Over all, acyclovir is a safe and effective drug with rare side effects when used as short term treatment. Its use in serious and life threatening HSV disease has curbed both morbidity and mortality in adults and children.

Acyclovir is also used as a suppressive drug for immunocompromised patients with chronic HSV blisters and ulcers, as well as in patients with frequently recurring, sometimes debilitating, genital herpes. In these cases, the drug is taken daily for a long period of time. It is important to note that long term suppressive therapy will not eradicate latent HSV.

No firm data exist regarding long term suppressive acyclovir treatment after neonatal herpes to prevent skin recurrences or to improve long term neurological outcome. Studies to address these points are ongoing.

There are some concerns about side effects when acyclovir is used as long term suppressive therapy in patients, particularly pertaining to the kidneys and the blood system.

The use of suppressive acyclovir regimens has led to the emergence of acyclovir-resistant HSV strains in severely immunocompromised patients. This is a concern, since the second line anti herpes drugs, foscarnet and cidofovir, are more toxic than acyclovir. One report exists in the literature, which describes the development of acyclovir-resistant HSV in an infant on long term suppressive acyclovir therapy. Another report describes an 10 day old infant with acyclovir-resistant HSV in the larynx.