In people whose immunity is deficient, persistent and/or severe mucocutaneous ulcerations may occur, often involving large areas of perianal, scrotal or penile skin. The lesions may be painful and atypical, making a clinical diagnosis difficult. The natural history of herpes sores may become altered. Most lesions of herpes in HIV infected persons will respond to acyclovir, but the dose may have to be increased and treatment given for longer than the standard recommended period. Subsequently, patients may benefit from chronic suppressive therapy. In some cases the patients may develop thymidine-kinase deficient mutants for which standard antiviral therapy becomes ineffective.

The recommended regimen in severe herpes simplex lesions with co-infection with HIV is acyclovir 400mg orally 3-5 times daily until clinical resolution is attained.