Foscarnet Therapy for Severe Acyclovir-Resistant Herpes Simplex Virus Type-2 Infections in Patients with the Acquired Immunodeficiency Syndrome (AIDS)

Erlich, Kim S.; Jacobson, Mark A.; Koehler, Jane E.; Follansbee, Stephen; Drennan, David P.; Goozé, Lisa; Safrin, Sharon; Mills, John

doi:10.7326/0003-4819-110-9-710

Cited by 106 publications

(22 citation statements)

References 18 publications

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“…DISCUSSION The results of our experiments indicate that HPMPC is highly effective in the treatment of various experimental HSV model infections, including encephalitis, and cutaneous and generalized HSV infections. In particular, HPMPC proved effective in the treatment of TK-HSV infection in athymic nude mice, a model that could be considered representative of TK-HSV infections in immunocompromised patients (9,16,17,28,30,32). TK-HSV infection in nude mice is refractory to ACV treatment ( Fig.…”

Section: Methodsmentioning

confidence: 99%

Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine in various models of herpes simplex virus infection in mice

Clercq

Holý

1991

Antimicrob Agents Chemother

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The phosphonylmethoxyalkyl derivative (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) was evaluated for its in vivo efficacy in several model infections for herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and thymidine kinase-deficient (TK-) HSV-1 in mice. In hairless mice infected intracutaneously with HSV-1 or HSV-2, HPMPC completely suppressed all manifestations of the disease (skin lesions, paralysis of the hind legs, and mortality) if it was administered topically at a concentration of as low as 0.1, 0.3, or 1%. Similarly, HPMPC completely suppressed TK-HSV-1 infection in athymic nude mice if it was administered topically at 0.1 or 0.3% or intraperitoneally at 100 or 250 mg/kg/day. HPMPC was also effective against intraperitoneal HSV infection if it was given orally at a dose of 50 mg/kg/day or higher. In mice inoculated intracerebrally with HSV-2, intraperitoneal HPMPC treatment achieved a significant and dose-dependent protection at doses ranging from 5 to 400 mg/kg/day. The protective effect of HPMPC (at 200 mg/kg/day) was accompanied by a complete inhibition of virus multiplication in the brain. In all models of infections studied, the efficacy of HPMPC proved to be superior to that of acyclovir. The most remarkable feature of HPMPC was that a single administration of the compound, even as late as 4 days after infection, conferred significant protection against HSV-1 or HSV-2 infection. Topical or systemic HPMPC treatment is efficacious in murine models of HSV-1, HSV-2, and TK-HSV infections.The phosphonylmethoxyalkylpurines and -pyrimidines have been identified as new classes of antiviral agents with broad-spectrum activities against a wide variety of DNA viruses (13,14). (S)-9-(3-Hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA), the prototype of this class of compounds, has proved to be active against adenoviruses (2) 9-(2-Phosphonylmethoxyethyl)adenine (PMEA), which can be considered as the truncated form of HPMPA in which the hydroxymethyl group has been deleted, is active against herpes-, hepadna-, and iridoviruses (13,14,19, 33) HPMPA, PMEA, and PMEDAP have been the subject of a previous study in which the efficacies of these phosphonylmethoxyalkyl derivatives were demonstrated in a variety of experimental HSV-1 and HSV-2 infections, including intracutaneous HSV-1 and HSV-2 infections in hairless mice; intracutaneous thymidine kinase-deficient (TK-) HSV-1 infections in athymic nude mice; systemic (intraperitoneal [i.p.]) HSV-1 infections in mice; and intracerebral HSV-1, HSV-2, or TK-HSV-1 infections in mice (12). These animal models for HSV infections have been used to * Corresponding author. assess the in vivo efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), another member of the class of phosphonylmethoxyalkyl derivatives (14), which, according to previous investigations (7), would be more efficacious than acyclovir [ACV; 9-(2-hydroxyethoxymethyl)guanine] in both the systemic and topical treatment of HSV infections in mice and guinea pigs. MATERIALS...

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Section: Methodsmentioning

confidence: 99%

Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine in various models of herpes simplex virus infection in mice

Clercq

Holý

1991

Antimicrob Agents Chemother

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“…Foscarnet is administered intravenously (40 mg/kg over 1 h every 8 to 12 h, with careful monitoring of renal function and adjustment for decreased renal function). Since foscarnet is effective against most acyclovir-resistant HSV mutants, it is the substitute of choice (13,28,67). Topical foscarnet is effective in treating cutaneous lesions but is not commercially available.…”

Section: Treatment Failurementioning

confidence: 99%

Herpes Simplex Virus Resistance to Acyclovir and Penciclovir after Two Decades of Antiviral Therapy

et al. 2003

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Acyclovir, penciclovir, and their prodrugs have been widely used during the past two decades for the treatment of herpesvirus infections. In spite of the distribution of over 2.3 × 106 kg of these nucleoside analogues, the prevalence of acyclovir resistance in herpes simplex virus isolates from immunocompetent hosts has remained stable at approximately 0.3%. In immuncompromised patients, in whom the risk for developing resistance is much greater, the prevalence of resistant virus has also remained stable but at a higher level, typically 4 to 7%. These observations are examined in the light of characteristics of the virus, the drugs, and host factors

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“…About 80% of patients respond with ulcer healing and symptom resolution (63,130,400,401). In this setting, foscarnet is also superior to vidarabine; the rate of lesion healing is higher and there is less toxicity (402).…”

Section: Foscarnetmentioning

confidence: 99%

Antiviral therapy: current concepts and practices

Bean

1992

Clin Microbiol Rev

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Drugs capable of inhibiting viruses in vitro were described in the 1950s, but real progress was not made until the 1970s, when agents capable of inhibiting virus-specific enzymes were first identified. The last decade has seen rapid progress in both our understanding of antiviral therapy and the number of antiviral agents on the market. Amantadine and ribavirin are available for treatment of viral respiratory infections. Vidarabine, acyclovir, ganciclovir, and foscarnet are used for systemic treatment of herpesvirus infections, while ophthalmic preparations of idoxuridine, trifluorothymidine, and vidarabine are available for herpes keratitis. For treatment of human immunodeficiency virus infections, zidovudine and didanosine are used. Immunomodulators, such as interferons and colony-stimulating factors, and immunoglobulins are being used increasingly for viral illnesses. While resistance to antiviral drugs has been seen, especially among AIDS patients, it has not become widespread and is being intensely studied. Increasingly, combinations of agents are being used: to achieve synergistic inhibition of viruses, to delay or prevent resistance, and to decrease dosages of toxic drugs. New approaches, such as liposomes carrying antiviral drugs and computer-aided drug design, are exciting and promising prospects for the future.

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Foscarnet Therapy for Severe Acyclovir-Resistant Herpes Simplex Virus Type-2 Infections in Patients with the Acquired Immunodeficiency Syndrome (AIDS)

Abstract: Foscarnet may be an effective treatment for severe mucocutaneous disease due to acyclovir-resistant, TK-negative strains of HSV-2.

Cited by 106 publications

References 18 publications

Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine in various models of herpes simplex virus infection in mice

Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine in various models of herpes simplex virus infection in mice

Herpes Simplex Virus Resistance to Acyclovir and Penciclovir after Two Decades of Antiviral Therapy

Antiviral therapy: current concepts and practices

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