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

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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 Figures Figure 1 Figure 2 Introduction 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. Methods 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. Results 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 (%) 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 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. Discussion 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. Conclusion 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. Declarations 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. References Marcel R. M. van den Brink, Enrico Velardi, Miguel-Angel Perales; Immune reconstitution following stem cell transplantation. Hematology Am Soc Hematol Educ Program (2015) 2015 (1): 215–219. d Meyers JD, Flournoy N, Thomas DE. Infection with herpes simplex virus and cell-Mediated immunity after marrow transplant. J Infect Dis 1980; 142 (3): 338–346. Saral R, Burns WH, Laskin OL, Santos GW, Lietman PS. Acyclovir prophylaxis of herpes-simplex-virus infections. N Engl J Med 1981; 305 (2): 63–67. Gluckman E, Lotsberg J, Devergie A, et al. Prophylaxis of herpes infections after bone-marrow transplantation by oral acyclovir. Lancet 1983; 2 (8352): 706–708. CDC. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep 2000; 49 (RR-10): 1–25, CE121-127. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 2.2020. http://www.nccn.org (Accessed on May 09, 2021) J C Wade, B Newton, N Flournoy, J D Meyers. Oral acyclovir for prevention of herpes simplex virus reactivation after marrow transplantation. Ann Intern Med. 1984;100(6):823–8. Yahav D, Gafter-Gvili A, Muchtar E. Antiviral prophylaxis in haematological patients: systematic review and meta-analysis. Eur J Cancer. 2009;45(18):3131–48. Epub 2009 Sep 30. Erard V, Wald A, Corey L, Leisenring WM, Boeckh M. Use of long-term suppressive acyclovir after hematopoietic stem-cell transplantation: impact on herpes simplex virus (HSV) disease and drug-resistant HSV disease. J Infect Dis. 2007;196(2):266. Epub 2007 Jun 7. E Baumrin et al. Severe Herpes Zoster Requiring Intravenous Antiviral Treatment in Allogeneic Hematopoietic Cell Transplantation Recipients on Standard Acyclovir Prophylaxis.Biol Blood Marrow Transplant 25 (2019) 1642–1647. Uhlin M, et al. Risk Factors and Clinical Outcome for Herpes Simplex Virus Reactivation in Patients after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. Volume 21, Issue 2, February 2015, Page S170 Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143–1238. doi: 10.1016/j.bbmt.2009.06.019 Alzahrani M, Damlaj M, Jeffries N, et al. Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres. Br J Haematol. 2021;192(4):761–768. doi: 10.1111/bjh.17311 Sorror ML, Logan BR, Zhu X, et al. Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index: A Center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant. 2015;21(8):1479–1487. doi: 10.1016/j.bbmt.2015.04.004 Acyclovir [package insert]. Greenville, North Carolina: GlaxoSmithKline; 2003. Additional Declarations Yes Cite Share Download PDF Status: Published Journal Publication published 16 Apr, 2024 Read the published version in Bone Marrow Transplantation → Version 1 posted Editorial decision: revise 30 Jan, 2024 Review # 1 received at journal 30 Jan, 2024 Review # 2 received at journal 18 Jan, 2024 Reviewer # 2 agreed at journal 16 Jan, 2024 Reviewer # 1 agreed at journal 14 Jan, 2024 Reviewers invited by journal 27 Dec, 2023 Submission checks completed at journal 27 Dec, 2023 First submitted to journal 24 Dec, 2023 Unknown event 14 Dec, 2023 Editor assigned by journal 13 Dec, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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AlAmri","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Mohammed","middleName":"","lastName":"AlAmri","suffix":""},{"id":263755727,"identity":"f24ae26c-4b67-4767-97cb-ddff13b1655a","order_by":8,"name":"Walid Alanazi","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Walid","middleName":"","lastName":"Alanazi","suffix":""},{"id":263755728,"identity":"73d6b452-b36b-43e3-8b9b-44eea9eab1d4","order_by":9,"name":"Saeed Alay","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Saeed","middleName":"","lastName":"Alay","suffix":""},{"id":263755729,"identity":"fda13162-1d28-420b-80f7-48999116ed84","order_by":10,"name":"Bader Alahmari","email":"","orcid":"","institution":"King Abdul-Aziz Medical City","correspondingAuthor":false,"prefix":"","firstName":"Bader","middleName":"","lastName":"Alahmari","suffix":""},{"id":263755730,"identity":"0133738e-40f1-4e13-993e-44c2046c01ce","order_by":11,"name":"Mohsen Alzahrani","email":"","orcid":"","institution":"King Abdul-Aziz Medical City","correspondingAuthor":false,"prefix":"","firstName":"Mohsen","middleName":"","lastName":"Alzahrani","suffix":""}],"badges":[],"createdAt":"2023-12-13 17:46:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3749711/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3749711/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41409-024-02273-8","type":"published","date":"2024-04-16T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49091385,"identity":"10d1eeb7-14a1-44a1-b6d2-c630f5f5742a","added_by":"auto","created_at":"2024-01-03 01:54:23","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":284909,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient screening, inclusion, and exclusion criteria\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3749711/v1/abe9f2f257918d2c6636fdb8.jpeg"},{"id":49091386,"identity":"3f9f1f3e-1596-43f2-be5f-a5497cf7097c","added_by":"auto","created_at":"2024-01-03 01:54:23","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":247047,"visible":true,"origin":"","legend":"\u003cp\u003eTime from transplant to HSV reactivation\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3749711/v1/cb18397f23590fae72c09fdf.jpeg"},{"id":54814651,"identity":"1702fa3b-dd80-491a-91c5-ca68e6603981","added_by":"auto","created_at":"2024-04-17 07:07:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":622924,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3749711/v1/17393b2b-2f4c-42c2-900c-7189667f2aa3.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e","formattedTitle":"Herpes Simplex Virus Reactivation Incidence and Prophylaxis in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmune 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.\u003csup\u003e1\u003c/sup\u003e Herpes complex virus (HSV) is a common viral infection after HSCT that affects up to 80% of seropositive recipients without prophylaxis.\u003csup\u003e2\u0026ndash;4\u003c/sup\u003e HSV infection is most likely to occur within the first month post-transplant, but can also occur later in the transplant course during immunosuppression.\u003csup\u003e5\u003c/sup\u003e International guidelines recommend antiviral prophylaxis for all HSV-seropositive allogeneic HSCT allo-HSCT recipients against HSV infection.\u003csup\u003e5,6\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe National Comprehensive Cancer Network (NCCN) recommends HSV prophylaxis for high-risk patients.\u003csup\u003e6\u003c/sup\u003e 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\u0026ndash;20% with prophylaxis, in contrast to a higher 68\u0026ndash;75% when a placebo is given.\u003csup\u003e3,4,7\u003c/sup\u003e Among these studies, acyclovir was predominantly utilized as the antiviral prophylaxis, with different dosage protocols.\u003c/p\u003e \u003cp\u003eAcyclovir, famciclovir, or valacyclovir are available antivirals for HSV prophylaxis, with acyclovir and valacyclovir being the most commonly used agents.\u003csup\u003e6\u003c/sup\u003e Acyclovir prophylaxis should be offered to all HSV-seropositive allo-HSCT recipients to prevent HSV reactivation.\u003csup\u003e5,6\u003c/sup\u003e The standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and through engraftment or resolution of mucositis (approximately day\u0026thinsp;+\u0026thinsp;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.\u003csup\u003e3\u0026ndash;10\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAcyclovir (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.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and setting\u003c/h2\u003e \u003cp\u003eThis 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.\u003c/p\u003e \u003cp\u003eThe 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.\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e 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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003ePatient 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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eChi-squared and Fisher\u0026rsquo;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\u0026rsquo;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.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy population\u003c/h2\u003e\n \u003cp\u003eOf the 498 patients screened, 371 patients met the inclusion criteria (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The baseline characteristics and clinical profiles of patients are displayed in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cstrong\u003eand\u003c/strong\u003e Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. 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.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline Characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup 1 - Malignant hem \u003cem\u003e(n\u0026thinsp;=\u0026thinsp;151)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup 2 - Non-malignant hem \u003cem\u003e(n\u0026thinsp;=\u0026thinsp;220)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, years, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.8\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI, kg/m2, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale gender, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90 (59.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e119 (54.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCardiovascular\u003c/p\u003e\n \u003cp\u003eDiabetes mellitus\u003c/p\u003e\n \u003cp\u003eCerebrovascular disease\u003c/p\u003e\n \u003cp\u003eRenal disease\u003c/p\u003e\n \u003cp\u003ePulmonary comorbidity\u003c/p\u003e\n \u003cp\u003eHepatic comorbidity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (10.6)\u003c/p\u003e\n \u003cp\u003e11 (7.3)\u003c/p\u003e\n \u003cp\u003e6 (4)\u003c/p\u003e\n \u003cp\u003e6 (4)\u003c/p\u003e\n \u003cp\u003e6 (4)\u003c/p\u003e\n \u003cp\u003e9 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (11.8)\u003c/p\u003e\n \u003cp\u003e2 (0.9)\u003c/p\u003e\n \u003cp\u003e35 (15.9)\u003c/p\u003e\n \u003cp\u003e12 (5.5)\u003c/p\u003e\n \u003cp\u003e49 (22.2)\u003c/p\u003e\n \u003cp\u003e106 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eType of donor, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eHAPLO\u003c/p\u003e\n \u003cp\u003eMMRD\u003c/p\u003e\n \u003cp\u003eMMUD\u003c/p\u003e\n \u003cp\u003eMRD\u003c/p\u003e\n \u003cp\u003eMUD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (14.6)\u003c/p\u003e\n \u003cp\u003e2 (0.5)\u003c/p\u003e\n \u003cp\u003e3 (2)\u003c/p\u003e\n \u003cp\u003e107 (70.9)\u003c/p\u003e\n \u003cp\u003e17 (11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (5)\u003c/p\u003e\n \u003cp\u003e1.3 (0.5)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e204 (92.7)\u003c/p\u003e\n \u003cp\u003e4 (01.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDonor-recipient HSV serostatus (D/R), n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e+/+\u003c/p\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003cp\u003e-/+\u003c/p\u003e\n \u003cp\u003e-/-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e111 (73.5)\u003c/p\u003e\n \u003cp\u003e5 (3.3)\u003c/p\u003e\n \u003cp\u003e13 (8.6)\u003c/p\u003e\n \u003cp\u003e1 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e136 (61.8)\u003c/p\u003e\n \u003cp\u003e11 (5)\u003c/p\u003e\n \u003cp\u003e23 (10.5)\u003c/p\u003e\n \u003cp\u003e17 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eStem cell source, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003ePBCs\u003c/p\u003e\n \u003cp\u003eBMH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e148 (91.3)\u003c/p\u003e\n \u003cp\u003e3 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e195 (89)\u003c/p\u003e\n \u003cp\u003e24 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eConditioning Regimens, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eReduced-intensity conditioning (RIC)\u003c/p\u003e\n \u003cp\u003eMyeloablative conditioning (MAC)\u003c/p\u003e\n \u003cp\u003eNonmyeloablative (NMA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42 (27.8)\u003c/p\u003e\n \u003cp\u003e45 (29.8)\u003c/p\u003e\n \u003cp\u003e64 (42.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e56 (25.5)\u003c/p\u003e\n \u003cp\u003e43 (19.5)\u003c/p\u003e\n \u003cp\u003e121 (55)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlemtuzumab underlying regimen, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAntithymocyte globulin (ATG), n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e34 (22.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e178 (80.9)\u003c/p\u003e\n \u003cp\u003e46 (20.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGVHD prophylaxis, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCyclosporine\u003c/p\u003e\n \u003cp\u003eMethotrexate\u003c/p\u003e\n \u003cp\u003eSirolimus\u003c/p\u003e\n \u003cp\u003eFK 506\u003c/p\u003e\n \u003cp\u003eMMF\u003c/p\u003e\n \u003cp\u003ePcY3\u003c/p\u003e\n \u003cp\u003eATG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e126 (83.4)\u003c/p\u003e\n \u003cp\u003e86 (57)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e88 (58.3)\u003c/p\u003e\n \u003cp\u003e43 (28.5)\u003c/p\u003e\n \u003cp\u003e25 (!6.6)\u003c/p\u003e\n \u003cp\u003e1 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (12.3)\u003c/p\u003e\n \u003cp\u003e10 (4.5)\u003c/p\u003e\n \u003cp\u003e190 (86.4)\u003c/p\u003e\n \u003cp\u003e14 (!6.4)\u003c/p\u003e\n \u003cp\u003e33 (15)\u003c/p\u003e\n \u003cp\u003e15 (16.8)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eHaplo, 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.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical Profiles and Outcomes\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup 1 - Malignant hem \u003cem\u003e(n\u0026thinsp;=\u0026thinsp;151)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup 2 - Non-malignant hem \u003cem\u003e(n\u0026thinsp;=\u0026thinsp;220)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDuration until engraftment, n (%)\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;7 days\u003c/p\u003e\n \u003cp\u003e8\u0026ndash;14 days\u003c/p\u003e\n \u003cp\u003e15\u0026ndash;21 days\u003c/p\u003e\n \u003cp\u003e22\u0026ndash;28 days\u003c/p\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;28 days\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e20 (13.2)\u003c/p\u003e\n \u003cp\u003e102 (67.5)\u003c/p\u003e\n \u003cp\u003e15 (9.9)\u003c/p\u003e\n \u003cp\u003e9 (6)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e3 (1.4)\u003c/p\u003e\n \u003cp\u003e18 (8.2)\u003c/p\u003e\n \u003cp\u003e114 (51.8)\u003c/p\u003e\n \u003cp\u003e67 (30.5)\u003c/p\u003e\n \u003cp\u003e16 (7.3)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdministered filgrastim, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e74 (49.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e124 (56.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAcute GvHD, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 (28.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eChronic GvHD, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (40.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSystemic steroids, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76 (50.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLongest duration of steroid use, days (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e197 (147)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e194 (166)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eGvHD, graft-versus-host disease.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eIncidence and clinical features of HSV reactivation\u003c/h2\u003e\n \u003cp\u003eThe 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\u0026thinsp;\u0026lt;\u0026thinsp;0.43). The overall median time from transplant to HSV reactivation was 34 days (IQR 11.5\u0026ndash;88). The median time from transplant to HSV reactivation was 53 days (IQR 34\u0026ndash;222) and 30 days (9\u0026ndash;53) among those with malignant hem and non-malignant hem, respectively (logrank p\u0026thinsp;=\u0026thinsp;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 \u003cstrong\u003e(\u003c/strong\u003eFig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cstrong\u003e).\u003c/strong\u003e Patients with HSV reactivation did not have a significantly lower probability of OS at one-year (adjHR 1.97, 95% CI 0.90\u0026ndash;4.34; p- = 0.09) or two-year (adjHR 1.60, 95% CI 0.80\u0026ndash;3.19; p\u0026thinsp;=\u0026thinsp;0.18) compared to those without HSV reactivation.\u003c/p\u003e\n \u003cp\u003eIn our multivariable logistic regression model (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e), 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\u0026ndash;10.84; p\u0026thinsp;=\u0026thinsp;\u003cstrong\u003e0.022\u003c/strong\u003e). Additionally, any GvHD (acute, chronic, or both) was associated with significantly higher odds for HSV reactivation (adjOR 2.44; 95%CI 1.05\u0026ndash;5.62; p\u0026thinsp;=\u0026thinsp;\u003cstrong\u003e0.036\u003c/strong\u003e). The model demonstrated adequate calibration (Hosmer-Lemeshow test \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;.05) and acceptable discrimination (C-statistics\u0026thinsp;=\u0026thinsp;0.7).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eHSV reactivation risk factors\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eMultivariable Logistic Regression\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;371)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eadj OR (95% CI; p-value)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.98 (0.95\u0026ndash;1.03; p\u0026thinsp;=\u0026thinsp;0.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.38 (0.67\u0026ndash;2.88; p\u0026thinsp;=\u0026thinsp;0.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHaploidentical transplant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.44 (0.093\u0026ndash;2.05; p\u0026thinsp;=\u0026thinsp;0.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMalignant vs. non-malignant hem\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.72 (0.17\u0026ndash;3.03; p\u0026thinsp;=\u0026thinsp;0.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny GvHD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.49 (1.07\u0026ndash;5.80; p\u0026thinsp;=\u0026thinsp;\u003cstrong\u003e0.034\u003c/strong\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHCT CI Score\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.46 (1.08\u0026ndash;11.08; p\u0026thinsp;=\u0026thinsp;\u003cstrong\u003e0.037\u003c/strong\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eConditioning regimen\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMAC vs. RIC\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNMA vs. RIC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.49 (0.58\u0026ndash;3.82; p\u0026thinsp;=\u0026thinsp;0.41)\u003c/p\u003e\n \u003cp\u003e1.44 (0.53\u0026ndash;4.01; p\u0026thinsp;=\u0026thinsp;0.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlmetuzumab use\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.63 (0.16\u0026ndash;2.56; p\u0026thinsp;=\u0026thinsp;0.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eWhen 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\u0026thinsp;\u0026lt;\u0026thinsp;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\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristics of acyclovir prophylaxis and safety outcomes\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup 1 - Malignant hem\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e(n\u0026thinsp;=\u0026thinsp;151)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup 2 - non-malignant hem \u003cem\u003e(n\u0026thinsp;=\u0026thinsp;220)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOn initial IV ACV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96 (63.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 (19.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eIV ACV duration\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;2 weeks\u003c/p\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;2 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85 (56.3)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54 (24.5)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOral ACV dose\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e400 mg every 8 hours\u003c/p\u003e\n \u003cp\u003e400 mg every 12 hours\u003c/p\u003e\n \u003cp\u003e400 mg daily\u003c/p\u003e\n \u003cp\u003e200 mg every 12 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e147 (97.4)\u003c/p\u003e\n \u003cp\u003e3 (2)\u003c/p\u003e\n \u003cp\u003e1 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (2.7)\u003c/p\u003e\n \u003cp\u003e199 (90.5)\u003c/p\u003e\n \u003cp\u003e5 (2.3)\u003c/p\u003e\n \u003cp\u003e10 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.085\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e0.852\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.032\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDuration of ACV prophylaxis, days, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e431\u0026thinsp;\u0026plusmn;\u0026thinsp;376\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e590\u0026thinsp;\u0026plusmn;\u0026thinsp;300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSwitched to different antiviral\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eIV ACV\u003c/p\u003e\n \u003cp\u003eFamciclovir\u003c/p\u003e\n \u003cp\u003eGanciclovir\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (6.6)\u003c/p\u003e\n \u003cp\u003e6 (4)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (5.1)\u003c/p\u003e\n \u003cp\u003e13 (5.9)\u003c/p\u003e\n \u003cp\u003e1 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.640\u003c/p\u003e\n \u003cp\u003e0.406\u003c/p\u003e\n \u003cp\u003e9.407\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eACV-related side effects\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003cp\u003eAcute kidney injury\u003c/p\u003e\n \u003cp\u003eElevated liver enzymes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.7)\u003c/p\u003e\n \u003cp\u003e2 (1.3)\u003c/p\u003e\n \u003cp\u003e1 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e2 (0.9)\u003c/p\u003e\n \u003cp\u003e1 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.703\u003c/p\u003e\n \u003cp\u003e0.703\u003c/p\u003e\n \u003cp\u003e0.780\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eIV, intravenous; ACV, acyclovir\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e*All values are expressed in frequencies (%) unless otherwise indicated.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur 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.\u003c/p\u003e \u003cp\u003eDespite 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.\u003csup\u003e11\u003c/sup\u003e However, the incidence of HSV reactivation observed in our study remained higher than that reported in most studies.\u003csup\u003e3,4,7\u003c/sup\u003e This suggests a potential need to increase acyclovir dosing to reduce reactivation rates in our patient population.\u003c/p\u003e \u003cp\u003eFor HSV prophylaxis, the NCCN guideline recommends a range of acyclovir doses between 400 to 800 mg orally twice daily.\u003csup\u003e6\u003c/sup\u003e 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.\u003csup\u003e7\u0026ndash;10\u003c/sup\u003e 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.\u003csup\u003e5\u0026ndash;12\u003c/sup\u003e Hence, based on the HSV reactivation rate, the institution policy was modified to increase the ACV dose to 800 mg every 12 hours.\u003c/p\u003e \u003cp\u003eLooking 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.\u003csup\u003e13\u003c/sup\u003e 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.\u003c/p\u003e \u003cp\u003eIn our multivariable logistic regression, we identified that an HCT CI score of \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;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 \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;3 indicates a high risk for non-relapse mortality, and overall survival.\u003csup\u003e14\u003c/sup\u003e These findings highlight that patients with a score\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;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.\u003csup\u003e11\u003c/sup\u003e We did not observe this finding in our study likely due to the relatively younger age in our cohort (median age 26, IQR 19\u0026ndash;35).\u003c/p\u003e \u003cp\u003eOur 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.\u003csup\u003e15\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis 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.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our study revealed a notable HSV reactivation rate of approximately 10% in our population. An HCT CI score\u0026thinsp;\u0026ge;\u0026thinsp;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.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo conflict of interest to be disclosed from all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors declare there is no competing interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNS, 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.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMarcel R. M. van den Brink, Enrico Velardi, Miguel-Angel Perales; Immune reconstitution following stem cell transplantation. \u003cem\u003eHematology Am Soc Hematol Educ Program (2015) 2015 (1): 215\u0026ndash;219.\u003c/em\u003e d\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeyers JD, Flournoy N, Thomas DE. Infection with herpes simplex virus and cell-Mediated immunity after marrow transplant. J Infect Dis 1980; 142 (3): 338\u0026ndash;346.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaral R, Burns WH, Laskin OL, Santos GW, Lietman PS. Acyclovir prophylaxis of herpes-simplex-virus infections. N Engl J Med 1981; 305 (2): 63\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGluckman E, Lotsberg J, Devergie A, et al. Prophylaxis of herpes infections after bone-marrow transplantation by oral acyclovir. Lancet 1983; 2 (8352): 706\u0026ndash;708.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCDC. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep 2000; 49 (RR-10): 1\u0026ndash;25, CE121-127.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNational Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 2.2020. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.nccn.org\u003c/span\u003e\u003cspan address=\"http://www.nccn.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (Accessed on May 09, 2021)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJ C Wade, B Newton, N Flournoy, J D Meyers. Oral acyclovir for prevention of herpes simplex virus reactivation after marrow transplantation. Ann Intern Med. 1984;100(6):823\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYahav D, Gafter-Gvili A, Muchtar E. Antiviral prophylaxis in haematological patients: systematic review and meta-analysis. Eur J Cancer. 2009;45(18):3131\u0026ndash;48. Epub 2009 Sep 30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eErard V, Wald A, Corey L, Leisenring WM, Boeckh M. Use of long-term suppressive acyclovir after hematopoietic stem-cell transplantation: impact on herpes simplex virus (HSV) disease and drug-resistant HSV disease. J Infect Dis. 2007;196(2):266. Epub 2007 Jun 7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eE Baumrin et al. Severe Herpes Zoster Requiring Intravenous Antiviral Treatment in Allogeneic Hematopoietic Cell Transplantation Recipients on Standard Acyclovir Prophylaxis.Biol Blood Marrow Transplant 25 (2019) 1642\u0026ndash;1647.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUhlin M, et al. Risk Factors and Clinical Outcome for Herpes Simplex Virus Reactivation in Patients after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. Volume 21, Issue 2, February 2015, Page S170\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143\u0026ndash;1238. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.bbmt.2009.06.019\u003c/span\u003e\u003cspan address=\"10.1016/j.bbmt.2009.06.019\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlzahrani M, Damlaj M, Jeffries N, et al. Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres. Br J Haematol. 2021;192(4):761\u0026ndash;768. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/bjh.17311\u003c/span\u003e\u003cspan address=\"10.1111/bjh.17311\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSorror ML, Logan BR, Zhu X, et al. Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index: A Center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant. 2015;21(8):1479\u0026ndash;1487. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.bbmt.2015.04.004\u003c/span\u003e\u003cspan address=\"10.1016/j.bbmt.2015.04.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAcyclovir [package insert]. Greenville, North Carolina: GlaxoSmithKline; 2003.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Herpes Simplex Virus, Acyclocvir, Hematopoeitic Stem Cell Transplantation ","lastPublishedDoi":"10.21203/rs.3.rs-3749711/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3749711/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePatients 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\u0026rsquo;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 (\u0026ge;\u0026thinsp;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.\u003c/p\u003e","manuscriptTitle":"Herpes Simplex Virus Reactivation Incidence and Prophylaxis in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-03 01:54:19","doi":"10.21203/rs.3.rs-3749711/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-01-30T12:04:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-01-30T06:07:00+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-01-18T14:55:29+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-01-16T16:16:53+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-01-14T17:51:28+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2023-12-27T16:32:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-12-27T14:13:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bone Marrow Transplantation","date":"2023-12-24T14:03:57+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2023-12-14T11:46:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-13T17:41:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"bc3789f6-c00e-4ef8-a4dd-26fd61cc5a60","owner":[],"postedDate":"January 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":27816747,"name":"Health sciences/Diseases/Infectious diseases"},{"id":27816748,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2024-04-17T07:07:25+00:00","versionOfRecord":{"articleIdentity":"rs-3749711","link":"https://doi.org/10.1038/s41409-024-02273-8","journal":{"identity":"bone-marrow-transplantation","isVorOnly":false,"title":"Bone Marrow Transplantation"},"publishedOn":"2024-04-16 04:00:00","publishedOnDateReadable":"April 16th, 2024"},"versionCreatedAt":"2024-01-03 01:54:19","video":"","vorDoi":"10.1038/s41409-024-02273-8","vorDoiUrl":"https://doi.org/10.1038/s41409-024-02273-8","workflowStages":[]},"version":"v1","identity":"rs-3749711","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3749711","identity":"rs-3749711","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}