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

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 load, it could potentially prevent organ involvement that is otherwise associated with these severe, often fatal consequences. The rapid viral clearance achieved in our study likely interrupts the progression of HHV-6 DNAemia to overt organ damage, thus preventing the severe manifestations associated with uncontrolled viral replication. It is important to note that umbilical cord blood was not used in our cohort, which may partly explain the differences in outcomes compared to previous UCBT studies. UCBT recipients typically have delayed immune reconstitution, particularly T-cell recovery, and a higher incidence of viral reactivation and severity of HHV-6 reactivation, which may limit preemptive antiviral effectiveness 15. In contrast, short-course foscarnet proved highly effective in our AHSCT population. Despite successful viral suppression and the absence of organ involvement, HHV-6 reactivation was associated with significantly worse OS and PFS compared to patients without reactivation in a 30-day landmark analysis. A high proportion of these patients had also BK virus reactivation, suggesting that the adverse impact on survival may be mediated through mechanisms other than direct HHV-6 organ damage. Notably, multivariable analysis revealed that foscarnet treatment for HHV-6 reactivation was not associated with a significant increase in NRM, suggesting that early treatment with foscarnet may help overcome negative effects associated with HHV-6 reactivation. Moreover, a comparison of immune reconstitution revealed no significant differences in the recovery of lymphocyte subsets between groups with and without HHV-6 reactivation, suggesting that foscarnet treatment did not impede immune recovery. However, quantitative immune parameters may not fully reflect overall immune competence and functional immune impairment or qualitative differences in immune responses. A major concern with foscarnet is nephrotoxicity, with an incidence exceeding 50% following full-dose administration 19, 20. In our cohort, only 7.7% developed transient renal toxicity that resolved with hydration, suggesting that a short-course, once-daily regimen with careful adjustment can mitigate nephrotoxicity while remaining highly effective for HHV-6 viral clearance. This study is limited by its single-center, retrospective design, and the lack of an untreated control group to directly evaluate the impact of foscarnet on transplant outcomes. The relatively small sample size also limits our ability to detect more rare outcomes, such as HHV-6 encephalitis. Nevertheless, this real-world study describes one of the larger analyses of patients with HHV-6 reactivation, demonstrating that a short course of preemptive foscarnet provides rapid clearance of HHV-6 viremia, and suggests that higher doses may not be required to prevent organ disease. In conclusion, an abbreviated course of once-daily foscarnet represents an effective and well-tolerated preemptive strategy for HHV-6 reactivation after AHSCT, achieving rapid viral clearance with minimal toxicity. Our findings advocate for a proactive approach to HHV-6 management, demonstrating that early viral suppression can avert devastating organ involvement without compromising safety. Study conception and design: S.O.C., P.K., and P.C. Data collection and verification: P.C. and P.V. Statistical design and data analysis: P.C., and P.K. Interpretation of results: P.C., P.K., and S.O.C. Draft manuscript preparation: P.C. Patient care: P.K., S.O.C., B.J.L., S.G., E.B., J.D. and team at the University of California, Irvine, for their dedication to patient care and data collection. The authors sincerely thank all patients for their trust and participation in this study. We are also grateful to the Hematopoietic Stem Cell Transplantation and Cellular Therapy Program team at the University of California, Irvine, for their dedication to patient care and data collection. The study was conducted in accordance with STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for cohort studies. All patients provided written informed consent for transplantation, and for research data collection and reporting, in accordance with the Declaration of Helsinki UCI International Review Board (IRB #20206215). The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.