Foscarnet Treatment for Human Herpes Simplex Virus Infection Resistant to Acyclovir after Hematopoietic Cell Transplantation

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Introduction Refractory mucocutaneous herpes simplex virus infection (HSV) with Acyclovir (ACV) resistance (R) carries substantial morbidity and has limited treatment options. The efficacy of foscarnet (FOS) for ACV-R HSV in hematopoietic cell transplantation (HCT) recipients is not well-studied. We report response to FOS as first-line or second-line treatment and overall time to lesion healing in a large case series of HCT from 6 US centers. Methods Retrospective, multicenter study of HCT recipients from 2009-2023 who had 1) HSV failing to improve after ≥7 days of appropriately dosed HSV treatment AND 2) ACV-R documented by phenotypic or genotypic assay performed as standard of care. The onset of ACV-R HSV was defined as the date of diagnosis of the HSV episode, which eventually was confirmed to be ACV-R. Antiviral treatment is categorized as FOS, ACV ≥30mg/kg/day (ACV-HD), or “other” defined as any of the following (acyclovir<30 mg/kg, valacyclovir , famciclovir , leflunomide , valganciclovir or topical agents) or Investigational (INV). Response to FOS is defined as complete healing of all lesions by Day 28 from the start of each FOS treatment regardless of switching to different antivirals prior to Day 28. Patients alive by Day 28 of FOS therapy were evaluable for response. Time to complete healing of all lesions from the onset of ACV-R HSV was calculated by the cumulative incidence function treating death as a competing risk. Results 70 patients with ACV-R HSV analyzed (Table 1). Sixty-eight (97%) patients were on HSV prophylaxis at HSV diagnosis ; ACV-R was confirmed by phenotypic or genotypic assays in 61 (87%) and 9 (13%) patients respectively. HSV occurred a median of 130 days post-HCT (interquartile range [IQR]: 27, 409.5). First-line therapy was FOS in 15 (21.4%), ACV ≥30mg/kg/day (ACV-HD) in 16 (22.4%) and other in 39 (55.7%) patients. Overall, 59 patients received second-line therapy, including FOS 18 (30.5%), ACV-HD 12 (20.3%), “other” 28 (47.5%) and INV 1 (1.7%). The response rate to either first-line or second-line FOS therapy was 20%. (Table 2). The rate of complete healing from the onset of ACV-R HSV (including all lines of therapy) was 30.7% by Day 42 and 48.9% by Day 90 (Figure). Conclusions Approximately 50% of HCT patients with breakthrough HSV (eventually ACV-R) received FOS as the first or second antiviral treatment. Among patients who received FOS as first-line or second-line treatment, only 20% achieved complete healing of lesions by Day 28 of FOS therapy. At 90 days after the onset of HSV, less than half (48.9%) of the patients achieved complete healing. Our results underscore the need for effective and safer antivirals for ACV-R HSV in HCT.

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