LAUSR

The two herpes simplex viruses (HSV-1 and HSV-2) can cause a spectrum of clinical diseases, from unsightly cold sores to vexatious genital lesions to life-threatening encephalitis. The very first antiviral agent for systemic treatment of HSV was vidarabine, which obtained FDA approval in 1976, but its use was soon supplanted by acyclovir (licensed in 1981) due to the latter’s superior efficacy and safety profile. Although there are other licensed agents with anti-HSV activities (including famciclovir, ganciclovir, foscarnet, and cidofovir), acyclovir and its valyl-ester valacyclovir remain the gold standard for HSV treatment. Unfortunately, the effectiveness of these antimicrobial agents is hampered by the emergence of drug-resistant pathogens, and the treatment of HSV is no exception. Drug-resistant HSV infections are a recognized clinical challenge among immunocompromised patients, particularly those with hematopoietic cell transplantation (HCT), as illustrated by the two cases of refractory HSV-1 oral lesions in HCT patients described by Bosetti et al. in this issue of Antimicrobial Agents and Chemotherapy (1). Without prophylaxis, HSV disease can occur in up to 70 to 80% of HCT recipients, but routine use of prophylaxis has reduced the incidence of early reactivation. However, prolonged viral shedding, long-term exposure to HSV prophylaxis, and issues with absorption (e.g., due to gut graft-versus-host disease) can lead to treatment-resistant HSV infections in immunocompromised patients (2). The prevalence of resistant HSV is noted around 5% among allogeneic HCT patients but can reach up to 14% to 30%; moreover, treatment options for acyclovir-resistant HSV are limited. Currently approved therapies for HSV largely rely on nucleoside analogues such as acyclovir or famciclovir that inhibit the synthesis of viral DNA by inhibiting HSV DNA polymerase after sequential phosphorylation by the viral thymidine kinase followed by the host kinase. HSV resistance to nucleoside analogues is most commonly due to mutations in viral thymidine kinase and rarely, in DNA polymerase (2). Although second-line antiviral drugs such as foscarnet and cidofovir can be utilized in cases of acyclovir resistance, they are frequently associated with significant toxicities, are available only in intravenous formulation for systemic dosing, and can also be rendered ineffective by certain mutations of the viral DNA polymerase, all of which limit their utility. For the two cases described by Bosetti et al. (1), the patients developed recurrent HSV-1 oral lesions while on valacyclovir prophylaxis and required multiple courses of intravenous foscarnet and/or cidofovir to control the infection. The patients were eventually treated with pritelivir, which resulted in resolution of their oral lesions. Others have also reported successful treatment of acyclovir-resistant HSV-2 genital infection in HCT patients with pritelivir, as cited by Bosetti et al. (1). Pritelivir is the first in a new class of antiviral thiazolylamide agents that target the HSV helicase-primase enzyme complex to inhibit de novo synthesis of viral DNA (3). It was noted to be more potent in cell culture than nucleoside analogues and was efficacious even after delayed onset of treatment, unlike acyclovir. The activity of pritelivir is not affected by Copyright © 2023 American Society for Microbiology. All Rights Reserved. Address correspondence to Dora Y. Ho, [email protected]. The authors declare no conflict of interest. For the case presentation, see https://doi.org/ 10.1128/AAC.01732-22. The views expressed in this article do not necessarily reflect the views of the journal or of ASM. Published 4 April 2023