition involved the presence of characteristic grouped vesicles on an erythematous base along a dermatome, a generalized cutaneous distribution, or microbiological and/or pathological confirmation. 2.4. Quality assessment
This systematic review was performed in accordance with the recommendations of the Meta-analysis of Observational Studies in Epidemiology Group and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (Stroup et al., 2000; Moher et al., 2009).
Two authors (H. M. Seo and C. H. Bang) independently evaluated the quality of the studies without blinding to authorship or to the journal of publication. The risk of bias in the observational studies included was assessed by the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS), which assesses the selection of participants, confounding variables, measurement of exposure, blinding of outcome assessments, incomplete outcome data, and selective outcome reporting. All parameters were categorized as having a low, unclear, or high risk of bias (Kim et al., 2013). In the case of disagreement between the two investigators, consensus was reached after discussion.
2.1. Data sources
2.5. Statistical analyses
Discrete literature searches were independently conducted by two reviewers (H.M. Seo and Y. S. Kim). The MEDLINE and EMBASE databases were searched from inception through May 1, 2016. Observational studies were identified using the following search terms: “herpes zoster” (Medical Subject Headings, MeSH) and “hematopoietic stem cell transplantation” (MeSH). All published articles written in English, limited to human studies, were included.
We have presented dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs). Heterogeneity was assessed using c2 tests and I2 statistics, with p < 0.1 for the c2 tests and with I2 > 50% used as a threshold to indicate moderate heterogeneity. We pooled the data using a Mantel-Haenszel method to calculate a summary estimate of effect (Mantel and Haenszel, 1959). If moderate heterogeneity was seen, then the results of a random effects model were reported after exploring the causes of heterogeneity. Otherwise the results of the fixed effects model were reported. All treatment regimens were combined for comparison, regardless of the kind or dosage of various antiviral agents. Subgroup analyses were conducted according to HSCT type and the duration of antiviral prophylaxis. The meta-analysis was performed with RevMan software, version 5.3 (Cochrane Collaboration, Copenhagen, Denmark).
2. Methods
2.2. Data extraction and study selection Two investigators (H. M. Seo and Y. S. Kim) independently reviewed the eligible reports in detail, and abstracted relevant information using a standard extraction sheet that covers study design, country, number and demographics of subjects, type of HSCT and antiviral prophylaxis, duration of antiviral prophylaxis,
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Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram of study flow. VZV, varicella-zoster virus.
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3. Results 3.1. Search results and characteristics of included studies Our literature search yielded a total of 498 articles. Twenty-nine articles remained after the screening of titles and abstracts by the
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two independent reviewers (Fig. 1). A total of 29 full-text articles were assessed for eligibility, 23 of which were excluded for the following reasons: (1) no VZV prophylaxis (n ¼ 9) (Blennow et al., 2014; Berman et al., 2006; Offidani et al., 2001; Onozawa et al., ski et al., 2015; Su et al., 2006; Srinivasan et al., 2014; Styczyn 2011; van der Beek et al., 2013; Verdeguer et al., 2011), (2) no
Table 1 Characteristics of studies included in review HZ, Herpes zoster. Study
Country Study design
Participants Transplantation Regimen of antiviral prophylaxis type
AsanoMori et al. (2008)
Japan
Treatment group Number: 137 Age: NS Sex (M/F): NS Control group Number: 105 Age: NS Sex (M/F): NS Treatment group A Number: 586 Age: 47 (0 e73), median (range) Sex (M/F): 358/228 Treatment group B Number: 1117 Age: 45 (1 e74), median (range) Sex (M/F): 576/541 Control group Number: 932 Age: 42 (1 e68), median (range) Sex (M/F): 487/445 Treatment group Number: 45 Age: NS Sex (M/F): NS Control group Number: 41 Age: NS Sex (M/F): NS Treatment group A Number: 7 Age: NS Sex (M/F): NS
Erard et al. USA (2007)
Kanda et al. Japan (2001)
Kawamura Japan et al. (2015)
Single center/ Retrospective cohort
Single center/ Retrospective cohort
Single center/ Retrospective cohort
Single center/ Retrospective cohort
Allogeneic HSCT Prophylaxis group Acyclovir 200 mg/d at least 1 year after HSCT Control group No treatment
Follow up duration Mean 486 days (range, 37e4209 days)
Co-prophylaxis Acyclovir given at 750 mg/day intravenously or at 1000 mg/ day orally from days 7e35 after HSCT
Allogeneic/ autologous HSCT
Prophylaxis group A 2 years Prophylaxis against HZ over 1 year after HSCT (acyclovir 250 mg/m2 intravenously followed by 800 mg orally or valacyclovir 500 mg orally, all drugs given twice per day; valacyclovir was preferred for patients who received 0.5 mg/ kg per day of steroids) Prophylaxis group B Prophylaxis against HZ for 1 year after HSCT (same regimen prescribed for prophylaxis A) Control group No treatment
Co-prophylaxis Not receiving acyclovir for HZ prevention; herpes simplex virus (HSV)epositive recipients were given acyclovir, 250 mg/m2 twice per day, from day 7 until engraftment and resolution of mucositis
Allogeneic HSCT/PBSCT
12 months Prophylaxis group Long-term low-dose (400 mg/day) oral administration of acyclovir as prophylaxis against HZ, which was continued until the end of immunosuppressive therapy (median 152 days)
Control group No treatment Co-prophylaxis 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 7e35 Autologous HSCT
2 years Prophylaxis group A Acyclovir was continued at 200 mg at the discretion of the attending physicians (1 year) Prophylaxis Group B Acyclovir was continued at 200 mg at the discretion of the attending physicians (36 days to 1 year) (continued on next page)
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Table 1 (continued ) Study
Country Study design
Kim et al. Canada/ Multi(2008a) Korea center/ Retrospective cohort
Truong et al. (2014)
USA
Single center/ Retrospective cohort
Participants Transplantation Regimen of antiviral prophylaxis type Treatment group B Number: 14 Age: NS Sex (M/F): NS Control group Number: 41 Age: NS Sex (M/F): NS Treatment group A Number: 27 Age: 49 (22 e69), median (range) Sex (M/F): 13/14 Treatment group B Number: 73 Age: 36 (16 e60), median (range) Sex (M/F): 45/28 Control group Number: 166 Age: 51 (17 e71), median (range) Sex (M/F): 96/70 Treatment group A Number: 40 Age: 55 (26 e70), median (range) Sex (M/F): 27/13 Treatment group B Number: 12 Age: 52 (22 e72), median (range) Sex (M/F): 9/3 Control group Number: 77 Age: 54 (16 e72), median (range) Sex (M/F): 49/28
Follow up duration
Control group No treatment
Co-prophylaxis Oral acyclovir at 200 mg once or five times daily from day 7 to engraftment (35 days)
Allogeneic PBSCT
Prophylaxis group A Long-term (more than 3 months) low-dose acyclovir prophylaxis (200 mg twice daily orally) Prophylaxis group B Oral acyclovir prophylaxis (400 mg twice daily) given routinely until immunosuppressive therapy was discontinued
Median 26.5 months (range, 2e77)
Control group No treatment
Co-prophylaxis Acyclovir was used intravenously at 160 mg daily in divided doses or orally at 400 mg orally for 28 d for herpes simplex virus (HSV) prophylaxis in group A, and 800 mg orally per day in group B and control
Autologous HSCT
Prophylaxis group A Median 23 (range 6e24) months for group Antiviral prophylaxis 12 months (±60 days) post-auto-HCT A, 13 (range 4e19) months for group B, 13 Prophylaxis group B (range 7e13) months for control Antiviral prophylaxis for 6 months (±60 days)
Control group Antiviral prophylaxis until neutrophil recovery to 500/ mm3 from post-HCT nadir
Co-prophylaxis Acyclovir 400 mg orally or intravenously twice daily or valacyclovir 500 mg orally/day starting at the initiation of preparatory chemotherapy for transplant
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Fig. 2. Forest plot estimating the risk of herpes zoster with antiviral prophylaxis in all HSCT recipients. A, Antiviral prophylaxis versus control. B, Antiviral prophylaxis given for at least one year versus control. C, Antiviral prophylaxis given for less than one year versus control. D, Antiviral prophylaxis given for at least one year versus antiviral prophylaxis given for less than one year. HSCT, hematopoietic stem cell transplantation.
control of VZV prophylaxis (n ¼ 5) (Aytac et al., 2011; Oshima et al., 2010; Rogers et al., 2011; Uchiyama et al., 2010; Steer et al., 2000), (3) not written in English (n ¼ 3) (Akiyama et al., 2000; Karasuno and Hiraoka, 2006; Li et al., 2011), (4) inadequate evidence of VZV reactivation (n ¼ 2) (Toze et al., 2012; Pergam et al., 2012), (5) randomized controlled studies comprising a small number of patients (n ¼ 2) (Boeckh et al., 2006; Klein et al., 2011), (6) antiviral prophylaxis at the discretion of attending physicians (n ¼ 1) (Leung et al., 2002), and (7) patients were also included in a previous trial (n ¼ 1) (Kim et al., 2008b). Finally, six observational studies met the inclusion criteria and were included in this review (Truong et al., 2014; Erard et al., 2007; Kanda et al., 2001; Asano-Mori et al., 2008; Kim et al., 2008a; Kawamura et al., 2015). 3.2. Description of included studies A total of 3420 patients from the six studies were available for analysis. Among them, 2058 patients received prophylactic antiviral prophylaxis, and 1362 were included as a control.
Five studies were single-center (Truong et al., 2014; Erard et al., 2007; Kanda et al., 2001; Asano-Mori et al., 2008; Kawamura et al., 2015) studies and one was a multi-center study (Kim et al., 2008a). Three studies were conducted in Japan (Kanda et al., 2001; AsanoMori et al., 2008; Kawamura et al., 2015), two studies were conducted in the United States (Truong et al., 2014; Erard et al., 2007), and the other included study was conducted in Canada/Korea (Kim et al., 2008a). The six studies were commonly designed as retrospective cohort studies. Most participants received antiviral prophylaxis for durations of at least 3 months. The number of participants receiving prophylaxis for a duration of at least 1 year was 1887 (91.7%) in the included studies (Truong et al., 2014; Erard et al., 2007; Asano-Mori et al., 2008; Kawamura et al., 2015). The dosages of acyclovir and valacyclovir used in the included studies ranged from 200 to 1600 mg/day and 500e1000 mg/day, respectively. The duration of follow up ranged from 12 months to a median of 26.5 months. The recipients of allogeneic HSCT were available for analyses in four studies (Erard et al., 2007; Kanda et al., 2001; Asano-Mori et al., 2008; Kim et al., 2008a) and recipients of
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autologous HSCT were available for analyses in three studies (Truong et al., 2014; Erard et al., 2007; Kawamura et al., 2015). Antiviral agents used for prophylaxis were only acyclovir in four studies (Kanda et al., 2001; Asano-Mori et al., 2008; Kim et al., 2008a; Kawamura et al., 2015) and acyclovir/valacyclovir in two studies (Truong et al., 2014; Erard et al., 2007). The use of VZV antiviral prophylaxis for a duration of at least 1 year was identified in four studies (Truong et al., 2014; Erard et al., 2007; Asano-Mori et al., 2008; Kawamura et al., 2015), and prophylaxis given for less than 1 year was identified in four studies (Truong et al., 2014; Kanda et al., 2001; Kim et al., 2008a; Kawamura et al., 2015). Detailed characteristics of the six included studies are presented in Table 1.
bias might exist. Thus we assessed publication bias using funnel plots. Possible asymmetry could not be found with visual examination. Accordingly, the plots were not suggestive of any publication bias (Fig. 4). Regarding the risk of bias, the selection of participants was considered inadequate in all but two studies. The most frequent reason whereby studies were designated as having a “high” risk of bias was a definition of control groups that were selected from different population groups (historical control). The results are summarized in Fig. 5. The graph provides an overview of the authors’ judgments about each risk of bias item using the RoBANS, presented as percentages across all included studies. Fig. 6 presents the risk of bias summary of the six observational studies included in our meta-analysis.
3.3. Influence of antiviral prophylaxis on the incidence of HZ In all HSCT recipients, the overall incidence of HZ in the prophylaxis group and control group was 7.8% and 25.6%, respectively, with a pooled RR of 0.31 (95% CI, 0.26e0.37). There was no heterogeneity across studies (p ¼ 0.92, I2 ¼ 0%) (Fig. 2A). Both prophylactic groups (i.e., prophylaxis given for at least 1 year and prophylaxis given for less than 1 year) had a lower risk of HZ events in comparison to the control group (RR, 0.30; 95% CI, 0.24e0.36 and RR, 0.41; 95% CI, 0.25e0.66, respectively) (Fig. 2B and C). The incidence of HZ in the subgroup wherein prophylaxis was given for at least 1 year and in the subgroup wherein prophylaxis was given for less than 1 year was 2.1% and 15.4%, respectively, with a pooled RR of 0.23 (95% CI, 0.04e1.39) (Fig. 2D). Subgroup analysis according to HSCT type revealed that both allogeneic and autologous HSCT groups with antiviral prophylaxis had a lower risk of HZ events in comparison to the control group (RR, 0.29; 95% CI, 0.24e0.36 and RR, 0.36; 95% CI, 0.25e0.54, respectively) (Fig. 3A and B). However, there were no significant differences in prophylactic effects on the development of HZ between allogeneic and autologous HSCT recipients. 3.4. Assessment of publication bias and risk of bias Given the tendency to publish only studies that show the prophylactic effects of antiviral prophylaxis on HZ, we were aware that
4. Discussion To our knowledge, this is the largest systematic review of existing literature and the first meta-analysis for preventing HZ in 3420 HSCT recipients. The analysis demonstrates two important findings, as follows. First, antiviral prophylaxis may significantly reduce HZ development in HSCT recipients. Second, long-term prophylaxis given for at least 1 year following HSCT demonstrates much better HZ preventive effects, irrespective of HSCT type. Recently, the 2016 NCCN guidelines recommended prolonged antiviral prophylaxis for the prevention of HZ with a duration of at least 6e12 months following autologous HSCT and with a duration of at least 12 months following allogeneic HSCT (Baden et al., 2016). In contrast, our analysis demonstrates that the incidence of HZ with antiviral prophylaxis given for at least 1 year was lower than the incidence of HZ with antiviral prophylaxis given for less than 1 year (2.1% and 15.4, respectively). Similarly, the work of Truong et al. reports that there might be suboptimal VZV-specific immunereconstitution at 6 months of antiviral prophylaxis versus a 12month period of antiviral prophylaxis following autologous HSCT (Truong et al., 2014). Thus it might be assumed that long-term antiviral prophylaxis given for at least 1 year is more suitable for preventing HZ, irrespective of HSCT type. Within the studies included in our meta-analysis, there was a lack of consensus about the proper dosage of antiviral agents to
Fig. 3. Forest plot estimating the risk of herpes zoster with antiviral prophylaxis according to each type of HSCT. Antiviral prophylaxis versus control in allogeneic (A) and autologous HSCT (B) HSCT, hematopoietic stem cell transplantation.
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Fig. 4. Funnel plot of comparison. Antiviral prophylaxis versus control in both groups (A), in allogeneic (B), and in autologous HSCT (C). Antiviral prophylaxis given for at least one year in both groups versus control (D). Antiviral prophylaxis given for less than one year versus control (E). Antiviral prophylaxis given for at least one year versus antiviral prophylaxis given for less than one year (F). HSCT, hematopoietic stem cell transplantation.
prevent HZ in HSCT recipients. The most frequently reported agent was acyclovir in HSCT recipients with a wide range of 200e3200 mg/day (Truong et al., 2014; Erard et al., 2007; Boeckh et al., 2006; Kanda et al., 2001; Asano-Mori et al., 2008; Kim et al., 2008a; Kawamura et al., 2015; Oshima et al., 2010; Steer et al., 2000; Selby et al., 1989). In the studies included in our metaanalysis, the long-term administration of acyclovir at a relatively low dosage of 200e1600 mg/day was shown to be effective in preventing HZ (Truong et al., 2014; Erard et al., 2007; Kanda et al., 2001; Asano-Mori et al., 2008; Kim et al., 2008a; Kawamura et al., 2015; Steer et al., 2000). Although the dosage of antiviral agents varied among the included studies, the RRs of each study were similar. Regarding valacyclovir, there were a few studies with long-
term prophylaxis for the prevention of HZ with valacyclovir at dosages ranging from 500 to 2000 mg/day, which showed comparable effects and safety profiles in the prevention of HZ in HSCT recipients (Truong et al., 2014; Erard et al., 2007; Klein et al., 2011; Asano-Mori et al., 2008). One pharmacokinetics study shows that 500 mg/day of valacyclovir has comparable efficacy to a dose of 400 mg/day of acyclovir (Koc et al., 2000). There were no included studies in which famciclovir was used as the prophylactic agent for preventing HZ in HSCT recipients. To prevent development of HZ, acyclovir and valacyclovir are recommended with dosages of 200e1600 mg/day and 500e2000 mg/day, respectively. There is concern about the rebound of HZ after discontinuation of antiviral prophylaxis in HSCT recipients. A previous randomized
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Fig. 5. Risk of bias graph of included observational studies. Authors' judgments about each risk of bias item presented as percentages across all included studies.
Fig. 6. Risk of bias summary of included observational studies. Authors' judgments about each risk of bias item for each included study.
trial reports that HZ episodes occurred in 2 of 13 recipients, at 3 and 8 months after discontinuation of 24 months of antiviral prophylaxis. Even if the numbers of patients are too small to draw any conclusions, antiviral prophylaxis might not allow sufficient immune reconstitution in some HSCT recipients (Klein et al., 2011). On the other hand, another randomized trial shows that antiviral prophylaxis in allogeneic HSCT recipients in fact allowed VZVspecific immune reconstitution (Boeckh et al., 2006). In addition, antiviral prophylaxis with acyclovir or valacyclovir given for at least 1 year in a large cohort shows persistent benefits after drug discontinuation, and shows no evidence of rebound effects in groups of patients that underwent both types of HSCT (Erard et al.,
2007). Despite some conflicting results, based on our review, longterm antiviral prophylaxis given for at least 1 year may have longterm benefits for the prevention of HZ. The emergence of resistant herpes simplex virus (HSV) type I has been demonstrated in a study with athymic nude mice (Ellis et al., 1986). In several existing reports, however, no breakthrough of antiviral-resistant HSV or VZV was observed, and symptomatic HZ events following discontinuation of antiviral prophylaxis were well treated with typical therapeutic doses of antiviral agents (Kanda et al., 2001; Kawamura et al., 2015). In addition, the work of Erard et al., reports that certain dosages of acyclovir or valacyclovir have been shown to also effectively prevent wild-type and drug-resistant HSV diseases in HSVseropositive recipients (Erard et al., 2007). According to our systematic review, the emergence of resistant HSV or VZV may not be a serious problem. Nonetheless, we should be careful not to overlook the emergence of antiviral-resistant HSV or VZV strains. Another concern is the tolerability of long-term use of antiviral agents. One study using acyclovir in a dose of 1600 mg/day for 1 year shows long-term use to be well tolerable except for mild gastrointestinal adverse effects (Boeckh et al., 2006). Another study using valacyclovir in a dose of 2000 mg/day for 2 years also reports the prophylactic regimen to be well tolerable (Klein et al., 2011). Thus long-term prophylaxis with antiviral agents in usual dosages is safe and well-tolerable in HSCT recipients. Our meta-analysis has some limitations. First, our results are based on a small number of studies. Second, there is too much heterogeneity in the duration, kind, and dosage of antiviral agents used in the studies to determine an optimal prophylactic regimen in preventing HZ in HSCT recipients. Third, there was a selection bias in participants across the studies due to the retrospective nature of the studies. Further studies are necessary to establish the optimal dosage of antiviral agents for the prevention of HZ in HSCT recipients. In conclusion, our results demonstrate that antiviral prophylaxis can reduce HZ development in recipients of both types of HSCT. Moreover, long-term prophylaxis given for at least 1 year may be recommended to get better preventive effects, irrespective of HSCT type. Authorship Contribution: H.M.S. developed the protocol, conducted the literature search, assessed the methodological quality, performed data extraction, conducted the statistical analysis, and wrote the
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manuscript; Y.S.K. conducted the literature search and performed data extraction; C.H.B. assessed methodological quality; J.H.L. reviewed the analysis and protocol; J.Y.L. and D.G.L. reviewed the protocol and the manuscript; Y.M.P. developed the protocol and reviewed the protocol and the manuscript. All the authors approved the final version of the manuscript. Conflict-of-interest disclosure The authors have no conflict of interest to declare. References Akiyama, H., Inoue, T., Okoshi, Y., Mori, S., Ohashi, K., Maeda, Y., et al., 2000. Varicella-zoster virus infection after hematopoietic stem cell transplantation. Rinsho ketsueki 41 (1), 20e24. Asano-Mori, Y., Kanda, Y., Oshima, K., Kako, S., Shinohara, A., Nakasone, H., et al., 2008. Long-term ultra-low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Am. J. Hematol. 83 (6), 472e476. Aytac, S., Yalcin, S.S., Kucukbayrak, O., Cetin, M., Uckan, D., 2011. Dynamics in children and adolescents who experience varicella zoster virus infections after haematopoietic stem cell transplantation: a case-control study. Epidemiol. Infect. 139 (11), 1701e1709. Baden, L.R., Swaminathan, S., Angarone, M., Blouin, G., Camins, B.C., Casper, C., et al., 2016. Prevention and Treatment of Cancer-Related Infections, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J. Nat. Compr. Canc. Netw. 14 (7), 882e913. Berman, J.N., Wang, M., Berry, W., Neuberg, D.S., Guinan, E.C., 2006. Herpes zoster infection in the post-hematopoietic stem cell transplant pediatric population may be preceded by transaminitis: an institutional experience. Bone marrow Transplant. 37 (1), 73e80. Blennow, O., Fjaertoft, G., Winiarski, J., Ljungman, P., Mattsson, J., Remberger, M., 2014. Varicella-zoster reactivation after allogeneic stem cell transplantation without routine prophylaxisethe incidence remains high. Biol. blood marrow Transplant. 20 (10), 1646e1649. Boeckh, M., Kim, H.W., Flowers, M.E., Meyers, J.D., Bowden, R.A., 2006. Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantationea randomized double-blind placebocontrolled study. Blood 107 (5), 1800e1805. Ellis, M.N., Martin, J.L., Lobe, D.C., Johnsrude, J.D., Barry, D.W., 1986. Induction of acyclovir-resistant mutants of herpes simplex virus type I in athymic nude mice. J. Antimicrob. Chemother. 18 (Suppl. B), 95e101. Erard, V., Guthrie, K.A., Varley, C., Heugel, J., Wald, A., Flowers, M.E., et al., 2007. One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicellazoster virus disease after drug discontinuation. Blood 110 (8), 3071e3077. Gnann Jr., J.W., 2002. Varicella-zoster virus: atypical presentations and unusual complications. J. Infect. Dis. 186 (Suppl. 1), S91eS98. Kanda, Y., Mineishi, S., Saito, T., Saito, A., Yamada, S., Ohnishi, M., et al., 2001. Longterm low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Bone marrow Transplant. 28 (7), 689e692. Karasuno, T., Hiraoka, A., 2006. Herpesvirus infections in hematological diseases. Nihon rinsho. 64 (Suppl. 3), 73e76. Kawamura, K., Hayakawa, J., Akahoshi, Y., Harada, N., Nakano, H., Kameda, K., et al., 2015. Low-dose acyclovir prophylaxis for the prevention of herpes simplex virus and varicella zoster virus diseases after autologous hematopoietic stem cell transplantation. Int. J. Hematol. 102 (2), 230e237. Kim, D.H., Kumar, D., Messner, H.A., Minden, M., Gupta, V., Kuruvilla, J., et al., 2008a. Clinical efficacy of prophylactic strategy of long-term low-dose acyclovir for Varicella-Zoster virus infection after allogeneic peripheral blood stem cell transplantation. Clin. Transplant. 22 (6), 770e779. Kim, D.H., Messner, H., Minden, M., Gupta, V., Kuruvilla, J., Wright, J., et al., 2008b. Factors influencing varicella zoster virus infection after allogeneic peripheral blood stem cell transplantation: low-dose acyclovir prophylaxis and pretransplant diagnosis of lymphoproliferative disorders. Transpl. Infect. Dis. 10 (2), 90e98. Kim, S.Y., Park, J.E., Lee, Y.J., Seo, H.J., Sheen, S.S., Hahn, S., et al., 2013. Testing a tool for assessing the risk of bias for nonrandomized studies showed moderate reliability and promising validity. J. Clin. Epidemiol. 66 (4), 408e414. Klein, A., Miller, K.B., Sprague, K., DesJardin, J.A., Snydman, D.R., 2011. A randomized, double-blind, placebo-controlled trial of valacyclovir prophylaxis to prevent zoster recurrence from months 4 to 24 after BMT. Bone Marrow Transplant. 46 (2), 294e299. Koc, Y., Miller, K.B., Schenkein, D.P., Griffith, J., Akhtar, M., DesJardin, J., et al., 2000. Varicella zoster virus infections following allogeneic bone marrow
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