Emerging therapies for herpes viral infections (types 1 – 8)

Abstract

There are eight members of the herpesviridae family: herpes simplex virus-1 (HSV-1), HSV-2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, human herpes virus-6, human herpes virus-7 and human herpes virus-8. The diseases caused by viruses of the herpesviridae family are treated with and managed by systemic and topical antiviral therapies and immunomodulating drugs. Because these viruses establish a latent state in hosts, antiherpetic agents, such as nucleoside analogues, only control symptoms of disease or prevent outbreaks, and cannot cure the infections. There is a need for treatments that require less frequent dosing, can be taken even when lesions are more advanced than the first signs or symptoms, and can treat resistant strains of the viruses without the toxicities of existing therapies. Immunomodulating agents, such as resiquimod, can act on the viruses indirectly by inducing host production of cytokines, and can thereby reduce recurrences of herpes. The new helicase primase inhibitors, which are the first non-nucleoside antiviral compounds, are being investigated for treatment of HSV disease, including infections resistant to existing therapy.

Human herpes simplex virus infections: Epidemiology, pathogenesis, symptomatology, diagnosis, and management

“…75,97 HSV2 is the most common cause of genital herpes; however, an increasing number of primary episodes in the genital region has been attributed to HSV1. 48,52,98 The prevalence of HSV1 genital herpes varies geographically, accounting for nearly half of the new cases in some European countries. 52,76,[99][100][101][102][103] Primary genital HSV1 infections are more frequent in women 48,52,53 and often symptomatic, leading to a greater awareness of one's infectious status.…”

“…8,10,12,24,25,69,72,124,174,175 Mucocutaneous recurrences are often protracted, more symptomatic, poorly responsive to therapy, associated with longer duration of shedding, involving multiple sites, and at risk for viremic dissemination. 8,12,72,98 Intraoral lesions are often extensive, surrounded by a white, elevated border, and involve both keratinized and nonkeratinized mucosa, mimicking primary HSV infection (Fig 7). 12,25,72,176 Oral HSV2 reactivation and viral shedding are also more frequent among HIV-infected individuals.…”

“…2,4,8,124 As the first step in the phosphorylation cascade necessitates viral enzymes, the adverse effects of guanosine analogues on host cells are attenuated. 98 The primary mode of action of acyclovir and valacyclovir triphosphates is selective inhibition of DNA polymerase and subsequent incorporation into the replicating viral DNA chain, irreversibly terminating its further elongation. 124,234,235 Compared with acyclovir, penciclovir has a longer half-life and a higher intracellular concentration within HSVinfected cells, but is 100 to 160 times less potent in inhibiting viral DNA polymerase.…”

“…8,236,237 Penciclovir halts viral DNA synthesis through irreversible, competitive inhibition of DNA polymerase rather than DNA chain termination. 2,98,124,238 Valacyclovir (Valtrex, Glaxo SmithKline, Research Triangle Park, NC) is a systemic antiviral agent approved for treatment of recurrent HSL. 73 It is the valine ester prodrug of acyclovir, which is more readily absorbed and fully metabolized to acyclovir and L-valine in the liver and intestine.…”

“…2,124,245,247,248 It competitively blocks pyrophosphate binding sites on the viral DNA polymerase, directly inhibiting its activity. 98,124,242,248 Serious adverse effects of foscarnet include renal toxicity, mandating close follow-up of serum creatinine throughout therapy. 69,124 Sufficient hydration before and during infusions and avoidance of other nephrotoxic medications may help prevent or minimize renal impairment.…”