Acyclovir-resistant herpes simplex virus infections in a bone marrow transplant population

Darville, J. M.; Ley, B. E.; Roome, A. P. C. H.; Foot, A. B. M.

doi:10.1038/sj.bmt.1701392

Cited by 49 publications

(29 citation statements)

References 7 publications

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“…Antiviral drugs with a non-TK-dependent mode of action, such as PFA, have been used since the emergence of ACVresistant strains (7,28), and PFA-resistant strains have appeared (8,13,33,34). In our study, among the 22 ACVresistant patients who received PFA, 14 excreted PFA-resistant strains (64%).…”

Section: Discussionmentioning

confidence: 84%

Surveillance Network for Herpes Simplex Virus Resistance to Antiviral Drugs: 3-Year Follow-Up

et al. 2004

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Herpes simplex virus (HSV) infections are very common in the general population and among immunocompromised patients. Acyclovir (ACV) is an effective treatment which is widely used. We deemed it essential to conduct a wide and coordinated survey of the emergence of ACV-resistant HSV strains . We have formed a network of 15 virology laboratories which have isolated and identified, between May 1999 and April 2002, HSV type 1 (HSV-1) and HSV-2 strains among hospitalized subjects. The sensitivity of each isolate to ACV was evaluated by a colorimetric test (C. Danve, F. Morfin, D. Thouvenot, and M. Aymard, J. Virol. Methods 105:207-217, 2002). During this study, 3,900 isolated strains among 3,357 patients were collected; 55% of the patients were immunocompetent. Only six immunocompetent patients excreted ACV-resistant HSV strains (0.32%), including one female patient not treated with ACV who was infected primary by an ACV-resistant strain. Among the 54 immunocompromised patients from whom ACV-resistant HSV strains were isolated (3.5%), the bone marrow transplantation patients showed the highest prevalence of resistance (10.9%), whereas among patients infected by human immunodeficiency virus, the prevalence was 4.2%. In 38% of the cases, the patients who excreted the ACV-resistant strains were treated with foscarnet (PFA), and 61% of them developed resistance to PFA. The collection of a large number of isolates enabled an evaluation of the prevalence of resistance of HSV strains to antiviral drugs to be made. This prevalence has remained stable over the last 10 years, as much among immunocompetent patients as among immunocompromised patients.Herpes simplex virus (HSV) infections are very common; they are localized on the face and torso in the case of HSV type 1 (HSV-1) and in the genital region in the case of HSV-2. HSV-1 infections in the genital region are on the increase (40). Ocular herpes is less frequent, and neonatal herpes and herpetic meningoencephalitis are very rare but have a severe functional and vital prognosis (37).Since acyclovir (ACV) {9-[(2-hydroxyethoxy)methyl)guanine]} was introduced to the market in 1983, it has been used primarily in the prevention and treatment of HSV infections. ACV-resistant HSV strains have been observed in vivo since the first large therapeutic trials (5, 10, 36). These resistant strains are detected in vitro by phenotypic tests which determine the antiviral concentration inhibiting viral replication by 50%. Several methods have been used to evaluate the sensitivity of the HSV strains to ACV, including techniques to detect the intensity of the cytopathic effect, such as the plaque reduction (17, 31) and colorimetric (11,22,26) techniques, but also the detection of DNA replication by hybridization (39) or antigen production by flow cytometry (30).Previous surveys among immunocompetent patients have shown a prevalence of resistance to ACV varying between 0 and 0.6%, whereas among immunocompromised patients, the prevalence varied between 3 and 6% (9,16,29). The use of ACV is co...

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Section: Discussionmentioning

confidence: 84%

Surveillance Network for Herpes Simplex Virus Resistance to Antiviral Drugs: 3-Year Follow-Up

et al. 2004

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“…Although in nucleoside analog-resistant cases TK-independent drugs such as the viral DNA polymerase inhibitors foscarnet and cidofovir can be administered, these compounds frequently mediate severe toxic side effects, particularly in patients with high comorbidities. Most alarmingly, HSV strains being resistant to both TK-dependent drugs as well as polymerase inhibitors have been isolated from highly immunocompromised patients undergoing stem cell/bone marrow transplantation (12,13).…”

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confidence: 99%

Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody

Krawczyk

Arndt

Grosse‐Hovest

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

105

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Despite the availability of antiviral chemotherapy, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections remain a severe global health problem. Of particular concern is the growing incidence of drug resistance in immunocompromised patients, which stresses the urgency to develop new effective treatment alternatives. We have developed a humanized monoclonal antibody (mAb hu2c) that completely abrogates viral cell-to-cell spread, a key mechanism by which HSV-1/2 escapes humoral immune surveillance. Moreover, mAb hu2c neutralized HSV fully independent of complement and/or immune effector cell recruitment in a highly efficient manner. Prophylactic and therapeutic administration of mAb hu2c completely prevented infection-related mortality of severely immunodeficient mice being challenged with a lethal dose of HSV-1. The high neutralization capacity of mAb hu2c was fully maintained toward clinical HSV isolates being multiresistant to standard antiviral drugs, and infection was fully resolved in 7/8 nonobese diabetic/SCID mice being infected with a multidrug resistant HSV-1 patient isolate. Immunohistochemical studies revealed no significant cross-reactivity of the antibody toward human tissues. These features warrant further clinical development of mAb hu2c as an immunotherapeutic compound for the management of severe and particularly drugresistant HSV infections.acyclovir resistance | immunocompromised mice | stem cell transplantation

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“…This drug may be considered as salvage therapy for patients with persisting, life-threatening HSV infections despite high-dose intravenous ACV and foscarnet. 3 …”

Section: Discussionmentioning

confidence: 99%

“…3 In 70 to 80% of previously seropositive recipients it occurs early, during the first 3 weeks after the end of myeloablative treatment. 1 Reactivation of HSV causes a severe increase in the oral mucositis usually observed after the conditioning regimens used in BMT for hematological malignancies.…”

Section: Discussionmentioning

confidence: 99%

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Treatment of an acyclovir and foscarnet-resistant herpes simplex virus infection with cidofovir in a child after an unrelated bone marrow transplant

Blot¹,

Schneider

Young

et al. 2000

Bone Marrow Transplant

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Summary:Herpes simplex virus (HSV) causes serious problems in immuno-compromised patients such as those receiving a bone marrow transplant (BMT) for a hematological malignancy. Resistance to acyclovir (ACV) is a growing major concern. Foscarnet is a non-thymidine kinasedependent agent, but the emergence of ACV and foscarnet-resistant HSV requires a new therapeutic approach. We describe a girl treated with cidofovir for a lifethreatening ACV-resistant HSV infection after an unrelated BMT for a relapse of an acute myeloblastic leukemia (AML). Bone Marrow Transplantation (2000) 26, 903-905. Keywords: AML; bone marrow transplantation; herpes simplex virus infection; cidofovir Herpes simplex virus (HSV) infection is the most common viral infection after bone marrow transplant (BMT). 1 Acyclovir (ACV) is the drug of choice for prophylactic and curative treatment of HSV infection. 2 However, the emergence of ACV-resistant HSV infection is a new and challenging problem. Foscarnet is usually effective in this situation. Cross-resistance to ACV and foscarnet has been previously described in patients after BMT. 2,3 Cidofovir has been recently approved for the treatment of CMV retinitis in acquired immuno-deficiency syndromes. It is the first of a new class of nucleotide antiviral agents with activity against a broad spectrum of herpes viruses. 4 Here, we report, successful treatment of an ACV and foscarnet cross-resistant herpetic infection with cidofovir in a child after an unrelated BMT. Case reportAn 18-month-old girl, was admitted in June 1998 with AML 4 with a t(9;11)(p12;q23). A complete remission was During the neutropenic period following induction chemotherapy, the patient developed a severe mucositis which was slowly but successfully treated with ACV 10 mg/m 2 every 8 h.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.After a conditioning regimen including busulfan 120 mg/m 2 /day p.o. in divided doses daily for 4 days (TD: 480 mg/m 2 ), cyclophosphamide 50 mg/kg/day once daily i.v. for 4 days (TD: 200 mg/kg) and anti-lymphocyte serum 5 mg/kg (TD: 20 mg/kg), the patient was transplanted with bone marrow from of an unrelated HLA matched donor. To prevent graft-versus-host-disease (GVHD) she received i.v. cyclosporin (2 mg/kg/day) and methotrexate (15 mg/m 2 day 1 then 10 mg/m 2 on days 3, 6, and 11).Before initiation of the BMT procedure, blood PCR assay for HSV was negative.At day +5 after bone marrow infusion, a recurrence of HSV mucositis occurred despite prophylaxis with ACV (250 mg/m 2 every 8 h). After a transient improvement 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. Only activated lymphocytes were observed on the bone marrow smears, without viral particles. The lesions became necrotic (Figure 1). At day +70, a life...

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Acyclovir-resistant herpes simplex virus infections in a bone marrow transplant population

Cited by 49 publications

References 7 publications

Surveillance Network for Herpes Simplex Virus Resistance to Antiviral Drugs: 3-Year Follow-Up

Surveillance Network for Herpes Simplex Virus Resistance to Antiviral Drugs: 3-Year Follow-Up

Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody

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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