Treatment of Acyclovir-Resistant Herpes Simplex Virus with Continuous Infusion of High-Dose Acyclovir in Hematopoietic Cell Transplant Patients

Abstract Background Acyclovir-resistant (ACVr) herpes simplex virus (HSV) infection management is a challenge in patients with hematologic malignancies (HM) and hematopoietic cell transplant (HCT) recipients. Methods Retrospective review of patients aged ≥ 18 years with underlying HM and/or HCT and culture-positive ACVr HSV between 1/1/2009 and December 1/2017 at a tertiary cancer center. Clinical, laboratory, microbiological, and treatment data collected. Results 33 patients identified; 25 (76%) acute leukemias, 3 (9%) chronic myeloid leukemia/chronic lymphocytic leukemia (CML/CLL), 3 (9%) lymphoma, 2 (6%) other HM, and 32 (97%) had HCT. Median age of patients was 59 years (25–73) and 64% of them are females. HCT type: 22 (67%) matched unrelated donor, 3 (9%) cord blood, and 7 (21%) matched related donor. All patients were on acyclovir prophylaxis prior to diagnosis. The median time to onset of ACVr HSV infection was 147 days after transplant. Infection site: 16 (49%) oral, 10 (30%), ano-genital, 5 (15%) oral and esophagus/lung, 2 (6%) esophagus/lung. Pertinent laboratory data on day of viral culture (median/range): white blood cell (WBC) 4.6 cells/µL (0.1–85.9), absolute neutrophil count (ANC) 2,316 cells/µL (0–17,000), absolute lymphocyte count (ALC) 574.5 cells/µL (0–84,182). Serum creatinine at start and end of treatment are 0.8 mg/dL (0.32–1.98) and 0.92 mg/dL (0.36–2.7), respectively. The median duration of treatment was 30 days (4–116). Treatment: 20 (61%) foscarnet, 2 (6%) cidofovir, 4 (12%) foscarnet and cidofovir, 1 (3%) valacyclovir, 5 (15%) high-dose acyclovir, 1 (3%) unknown. 8 (24%) received adjunctive topical therapy: 5 imiquimod, 3 cidofovir. 31 included in outcome analysis (data missing in 2). Infection resolved in 15/31 (48%) while 5/31 (16%) had persistent infection. Median ANC and ALC in those with resolved vs. persistent infection (respectively): 3,082 cells/µL and 642 cells/µL vs. 1,895 cells/µL and 380 cells/µL with a trend toward lower ANC and ALC in patients with persistent infection. Overall mortality was 35% (9/31) while ACVr HSV attributable mortality was 6.4% (2/31). Conclusion ACVr HSV is predominantly encountered in allogeneic HCT, particularly the unrelated donor recipients, and lower ANC/ALC may predispose to persistent infection. Disclosures All authors: No reported disclosures.

Download Full-text

Treatment of Severe Acyclovir-Resistant Herpes Simplex Virus Infection with Continuous Infusion of High Dose Acyclovir Following Hematopoietic Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.2224.2224 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2224-2224

Author(s):

Janet H. Kim ◽

Joanna Schaenman ◽

Dora Y. Ho ◽

Janice (Wes) M. Brown

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Continuous Infusion ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Hematopoietic Cell ◽

Myelogenous Leukemia ◽

High Dose ◽

Simplex Virus

Abstract Abstract 2224 Poster Board II-201 Although acyclovir (ACV)-resistant herpes simplex virus (HSV) occurs in healthy patients, higher rates have been reported in 7-27% of immunocompromised patients, particularly in the setting of acyclovir prophylaxis. Infection due to ACV-resistant HSV (ACV-R HSV) is frequently severe and poses challenges to treatment, particularly following hematopoietic cell transplantation (HCT). Unfortunately, currently available alternative therapies including foscarnet, cidofovir, and ganciclovir are frequently limited by their toxicity profile. We present a series of five HCT patients from 1997-2008 with severe infections due to ACV-R HSV who were successfully treated with continuous infusion of high dose acyclovir. A Pubmed search of published literature from 1948-2009 confirmed this as the first report of ACV-R HSV in HCT patients treated with this regimen. The characteristics of the patients are summarized in the table. Patients ranged in age from 24 to 55 and had undergone an allogeneic HCT following a myeloablative preparative regimen. All grafts were composed of peripheral blood hematopoietic cells. Underlying diseases included acute myelogenous leukemia, myelodysplastic syndrome, and essential thrombocytosis. Four of the five patients were receiving treatment for GVHD of the skin (grades 2-4), with regimens that included varying doses of prednisone. Infection was due to HSV-1 in three patients and HSV-2 in two. In vitro testing revealed that high median inhibitory concentrations were necessary to inhibit viral replication by 50% (MIC50) for all five isolates consistent with resistance to acyclovir, ganciclovir, and foscarnet. Failed HSV treatment regimens included standard, intermittent doses of acyclovir (5-10 mg/kg IV every eight hours), foscarnet, cidofovir, and/or famciclovir. Adverse reactions to these agents included severe renal insufficiency, hyponatremia, and neutropenia. The doses of ACV administered via continuous infusion ranged from 30 to 50 mg/kg per day, and time to resolution of lesions ranged from 1 week to 2 months. No patients experienced toxicity associated with continuous infusion of high dose acyclovir and therapy could be continued as an outpatient when appropriate. Conclusions: Continuous infusion of high dose acyclovir for acyclovir resistant HSV is an attractive and more tolerable alternative for patients failing standard dose intermittent infusion acyclovir or intolerant of alternative standard therapies such as foscarnet, cidofovir, or ganciclovir. At this time it is not clear how the altered pharmacokinetics that results from continuous infusion of high doses of acyclovir overcomes viral resistance. We are currently investigating the mechanisms by which the sustained levels of ACV provide this therapeutic advantage. Disclosures: No relevant conflicts of interest to declare.

Download Full-text