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Although in healthy patients clinical signs and symptoms of HSV infection are usually mild and self\u2010limiting, HSV\u2010infections in immunocompromised patients are frequently more aggressive, persistent, and even life\u2010threatening. Acyclovir and its derivatives are the gold standard antiviral drugs for the prevention and treatment of HSV infections. Although the development of acyclovir resistance is a rather uncommon condition, it may be associated with serious complications, especially in immunocompromised patients. In this review, we aim to address the problem of drug resistant HSV infection and discuss the available alternative therapeutic interventions. All relative studies concerning alternative treatment modalities of acyclovir resistant HSV infection published in PubMed between 1989 to 2022 were reviewed. Long\u2010term treatment and prophylaxis with antiviral agents predisposes to drug resistance, especially in immunocompromised patients. Cidofovir and foscarnet could serve as alternative treatments in these cases. Although rare, acyclovir resistance may be associated with severe complications. Hopefully, in the future, novel antiviral drugs and vaccines will be available in order to avoid the existing drug resistance.<\/jats:p>","DOI":"10.1111\/odi.14635","type":"journal-article","created":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T22:40:56Z","timestamp":1686177656000},"page":"877-894","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Management of oral herpes simplex virus infections: The problem of resistance. 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