Case Report Treatment of an Acyclovir and Foscarnet-Resistant Herpes Simplex Virus Infection with Cidofovir in a Child After an Unrelated Bone Marrow Transplant

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Bone Marrow Transplantation (2000) 26, 903–905  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Case report Treatment of an acyclovir and foscarnet-resistant herpes simplex virus infection with cidofovir in a child after an unrelated bone marrow transplant

N Blot1, P Schneider2, P Young3, C Janvresse4, D Dehesdin5, P Tron2 and JP Vannier2

1Pediatrics, General Hospital, Sallanches, 2Pediatric Hematology and Oncology, 3Dermatology, 4Virology, 5ENT, Charles Nicolle Hospital, Rouen, France

Summary: obtained after a course of cytarabine (200 mg/m2/day by continuous i.v. infusion for 7 consecutive days, total dose Herpes simplex virus (HSV) causes serious problems in (TD): 1400 mg/m2) and mitoxanthrone (12 mg/m2/day for immuno-compromised patients such as those receiving 5 days, TD: 60 mg/m2). Shortly after the first course of a bone marrow transplant (BMT) for a hematological consolidation a relapse occurred. A second complete malignancy. Resistance to acyclovir (ACV) is a growing remission was obtained with an intensified Flag-based major concern. Foscarnet is a non-thymidine kinase- regimen: fludarabine 30 mg/m2/day for 4 days (TD: dependent agent, but the emergence of ACV and foscar- 120 mg/m2), high-dose cytarabine 2000 mg/m2/day for 4 net-resistant HSV requires a new therapeutic approach. days (TD: 8000 mg/m2), cerubidine 45 mg/m2/day for 3 We describe a girl treated with cidofovir for a life- days (TD: 135 mg/m2) and G-CSF 5 ␮g/kg/day started 2 threatening ACV-resistant HSV infection after an days before chemotherapy.5 unrelated BMT for a relapse of an acute myeloblastic During the neutropenic period following induction leukemia (AML). Bone Marrow Transplantation (2000) chemotherapy, the patient developed a severe mucositis 26, 903–905. which was slowly but successfully treated with ACV Keywords: AML; bone marrow transplantation; herpes 10 mg/m2 every 8 h. simplex virus infection; cidofovir The two subsequent courses of consolidation were complicated with the same HSV mucositis. No investigations were performed to study the HSV sensitivity to antiviral treatment because of the good prior response to ACV. Herpes simplex virus (HSV) infection is the most common After a conditioning regimen including busulfan 1 viral infection after bone marrow transplant (BMT). Acy- 120 mg/m2/day p.o. in divided doses daily for 4 days (TD: clovir (ACV) is the drug of choice for prophylactic and 480 mg/m2), cyclophosphamide 50 mg/kg/day once daily 2 curative treatment of HSV infection. However, the emer- i.v. for 4 days (TD: 200 mg/kg) and anti-lymphocyte serum gence of ACV-resistant HSV infection is a new and 5 mg/kg (TD: 20 mg/kg), the patient was transplanted with challenging problem. Foscarnet is usually effective in this bone marrow from of an unrelated HLA matched donor. situation. Cross-resistance to ACV and foscarnet has been To prevent graft-versus-host-disease (GVHD) she received 2,3 previously described in patients after BMT. i.v. cyclosporin (2 mg/kg/day) and methotrexate (15 mg/m2 Cidofovir has been recently approved for the treatment of day 1 then 10 mg/m2 on days 3, 6, and 11). CMV retinitis in acquired immuno-deficiency syndromes. It Before initiation of the BMT procedure, blood PCR is the first of a new class of nucleotide antiviral agents with assay for HSV was negative. 4 activity against a broad spectrum of herpes viruses. At day +5 after bone marrow infusion, a recurrence of Here, we report, successful treatment of an ACV and HSV mucositis occurred despite prophylaxis with ACV foscarnet cross-resistant herpetic infection with cidofovir in (250 mg/m2 every 8 h). After a transient improvement a child after an unrelated BMT. related to the end of aplasia (day +15) the HSV lesions extended to the right cheek, the larynx and the nose. The evolution was complicated by a subsequent failure of BMT. Case report Only activated lymphocytes were observed on the bone marrow smears, without viral particles. The lesions became An 18-month-old girl, was admitted in June 1998 with necrotic (Figure 1). At day +70, a life-threatening laryngeal AML 4 with a t(9;11)(p12;q23). A complete remission was obstruction occurred requiring a tracheotomy. No improvement was obtained despite high-dose ACV (500 mg/m2 Correspondence: Prof JP Vannier, Pediatric Hematology and Oncology, every 8 h) and the addition of foscarnet (80 mg/kg/day) and Charles Nicolle Hospital, 1, rue de Germont, 76 000, Rouen, France later ganciclovir (5 mg/kg every 12 h). Viral cultures per- Received 19 January 2000; accepted 8 June 2000 formed from a skin biopsy were positive for a strain of Cidofovir for ACV-resistant HSV infection N Blot et al 904 Discussion

The emergence of ACV-resistant HSV infections in sever- ely immuno-compromised patients is a new and challenging problem. In a recent study carried out on a series of 222 patient who underwent BMT, HSV infection was diagnosed in 23 adults and five children.6 Among these, seven were resistant to ACV. Despite its potential toxicity, cidofovir appears to be an important salvage agent when first-line anti-herpes drugs fail to control infection. Allogeneic BMT is always associated with transient neutropenia and long-lasting immunodeficiency.1 Risk of infection is increased by the underlying disease and previous treatments, particularly high-dose chemotherapy. Some drugs such as fludarabine, daunorubicine and cytarabine are responsible for a profound cellular immune deficiency.7,8 GVHD prophylaxis with highly efficient immunosuppres- sive drugs increases and prolongs the risk of opportun- istic infections. Reactivation of latent HSV is frequent after BMT and adds substantially to morbidity.3 In 70 to 80% of previously seropositive recipients it occurs early, during the first 3 weeks after the end of myeloablative treatment.1 Reacti- vation of HSV causes a severe increase in the oral mucositis usually observed after the conditioning regimens used in BMT for hematological malignancies.9 The infection spreads locally to produce extensive hemorragic ulcerations of adjacent skin and mucous membranes. As in our patient, extension to the larynx may be life-threatening.1 Systemic dissemination of virus may cause multiple organ failure especially where bone marrow aplasia enhances risk of infections.1,10 Reactivation of latent HSV is avoided in 90% of seropositive patients with prophylactic 2 Figure 1 Photograph of the patient showing HSV lesion extending to ACV at a dose of 250 mg/m every 8 h. However, clinical the right cheek, the larynx and the nose. resistance to ACV is a growing concern in bone marrow transplant patients. ACV-resistant HSV strains have been isolated from 5 to 10% of patients taking prophylactic therapy, and in these patients, overwhelming infection may lead HSV-1 which was shown by phenotyping to be resistant in to multiple organ failure.10 vitro to ACV and foscarnet. Usually, ACV-resistant HSV strains emerge as a result Treatment with cidofovir (5 mg/kg i.v.) was started on of mutations within the viral thymidine kinase. DNA day +88. To circumvent nephrotoxicity, each injection was polymerase mutations are less frequent. Thymidine kinase given with saline hydration, and probenecid, 50 mg/kg p.o. performs the initial phosphorylation step in the intracellular 3 h before, then 2 and 6 h after cidofovir injections. The activation of ACV and other antiherpes nucleoside treatment was administered once a week for 3 weeks, then analogues such as ganciclovir, famciclovir and valaciclovir. every other week for 2 months. Foscarnet does not require the viral thymidine kinase for Due to persisting aplasia, a second BMT was performed its activity and is currently the only approved treatment for 2 days after the first injection of cidofovir without any con- ACV-resistant HSV infections.2,11 ditioning regimen. The second BMT was part of the initial Failure of foscarnet has previously been described in harvest, which had been previously frozen. HIV infections and in hematological malignancies.2 A spectacular improvement was observed after each dose Cross-resistance to foscarnet suggests either an alteration of cidofovir (5 mg/kg) and the mucous and cutaneous in the DNA polymerase or a combination of separate HSV lesions were completely healed after the seventh injection. drug-resistant populations. Only a restricted number of sites No recurrence has occurred to date. ACV had never been of mutation in the DNA polymerase gene may give drug stopped during the treatment. Rapid bone marrow reconsti- resistance while maintaining a functional enzyme.12 tution was observed after the second BMT, and only transi- Cidofovir (HPMPC, GS504) is a nucleotide analogue ent proteinuria and a brief generalized rash were observed with a spectrum against HSV 1 and 2, CMV, VZV, EBV after each day of treatment. Twelve months after the second and human papilloma viruses. Cidofovir targets viral DNA BMT the patient is free of HSV-1 infection and leukemia. polymerase. Unlike ACV or ganciclovir, which require She is currently being treated for chronic GVHD. She has intracellular phosphorylation by a virally encoded enzyme, no renal impairment. cidofovir is a monophosphate nucleotide analogue which

Bone Marrow Transplantation Cidofovir for ACV-resistant HSV infection N Blot et al 905 is phosphorylated into an active form by cellular enzymes of an acyclovir- and foscarnet-resistant herpes simplex virus independently of any viral participation. Thus, viral type-1 lesion with intravenous cidofovir. Clin Infect Dis 1998; mutations leading to altered phosphorylase activity will not 26: 512–513. result in resistance to cidofovir. Other mechanisms of 3 Darville JM, Ley BE, Roome APCH et al. Acyclovir-resistant resistance cannot be excluded.4,13 herpes simplex virus infections in a bone marrow transplant population. Bone Marrow Transplant 1998; 22: 587–589. With the long intracellular half-life of its metabolites, 4 Lea AP, Bryson HM. Cidofovir. Drugs 1996; 52: 225–230. cidofovir can be administered weekly during the initial 5 Estey E, Plunkett W, Gandhi V et al. Fludarabine and arabino- phase of treatment and then every other week until a bone sylcytosine therapy of refractory and relapsed acute myelogen- marrow reconstitution is obtained.11 Proteinuria (83%) and ous leukemia. Leuk Lymphoma 1993; 9: 343–350. neutropenia (15%) are the most common adverse effects. 6 Morfin F, Thouvenot D, Souillet G et al. Acyclovir-resistant Administration of probenecid, an uricosuric agent which herpes viruses (HSV, VZV in bone marrow transplant decreases renal tubular secretion of anionic drugs, and patients). 3rd Annual Meeting of the European Society for saline hydration reduces the incidence and severity of Clinical Virology. Budapest, Hungary, September 1999. nephrotoxicity in patients receiving cidofovir. However, 7 Mc Carthy AJ, Pitcher LA, Hann IM et al. FLAG probenecid can cause mild to moderate adverse reactions (fludarabine , high-dose cytarabine, and G-CSF) for refractory and high-risk relapsed acute leukemia in children. Med Pedi- which include nausea, vomiting, headache, fever and 4 atr Oncol 1999; 32: 411–415. flushing. 8 Lam MT, Pazin GJ, Armstrong JA et al. Herpes simplex infec- The indications of cidofovir for HSV infections are still tion in acute myelogenous leukemia and other hematologic under discussion and efficacy and toxicity of cidofovir in malignancies: a prospective study. Cancer 1981; 41: 2168– children infected with HSV have not been evaluated yet. 2171. This drug may be considered as salvage therapy for patients 9 Bergmann OJ, Ellermann-Eriksen S, Mogensen SC et al. Acy- with persisting, life-threatening HSV infections despite clovir given as prophylaxis against oral ulcers in acute high-dose intravenous ACV and foscarnet.3 myeloid leukemia: randomized, double-blind, placebo con- trolled trial. Br Med J 1995; 310: 1169–1172. 10 Wade JC, Mc Laren C, Meyers JD. Frequency and signifi- cance of acyclovir resistant herpes simplex virus isolated from Acknowledgements marrow transplant recipients receiving multiple courses of treatment with acyclovir. J Infect Dis 1983; 148: 1077–1082. 11 Horsburgh BC, Chen SH, Hu A et al. Recurrent acyclovir- We thank Vale´rie Greene for her English language assistance. resistant herpes simplex in an immuno-compromised patient: can strain differences compensate for loss of thymidine kinase in pathogenesis? J Infect Dis 1998; 178: 618–625. 12 Scnoeck R, Andrei G, Gerard M et al. Successful treatment References of progressive mucocutaneous infection due to acyclovir and foscarnet-resistant herpes simplex virus with (S)-1-(3-hy- 1 Wood MJ. Viral infections in neutropenia-current problems droxy-2-phosphonylmethoxypropyl) cytosine (HPMPC). Clin and chemotherapeutic control. J Antimicrob Chemother 1998; Infect Dis 1994; 18: 570–578. 41 (Suppl. D): 81–93. 13 Alrabiah FA, Sacks SL. New antiherpes agents. Their targets 2 Lopresti AE, Levine JF, Munk GB et al. Successful treatment and therapeutic potential. Drugs 1996; 52: 17–32.

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