Rapid HHV ‐6 Clearance Following Preemptive Short‐Course Foscarnet in Allogeneic Stem Cell Transplant Recipients

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Human Herpesvirus 6 (HHV-6) represents a frequent and significant viral reactivation in allogeneic hematopoietic cell transplantation (AHSCT), occurring in approximately 30%–70% within the first 100 days after AHSCT [1-4]. Reactivation has been associated with serious complications, including graft failure, encephalitis, hepatitis, and pneumonia. HHV-6 reactivation has been associated with higher mortality, higher incidence of grade III-IV acute graft versus host disease, cytomegalovirus (CMV) reactivation, and delayed platelet engraftment [3, 5, 6]. Despite these risks, there are currently no established recommendations for prophylaxis or preemptive treatment, as prior studies have not consistently demonstrated clinical benefit, particularly in preventing end-organ dieases [7-12]. We previously reported that a 7-day course of once-daily foscarnet achieved rapid HHV-6 clearance in a small cohort, potentially reducing HHV-6-related complications [13]. Therefore, we hypothesized that lower-than-standard doses of foscarnet for 1 week are effective and well-tolerated as preemptive therapy in patients with clinically significant HHV-6 reactivation and analyzed outcomes in a larger patient cohort. We retrospectively analyzed 148 adults undergoing their first AHSCT at our institution between 05/2020–10/2025. All patients provided written informed consent. Plasma HHV-6 DNA was monitored using quantitative PCR (qPCR; lower limit of detection: 188 copies/mL) twice monthly during the first 100 days post-transplant, per established protocol [13]. Additional testing was performed in cases of delayed engraftment, altered mental status, or abnormal liver function. A confirmatory qPCR was obtained within 3 days of any initial positive result. Clinically significant HHV-6 reactivation was defined as the new detection of HHV-6 DNA in two consecutive blood samples. All patients with HHV-6 reactivation received a 7-day course of intravenous foscarnet (60–90 mg/kg/day) in the ambulatory setting, administered at the discretion of the treating physician, with dose adjustments based on renal function or concomitant medications. HHV-6 qPCR was monitored twice weekly until clearance. Resolution of HHV-6 reactivation was defined as undetectable plasma HHV-6 DNA on three consecutive occasions. Lymphocyte subsets were assessed using multicolor flow cytometry. Adverse events were closely monitored and graded according to standard criteria. HHV-6 reactivation occurred in 47 of 148 patients (31.8%), with 39 patients (82.9%) receiving once-daily foscarnet for 7 days. The remaining 8 patients with HHV-6 reactivation received standard-dose foscarnet for concomitant CMV reactivation (N = 4) or did not receive any treatment due to transiently low levels of HHV-6 viral load (N = 3) or medical comorbidities (N = 1). Twenty-one patients (44.7%) experienced CMV reactivation with a median time of 22 days (range, 4–375) post-transplant. Baseline and transplant characteristics in Table 1. HHV-6 reactivation was diagnosed at a median of 26 days (range, 6–89). Cumulative incidence of HHV-6 reactivation at 30, 60, and 100 days was 21.6% (95% confidence incidence [CI], 15.4%–28.6%), 29.1% (95% CI, 22.0%–36.5%), and 31.9% (95% CI, 24.5%–39.4%), respectively. In the multivariable competing-risks regression model, HHV-6 reactivation was significantly associated with age > 60 years old [subdistribution hazard (SHR) 2.80, 95% CI: 1.39–5.65; p = 0.004] and mismatched donor type (SHR 2.42, 95% CI: 1.04–5.61; p = 0.040). Neither the conditioning intensity, GHVD prophylaxis, nor stem cell source was associated with cumulative incidence of HHV-6 reactivation (Table 2). Among the 39 patients who received a 7-day course of foscarnet, 32 (82.1%) received 90 mg/kg/day while 7 (17.9%) received 60 mg/kg/day. Median plasma HHV-6 DNA level at diagnosis was 1400 copies/mL (range, 210 to 118 000), with a median peak of 7600 copies/mL (range, 243 to 983 000), at a median of 27 days post-transplant (range, 9–89). Sixteen patients (41.0%) had high-level reactivation, defined as a viral load ≥ 104 copies/mL. Five patients (12.8%) had HHV-6 reactivation before neutrophil engraftment and 17 patients (43.6%) before platelet engraftment. Foscarnet was initiated a median of 4 days after first detection (range, 1–28). All patients achieved viral clearance, with a median time to clearance of 6 days (range, 2–31). Cumulative incidence of successful viral clearance was 89.7% at 14 days and 94.9% at 28 days. Only one patient showed a partial decline in HHV-6 DNAemia and subsequently needed 2-week of foscarnet to achieve complete clearance at 31 days. Three patients (7.7%) developed recurrent HHV-6 reactivation at day 55, 61, and 76 post-transplant (9, 8, and 44 days post-foscarnet completion), all responding to retreatment. No encephalitis, pneumonitis, or HHV-6-related organ involvement occurred. Three patients developed transient acute kidney injury (7.7%) attributed to foscarnet treatment, which resolved after hydration. No grade 3–4 foscarnet-related toxicities were reported. Median follow-up duration was 807 days (IQR, 361–1425). All patients with HHV-6 reactivation achieved neutrophil and platelet engraftment without secondary graft failure. Cumulative incidence of neutrophil engraftment was 100% at 30 days and platelet engraftment was 88.2% (95% CI 72.0–95.3) at 100 days, with median times to engraftment of 17 days (range, 8–24) and 25 days (range, 12–162), respectively. In a multivariable landmark analysis at day 30 post-transplant, HHV-6 reactivation was associated with significantly inferior overall survival (OS) (HR 2.956, 95% CI 1.491–5.861, p = 0.002) and progression-free survival (PFS) (HR 2.253, 95% CI 1.202–4.222, p = 0.011) compared with patients without HHV-6 reactivation. However, foscarnet treatment was not associated with increased risk of non-relapse mortality (NRM) (SHR: 2.078, 95% CI 0.847–5.099, p = 0.110). The cumulative incidence of relapse, acute GVHD grade II-IV, and chronic GVHD were comparable in both groups. Immune reconstitution, including recovery of lymphocyte subsets, was similar between patients with and without HHV-6 reactivation (Figure 1). HHV-6 reactivation remains a significant post-AHSCT complication, consistently linked to serious morbidity and mortality [14]. The cumulative incidence of HHV-6 reactivation in our cohort was 31.9% at 100 days, with a median onset of 26 days post-transplant, consistent with previous reports, highlighting its common and potentially life-threatening nature in AHSCT patients [1, 4]. An association between HHV-6 reactivation and older age likely reflects age-related immune senescence and delayed immune recovery. Similarly, mismatched donors were associated with increased risk, suggesting a role for greater alloimmune dysregulation, delayed HHV-6-specific T-cell immunity recovery, and intensified early immunosuppression [4, 15, 16]. Despite the clear risks, optimal management of HHV-6 reactivation remains challenging. Previous studies, particularly in umbilical cord blood transplantation (UCBT), have not consistently demonstrated a benefit in preventing encephalitis or improving clinical outcomes [7-9, 17, 18]. However, the severe and potentially irreversible consequences of HHV-6-associated end-organ disease underscore the critical need for effective preventive strategies. Our study addresses this critical gap by providing compelling evidence that a timely and aggressive approach to viral load suppression can profoundly impact patient outcomes. Our study demonstrates that a short 7-day course of once-daily foscarnet as preemptive treatment achieved rapid HHV-6 clearance, with a median time of 6 days, without evidence of end-organ diseases. Notably, effective viral suppression was observed even among patients with high-level viremia, and all were managed in the outpatient setting with acceptable toxicity. We posit that if any treatment helps to suppress viral

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