Few randomised, controlled trials have been performed in patients with HIV infection. Acyclovir, famciclovir and valaciclovir have all been shown to be safe and effective as both intermittent and continuous therapy for HSV-2 clinical and subclinical infection in HIV-positive men and women.[40]

In the majority of situations, mucocutaneous HSV responds to oral therapy with acyclovir (400 mg three times a day); valaciclovir (1g twice a day); or famciclovir (250 mg three times a day). Primary episodes are treated for 7 to 10 days; recurrent episodes are treated for 5 days.[41] If standard dosing fails, biopsy and culture should be performed to obtain viral sensitivities and to exclude alternative pathology. Higher doses may be useful with acyclovir 800 mg twice a day or valaciclovir 1 g three times a day.[42] Severe cases or clinically-unresponsive confirmed cases may require high doses of oral agents or, rarely, intravenous acyclovir. Treatment of acyclovir-resistant HSV includes non-thymidine kinase dependent therapies such as foscarnet or cidofovir.[43]