To the Editor

Herpes complex virus (HSV) is a common viral infection post hematopoietic stem cell transplantation (HSCT), which affects up to 80% of seropositive recipients without prophylaxis [1,2,3]. International guidelines recommend antiviral prophylaxis for all HSV-seropositive allogeneic HSCT (allo-HSCT) recipients against HSV infection [4, 5]. Studies show that HSV reactivation rates post-HSCT range from 0 to 20% with prophylaxis, significantly lower than the 68–75% observed with placebo, highlighting acyclovir’s role as the preferred antiviral, despite varying dosage protocols [2, 3, 6].

The standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and through engraftment or resolution of mucositis (approximately day +30) [4, 5]. The recommended prophylactic acyclovir dose ranges from 400 to 800 mg orally twice daily, but a wide spectrum of doses has been reported [2,3,4,5,6,7,8,9]. Acyclovir (ACV) 400 mg orally twice daily is the standard of care at our tertiary care hospital in the Ministry of National Guard Health Affairs (MNGHA) for HSV prevention. The rate of HSV reactivation after allo-HSCT is unknown in our population, and to date there have been no studies examining the incidence of HSV reactivation in Saudi Arabia. The study aimed to evaluate the incidence of HSV reactivation and identify risks of reactivation among patients who received ACV for HSV prevention post-HSCT.

Methods

This retrospective single center study evaluated HSV infection incidence and risk factors in allo-HSCT recipients between January 2016 and March 2023. It included patients over 14 years old who received oral acyclovir (ACV) prophylaxis post-transplant, excluding those on other antivirals or with prior HSV reactivation or incomplete data. The primary outcome was HSV incidence post-HSCT, identified through PCR, with secondary outcomes assessing risk factors, treatment-emergent adverse events, and overall survival (OS). The study was approved by the Institutional Review Board (NRC22R/122/03).

Statistical analyses utilized chi-squared, Fisher’s exact test, and independent t tests for data evaluation, with time to HSV reactivation analyzed via logrank test. OS impact and risk factor identification employed Cox proportional hazards and multivariable logistic regression models, respectively, adjusted for relevant covariates including age, sex, and clinical factors, ensuring robust analysis through SPSS and STATA software.

Results

Of the 498 patients screened, 371 patients met the inclusion criteria. The baseline characteristics and clinical outcomes of patients are displayed in Table 1. Patients were categorized into two groups: Group 1 (Malignant Hematological) included 151 patients, and Group 2 (Non-Malignant Hematological) included 220 patients. More than 60% of patients in both groups had donor-recipient positive HSV serostatus.

Table 1 Baseline characteristics and clinical outcomes.
Full size table

Incidence and clinical features of HSV reactivation

The overall two-year incidence of HSV reactivation was 17 patients (11.3%) in the malignant hem group, and 19 patients (8.6%) in the non-malignant hem group (p = 0.43). The overall median time from transplant to HSV reactivation was 34 days (IQR 11.5–88). The median time from transplant to HSV reactivation was 53 days (IQR 34–222) and 30 days (9–53) among those with malignant hem and non-malignant hem, respectively (logrank p = 0.019). Figure 1 demonstrates that approximately 50% of patients developed HSV reactivation in the malignant hem group compared to nearly 80% of patients in the non-malignant hem group within 60 days post-HSCT. Patients with HSV reactivation did not have a significantly lower probability of OS at one-year (adjHR 1.97, 95% CI 0.90–4.34; p = 0.09) or two-year (adjHR 1.60, 95% CI 0.80–3.19; p = 0.18) compared to those without HSV reactivation.

Fig. 1: Time from transplant to HSV reactivation.
figure 1

Shown is the time from transplant to HSV reactivation, in days, among patients with non-malignant (blue bar) hematologic diseases vs. hematologic malignancies (red bar).

Full size image

In our multivariable logistic regression model, which aimed to identify risk factors associated with HSV reactivation, a higher HCT CI score (≥ 3) significantly increased the odds of HSV reactivation (adjOR 3.61, p = 0.022), as did any form of GvHD (adjOR 2.44, p = 0.036). However, no correlation for risk factor with alemtuzumab use (adjOR 0.63; p = 0.53). When it comes to the prophylaxis regimen of ACV, most patients (93.5%) received 400 mg acyclovir twice daily. Initial intravenous acyclovir was more common in the malignant hematology group (63.5% vs. 19.5%, p < 0.001), but side effects were similar between groups. The non-malignant hem group had a longer duration of acyclovir therapy (p < 0.001).

Discussion

The study objective was to evaluate the incidence of HSV reactivation and identify associated risk factors for reactivation among patients who received oral ACV for HSV prevention post-HSCT. Despite the administration of antiviral prophylaxis, the observed incidence of HSV reactivation in our patients post-HSCT was relatively high at 11.3% in patients with malignant hem and 8.6% in patients with non-malignant hem. Most reactivation cases occurred within the first 6 months post-transplant with a median time of 34 days for reactivation. Nonetheless, the incidence of HSV reactivation we observed were higher than those commonly reported in the literature [2, 3, 6]. This suggests a potential need to increase acyclovir dosing to reduce reactivation rates in our patient population.

For HSV prophylaxis, NCCN guidelines recommend a range of acyclovir doses between 400 and 800 mg orally twice daily [5]. The protocol at MNGHA follows the lowest range of the recommendation of acyclovir 400 mg orally twice daily, which differs somewhat from other observed practices [6,7,8,9]. Approximately 63.5% of the malignant hem group and 19.5% of the non-malignant hem group were initially on IV acyclovir, which might offer a slight difference in its efficacy in preventing reactivation. In terms of oral acyclovir dosing, most patients in both groups received 400 mg orally twice daily. Moreover, the duration of acyclovir prophylaxis was significantly longer in the non-malignant group, suggesting a higher perceived risk in this group. In other studies, various acyclovir doses were used; however, the higher dose of acyclovir is recommended for maximal viral suppression and minimization of resistance [4,5,6,7,8,9,10,11]. Hence, based on the HSV reactivation rate, the institution policy was modified to increase the ACV dose to 800 mg every 12 h.

Looking at potential risk factors for HSV reactivation in our cohort, conditioning regimens containing alemtuzumab had no correlation with HSV reactivation. Another study conducted at our institution by Mohsen et al. found that conditioning regimens based on alemtuzumab carried a 1.2% risk of HSV reactivation within a 4-year follow-up post allo-HSCT [12]. This difference in HSV reactivation in the non-malignant hem group within the same institution prompts further inquiry. This suggests that alemtuzumab-based regimens could be safe concerning HSV reactivation, and that distinct risk factors could influence the observed variations.

This study had several limitations. First, it was a single-center retrospective study. Furthermore, owing to the retrospective nature of this study, some missing data could bias the results as possible unmeasured confounding factors that could hinder the statistical analysis. Future prospective and multicenter studies are necessary to further investigate appropriate dosing for HSV prophylaxis in this specific patient population to mitigate these limitations.

Conclusion

In conclusion, our study revealed a notable HSV reactivation rate of approximately 10% in our population. Our institution has adjusted clinical practices by increasing the dosing of acyclovir to accommodate for the risk of HSV reactivation. These findings have significant implications for guiding future practice modifications and optimizing prophylactic strategies.