Penciclovir

Abstract: Herpes simplex viruses (HSV) type 1 and type 2 are responsible for recurrent orolabial and genital infections. The standard therapy for the management of HSV infections includes acyclovir (ACV) and penciclovir (PCV) with their respective prodrugs valacyclovir and famciclovir. These compounds are phosphorylated by the viral thymidine kinase (TK) and then by cellular kinases. The triphosphate forms selectively inhibit the viral DNA polymerase (DNA pol) activity. Drug-resistant HSV isolates are frequently recovered from immunocompromised patients but rarely found in immunocompetent subjects. The gold standard phenotypic method for evaluating the susceptibility of HSV isolates to antiviral drugs is the plaque reduction assay. Plaque autoradiography allows the associated phenotype to be distinguished (TK-wild-type, TK-negative, TK-lowproducer, or TK-altered viruses or mixtures of wild-type and mutant viruses). Genotypic characterization of drug-resistant isolates can reveal mutations located in the viral TK and/or in the DNA pol genes. Recombinant HSV mutants can be generated to analyze the contribution of each specific mutation with regard to the drug resistance phenotype. Most ACV-resistant mutants exhibit some reduction in their capacity to establish latency and to reactivate, as well as in their degree of neurovirulence in animal models of HSV infection. For instance, TK-negative HSV mutants establish latency with a lower efficiency than wild-type strains and reactivate poorly. DNA pol HSV mutants exhibit different degrees of attenuation of neurovirulence. The management of ACV- or PCV-resistant HSV infections includes the use of the pyrophosphate analogue foscarnet and the nucleotide analogue cidofovir. There is a need to develop new antiherpetic compounds with different mechanisms of action. Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are responsible for recurrent orolabial and genital infections. In the United States, the seroprevalence of HSV-1 and HSV-2 infections has been estimated to be approximately 50% and 20%, respectively (243). Transmission occurs by contact with secretions from an infected person with either overt infection or asymptomatic excretion of virus. After primary infection, HSV establishes long-term latency in the ganglia of sensory nerves, from which it can reactivate episodically. These reactivations may be accompanied by symptoms or may be clinically silent. The most common clinical manifestations of HSV infections are vesicular lesions affecting the mucous membranes principally of the mouth, nose, or eyes for HSV-1 and the anogenital region for HSV-2. However, an increasing proportion of genital infections are caused by HSV-1 (243). The symptoms associated with both viruses are usually self-limiting, and the goals of treatment are to accelerate lesion healing and to prevent transmission in immunocompetent individuals (61). Both HSV-1 and HSV-2 can also cause infrequent but serious diseases, such as encephalitis and disseminated neonatal infections. HSV infections may be severe in immunocompromised patients, particularly those with defects in cell-mediated immunity. In patients with HIV infection and in recipients of solid organ or bone marrow transplants, herpetic lesions can be extensive, tend to persist for longer periods, and have the potential to disseminate. Recurrences tend to be more frequent and may be atypical in appearance (140). In addition to persistent mucocutaneous lesions, HSV can also lead to disseminated visceral infections, such as esophagitis, hepatitis, or pneumonia, as well as meningoencephalitis, in immunocompromised hosts (94, 99, 174).