Current and future therapies for herpes simplex virus infections: mechanism of action and drug resistance

•We review the current state of anti-HSV chemotherapy, including resistance rates.•We highlight novel agents under investigation for the treatment of HSV infections.•Focus is given to mechanisms of activity and the potential for drug resistance.•Combination therapy directed at multiple molecular targets may be favorable. Forty years after the discovery of acyclovir (ACV), it remains the mainstay of therapy for herpes simplex virus (HSV) infections. Since then, other antiviral agents have also been added to the armamentarium for these infections but ACV remains the therapy of choice. As the efficacy of ACV is reassessed, however, it is apparent that a therapy with increased efficacy, reduced potential for resistance, and improved pharmacokinetics would improve clinical outcome, particularly in high risk patients. Inhibitors of viral targets other than the DNA polymerase, such as the helicase primase complex, are of particular interest and will be valuable as new therapeutic approaches are conceived. This review focuses on currently approved HSV therapies as well as new systemic therapies in development.