Herpes Simplex Virus Reactivation Incidence and Prophylaxis in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation

doi:10.21203/rs.3.rs-3749711/v1

Patients undergoing Hematopoietic Stem Cell Transplantation (HSCT) are at increased risk for reactivation of herpes simplex virus (HSV) infection due to their immunocompromised state. This retrospective cohort study assesses the efficacy of Acyclovir (ACV) prophylaxis against HSV reactivation in allogeneic HSCT (allo-HSCT) recipients in Saudi Arabia. Conducted at a single institution from January 2016 to March 2023, and the study included 371 allo-HSCT patients aged over 14 who received oral ACV post-transplantation. Statistical analyses, including Chi-squared, Fisher’s exact, and independent T-tests, evaluated the data, while Cox and multivariable logistic regression models identified risk factors and the impact on overall survival (OS). Findings show that the two-year incidence of HSV reactivation was 11.3% in patients with malignant hematological conditions and 8.6% in those with non-malignant conditions. A total of 93.5% of patients received 400 mg of ACV orally twice daily. High HCT CI scores (≥ 3), underlying malignant conditions, and graft-versus-host disease emerged as significant reactivation predictors. The study concludes that HSV reactivation, occurring in approximately 10% of the cohort, correlates with a decline in OS. It suggests that patients with higher risk profiles may benefit from intensified HSV prophylaxis, providing a foundation for potential adjustments in clinical protocols at our institution.

Health sciences/Diseases/Infectious diseases

Health sciences/Risk factors

Herpes Simplex Virus

Acyclocvir

Hematopoeitic Stem Cell Transplantation

Immune reconstitution is often impaired in patients post allogeneic hematopoietic stem cell transplantation (allo-HSCT) for months to years, increasing their susceptibility to various infectious complications.¹ Herpes complex virus (HSV) is a common viral infection after HSCT that affects up to 80% of seropositive recipients without prophylaxis.^2–4 HSV infection is most likely to occur within the first month post-transplant, but can also occur later in the transplant course during immunosuppression.⁵ International guidelines recommend antiviral prophylaxis for all HSV-seropositive allogeneic HSCT allo-HSCT recipients against HSV infection.^5,6

The National Comprehensive Cancer Network (NCCN) recommends HSV prophylaxis for high-risk patients.⁶ This includes those with acute leukemias, those who have undergone allo-HSCT, those on alemtuzumab therapy, and individuals who have experienced graft-versus-host disease (GvHD) and subsequently received systemic steroid treatment. Multiple small retrospective studies indicate that the incidence of HSV reactivation post-HSCT lies between 0–20% with prophylaxis, in contrast to a higher 68–75% when a placebo is given.^3,4,7 Among these studies, acyclovir was predominantly utilized as the antiviral prophylaxis, with different dosage protocols.

Acyclovir, famciclovir, or valacyclovir are available antivirals for HSV prophylaxis, with acyclovir and valacyclovir being the most commonly used agents.⁶ Acyclovir prophylaxis should be offered to all HSV-seropositive allo-HSCT recipients to prevent HSV reactivation.^5,6 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). The recommended prophylactic acyclovir dose ranges from 400 mg to 800 mg orally twice daily, but a wide spectrum of doses has been reported.^3–10

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 patient population, and to date there have been no studies examining the incidence of HSV reactivation in Saudi Arabia. More studies are warranted to identify risk factors for HSV reactivation and to evaluate the optimal antiviral dosing regimen for prophylaxis. Our study aim was to evaluate the incidence of HSV reactivation and identify risks associated with reactivation among patients who received oral ACV for HSV prevention post-HSCT.

Study design and setting

This was a retrospective, single-center, cohort study of patients who underwent allo-HSCT between January 2016 and March 2023 either for malignant or non-malignant underlying disease. We included patients aged 14 years of age or older who received oral ACV prophylaxis post-transplantation. We excluded patients who received antiviral agents other than oral ACV for HSV prophylaxis, those who had an HSV reactivation before their transplant and were on treatment doses, and those with incomplete data.

The primary outcome of this study was to evaluate the incidence of HSV infection among patients who received oral acyclovir for HSV prophylaxis post-HSCT. Specifically, this study determined the incidence of HSV infection as defined by a positive HSV polymerase chain reaction (PCR). Secondary outcomes included the identifying risk factors associated with HSV reactivation while post allo-HSCT while on acyclovir prophylaxis, treatment-emergent adverse events, and HSV-reactivation effect on overall survival (OS). The study defined overall OS as the time elapsed from allo-HSCT to death from any cause. HSV reactivation was identified based on clinical presentation and/or the results of a Polymerase Chain Reaction (PCR) blood test.⁶

This study received Institutional Review Board (IRB) approval (NRC22R/122/03) from the King Abdullah International Research Center (KAIRMC) at the MNGHA hospital in Riyadh, Saudi Arabia.

Data collection

Patient clinical data, including demographic and comorbidities, underlying disease, hematopoietic cell transplantation Comorbidity Index (HCT CI) score, and HSV serostatus status were obtained from the electronic health records (EHR). Treatment/immunosuppressant received, type of donor and conditioning received, matching status (HLA typing), stem cell source, GvHD, disease relapse, and mortality were also collected.

Statistical analysis

Chi-squared and Fisher’s exact test were used for nominal data and independent t-test was used for continuous data. Logrank test was used to evaluate time to HSV reactivation. The study examined the impact of HSV reactivation on OS using Cox proportional hazards regression. This model was adjusted for age, sex, haploidentical transplantation, HCT CI Score, disease type (malignant vs. non-malignant), conditioning regimen, and GvHD. In addition, a multivariable logistic regression was conducted to identify risk factors associated with HSV reactivation. Covariates included in the models were: age, sex, haploidentical transplantation, HCT CI score, underlying disease type, conditioning regimen, and GvHD. These covariates were selected based on their clinical significance and the results of the univariable logistic regression. The calibration of the logistic regression model was evaluated using Hosmer-Lemeshow test, and the model’s discrimination was assessed using the receiver operating characteristic curve. All statistical analyses were performed using SPSS statistical package version 29 and STATA version 14.

Study population

Of the 498 patients screened, 371 patients met the inclusion criteria (Fig. 1). The baseline characteristics and clinical profiles of patients are displayed in Table 1 and Table 2. Patients were categorized into two groups: Group 1 (Malignant Hematological) included 151 patients, with a mean age of 32, of which 59.6% were male; and Group 2 (Non-Malignant Hematological) consisted of 220 participants, with an average age of 25, and 54% of them were male. Among group 1, acute lymphoblastic leukemia was the most prevalent underlying disease (37%), followed by acute myeloid leukemia (33.5%). In group 2, sickle cell disease was the predominant underlying condition in almost all patients within the group (90%), followed by aplastic anemia (AA) in 9% of patients. More than 60% of patients in both groups had donor-recipient positive HSV serostatus. In terms of the conditioning regimens, the most common conditioning regimens were nonmyeloablative (NMA) in 42.4% of group 1 and 55% in group 2, followed by reduced intensity conditioning (RIC), and lastly myeloablative conditioning (MAC). Additionally, 34 (22.5%) patients in the malignant hematological (hem) group received antithymocyte globulin (ATG) as part of their conditioning regimen compared to 46 (20.9%) patients in the non-malignant hem group. Additionally, none of the patients in the malignant hem group received alemtuzumab, compared to 198 (80.9%) patients in the non-malignant hem group.

Table 1

Baseline Characteristics
Characteristics	Group 1 - Malignant hem (n = 151)	Group 2 - Non-malignant hem (n = 220)
Age, years, mean ± SD	32.8 ± 14	25.8 ± 7.7
BMI, kg/m2, mean ± SD	25.1 ± 6	22.6 ± 5
Male gender, n (%)	90 (59.6)	119 (54.1)
Comorbidities, n (%) Cardiovascular Diabetes mellitus Cerebrovascular disease Renal disease Pulmonary comorbidity Hepatic comorbidity	16 (10.6) 11 (7.3) 6 (4) 6 (4) 6 (4) 9 (6)	26 (11.8) 2 (0.9) 35 (15.9) 12 (5.5) 49 (22.2) 106 (48)
Type of donor, n (%) HAPLO MMRD MMUD MRD MUD	22 (14.6) 2 (0.5) 3 (2) 107 (70.9) 17 (11.3)	11 (5) 1.3 (0.5) 0 (0) 204 (92.7) 4 (01.8)
Donor-recipient HSV serostatus (D/R), n (%) +/+ +/- -/+ -/-	111 (73.5) 5 (3.3) 13 (8.6) 1 (0.7)	136 (61.8) 11 (5) 23 (10.5) 17 (7.7)
Stem cell source, n (%) PBCs BMH	148 (91.3) 3 (2)	195 (89) 24 (11)
Conditioning Regimens, n (%) Reduced-intensity conditioning (RIC) Myeloablative conditioning (MAC) Nonmyeloablative (NMA)	42 (27.8) 45 (29.8) 64 (42.4)	56 (25.5) 43 (19.5) 121 (55)
Alemtuzumab underlying regimen, n (%) Antithymocyte globulin (ATG), n (%)	0 (0) 34 (22.5)	178 (80.9) 46 (20.9)
GVHD prophylaxis, n (%) Cyclosporine Methotrexate Sirolimus FK 506 MMF PcY3 ATG	126 (83.4) 86 (57) 0 (0) 88 (58.3) 43 (28.5) 25 (!6.6) 1 (0.7)	27 (12.3) 10 (4.5) 190 (86.4) 14 (!6.4) 33 (15) 15 (16.8) 0 (0)
Haplo, haploidentical; MMURD, mismatched unrelated donor; MMRD, mismatched related donor; MUD, matched unrelated donor; MRD, matched related donor; PBCs, peripheral blood cells; BM, bone marrow; FK 506, tacrolimus; MMF, mycophenolate mofotil; PcY3, Post transplant cyclophosphamide; ATG, anti-thymocyte globulin.

Table 2

Clinical Profiles and Outcomes
Characteristics	Group 1 - Malignant hem (n = 151)	Group 2 - Non-malignant hem (n = 220)
Duration until engraftment, n (%) < 7 days 8–14 days 15–21 days 22–28 days > 28 days	0 (0) 20 (13.2) 102 (67.5) 15 (9.9) 9 (6)	3 (1.4) 18 (8.2) 114 (51.8) 67 (30.5) 16 (7.3)
Administered filgrastim, n (%)	74 (49.7)	124 (56.6)
Acute GvHD, n (%)	43 (28.9)	14 (6.4)
Chronic GvHD, n (%)	61 (40.4)	14 (6.4)
Systemic steroids, n (%)	76 (50.3)	15 (6.8)
Longest duration of steroid use, days (IQR)	197 (147)	194 (166)
GvHD, graft-versus-host disease.

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). The two-year incidence figure shows that 6 months post-HSCT, the malignant hem group had almost half of the patients with HSV reactivation compared to nearly 85% of patients in the non-malignant hem group (Fig. 2). 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.

In our multivariable logistic regression model (Table 3), which aimed to identify risk factors associated with HSV reactivation, an HCT CI score of 3 or higher was associated with significantly higher odds for HSV reactivation after adjusting for covariates (adjOR 3.61, 95%CI 1.20–10.84; p = 0.022). Additionally, any GvHD (acute, chronic, or both) was associated with significantly higher odds for HSV reactivation (adjOR 2.44; 95%CI 1.05–5.62; p = 0.036). The model demonstrated adequate calibration (Hosmer-Lemeshow test P > .05) and acceptable discrimination (C-statistics = 0.7).

Table 3

HSV reactivation risk factors
Multivariable Logistic Regression (n = 371)
Variable	adj OR (95% CI; p-value)
Age	0.98 (0.95–1.03; p = 0.23)
Male	1.38 (0.67–2.88; p = 0.38)
Haploidentical transplant	0.44 (0.093–2.05; p = 0.29)
Malignant vs. non-malignant hem	0.72 (0.17–3.03; p = 0.66)
Any GvHD	2.49 (1.07–5.80; p = 0.034)
HCT CI Score ≥ 3	3.46 (1.08–11.08; p = 0.037)
Conditioning regimen MAC vs. RIC NMA vs. RIC	1.49 (0.58–3.82; p = 0.41) 1.44 (0.53–4.01; p = 0.48)
Almetuzumab use	0.63 (0.16–2.56; p = 0.53)

When it comes to the prophylaxis regimen of ACV, most patients, 347 (93.5%) received acyclovir 400 mg twice daily. Patients in the malignant hem group were more likely to receive initial intravenous acyclovir (63.5% vs 19.5%; p < 0.001), however, both groups had similar experiences in regards to acyclovir-related side effects, including acute kidney injury (2 vs 2), and elevated liver enzymes (1 vs 1). The duration of acyclovir therapy was significantly longer in patients in the non-malignant hem group (p < 0.001) (Table 4).

Table 4

Characteristics of acyclovir prophylaxis and safety outcomes
Characteristics	Group 1 - Malignant hem (n = 151)	Group 2 - non-malignant hem (n = 220)	p-value
On initial IV ACV	96 (63.5)	43 (19.5)	< 0.001
IV ACV duration < 2 weeks > 2 weeks	85 (56.3) 0 (0)	54 (24.5) 0 (0)	< 0.001
Oral ACV dose 400 mg every 8 hours 400 mg every 12 hours 400 mg daily 200 mg every 12 hours	0 (0) 147 (97.4) 3 (2) 1 (0.7)	6 (2.7) 199 (90.5) 5 (2.3) 10 (4.5)	0.085 0.009 0.852 0.032
Duration of ACV prophylaxis, days, mean ± SD	431 ± 376	590 ± 300	< 0.001
Switched to different antiviral IV ACV Famciclovir Ganciclovir	10 (6.6) 6 (4) 0 (0)	12 (5.1) 13 (5.9) 1 (0.5)	0.640 0.406 9.407
ACV-related side effects Rash Acute kidney injury Elevated liver enzymes	1 (0.7) 2 (1.3) 1 (0.7)	0 (0) 2 (0.9) 1 (0.5)	0.703 0.703 0.780
IV, intravenous; ACV, acyclovir
*All values are expressed in frequencies (%) unless otherwise indicated.

Our analysis included 371 participants who underwent allo-HSCT at MNGHA in Riyadh, Saudi Arabia. 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. The use of prophylaxis in patients with known risk factors prior to allo-HSCT brought the incidence to similar levels as patients without risk factors.¹¹ However, the incidence of HSV reactivation observed in our study remained higher than that reported in most studies.^3,4,7 This suggests a potential need to increase acyclovir dosing to reduce reactivation rates in our patient population.

For HSV prophylaxis, the NCCN guideline recommends a range of acyclovir doses between 400 to 800 mg orally twice daily.⁶ 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.^7–10 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.^5–12 Hence, based on the HSV reactivation rate, the institution policy was modified to increase the ACV dose to 800 mg every 12 hours.

Looking at potential risk factors for HSV reactivation in our cohort, conditioning regimens containing alemtuzumab had no correlation with HSV reactivation. However, non-malignant hem patients experienced HSV reactivation significantly quicker than the malignant hem patients. 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.¹³ 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.

In our multivariable logistic regression, we identified that an HCT CI score of ≥ 3 and GVHD were independent predictors of HSV reactivation after adjusting for age, sex, haploidentical HSCT, underlying disease category, and conditioning regimen. An HCT CI score of ≥ 3 indicates a high risk for non-relapse mortality, and overall survival.¹⁴ These findings highlight that patients with a score ≥ 3 or any GVHD warrant close monitoring for HSV reactivation, and may need higher doses of HSV prophylaxis. Other studies have demonstrated that age was a risk factor for HSV reactivation among allo-HSCT recipients with HSV prophylaxis.¹¹ We did not observe this finding in our study likely due to the relatively younger age in our cohort (median age 26, IQR 19–35).

Our study demonstrated a favorable safety profile of acyclovir, with low treatment-emergent adverse events. We observed a few cases of rash, acute kidney injury, and liver dysfunction, which were similar in both groups. The adverse events observed in our study were comparable to those reported in the acyclovir package insert.¹⁵

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.

In conclusion, our study revealed a notable HSV reactivation rate of approximately 10% in our population. An HCT CI score ≥ 3 and the presence of GVHD were identified as predictors for HSV reactivation in high-risk allo-HSCT recipients requiring HSV prophylaxis. These findings have significant implications for clinical practice at our institution and provide valuable insights for future practice modifications.

Conflict of interest:

No conflict of interest to be disclosed from all authors.

Competing Interests:

Authors declare there is no competing interest.

Author contributions:

NS, BS, HQ, ME, MZ and BA were responsible for designing the review protocol, and reviewing the final manuscript. AD, and ME were responsible for data analysis, and interpreting the results writing the manuscript. KB, BM, MA, WA, and SA were responsible for data collection and writing part of the manuscript.

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Herpes Simplex Virus Reactivation Incidence and Prophylaxis in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

Study design and setting

Data collection

Statistical analysis

Results

Study population

Incidence and clinical features of HSV reactivation

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1