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

Abstract

Abstract 2224Poster Board II-201Although 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.Age, sexDiseaseHCT TypeConcomitant risk factorsHSV Serotype, locationMIC50(mcg/mL)Failed HSV Treatment Regimens***High-dose continuous ACV (mg/kg/d)Outcome, Time to responseGVHDPREDOtherACVGCVFOS37, FAMLTCD URD MASkin, Grade 2 GI<0.5 mg/k/dCSAHSV-2; genitalia102222ACV IV FOS IV CID IV30Resolved; 3 weeks47, FMDS, AMLURD MASkin, Grade 4<0.5-2 mg/k/dFK506 MMFHSV-2; genitalia, buttocks, upper thighs>48>48>200ACV IV FOS IV45Resolved; 2 months55, FMDSURD MASkin, Grade 250 mg qdTAC MMFHSV-1; Oro-pharynx>48>48>48ACV IV FOS IV30Resolved; 1 week44, FET, AMLURD MASkin, Grade 460 mg qdPrografHSV-1; Tongue>48>48>48ACV IV FAM PO30 - 50Partially resolved***24, MATMRD MANoneNoneCSA ATGHSV-1 Nare>48>48>100ACV PO FAM PO30Resolved; 1 week*All pts received allogeneic transplants and HSV prophylactic regimen of acyclovir**Dose ranges: Acyclovir 400 mg po 5x qd to 10 mg/kg IV q 8 hrs; cidofovir 5 mg/kg q week; foscarnet 40 mg/kg qd to 25 mg/kg q 12 hrs; famciclovir 500 mg po bid to 1000 mg po tid***Patient expired prior to resolution of lesions MDS = myelodysplastic syndrome; AML = acute myelogenous leukemia; URD = unrelated donor; MRD = matched-related donor; TCD = T-cell depleted; MA = myeloablative; ET = Essential thrombocytosis, AT = Amegakarocytic thrombocytopenia PRED = prednisone PO ; ACV = acyclovir, GCV = ganciclovir; FOS = foscarnet; CID = cidofovir; FAM = famciclovir; TAC = tacrolimus 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.