Acyclovir is an agent used to treat infections caused by the herpes simplex virus (HSV). It is FDA approved to treat genital herpes and HSV encephalitis. Non-FDA approved indications are mucocutaneous HSV, herpes zoster (shingles), and varicella-zoster (chickenpox).[1][2] Acyclovir is the first-line treatment for HSV encephalitis. Currently, there are no other medications indicated for the treatment of this condition.[3]

Despite the long term use of acyclovir to treat HSV encephalitis, there has not been a systematic review regarding the efficacy of this disease/treatment combination. Current systematic reviews to address its safety and efficacy are currently ongoing, with the primary outcome being mortality rate. A secondary outcome measure is the quality of life.[4]

HSV keratitis has been shown to respond to oral acyclovir and topical steroids in pediatric patients.[5]

In patients with human immunodeficiency virus (HIV), acyclovir is sometimes used to treat eczema herpeticum. It is also used to prevent infections of the skin, eyes, nose, and mouth. Eczema herpeticum is rare but rapidly progressive if untreated. Those with extensive involvement, systemic symptoms, or decreased oral intake should undergo admission for intravenous acyclovir treatment.[6] Also, acyclovir treats oral hairy leukoplakia.[7][8]

Acyclovir has been proven useful in treating myelopathy secondary to varicella-zoster infection. In a small case series, researching patients from 1994 to 2014 with laboratory-confirmed varicella-zoster virus (VZV) and MRI confirmed myelopathy, marked improvement of symptoms was the outcome in most patients within two months.[9]

Brachial plexus neuritis secondary to VZV infection and visceral disseminated VZV infection (characteristic features are abdominal and absence of skin lesions) has also responded to acyclovir, alleviating all symptoms.[10]

In recipients of hematopoietic stem cell transplantation, herpes simplex virus and varicella-zoster reactivation may respond to treatment with acyclovir prophylaxis. Prophylactic use of acyclovir should be considered in HSV-1 and HSV-2-seropositive organ recipients, as well.[11] Diseases from such viruses have decreased secondary to this intervention. However, a breakthrough infection may occur. Not surprisingly, HSV and VZV infection is not uncommon in patients that have discontinued acyclovir prophylaxis.[12]

Another form of prophylactic acyclovir use is juvenile-onset recurrent respiratory papillomatosis. In a prospective observational study involving 21 patients, oral acyclovir was a postoperative adjuvant. It was shown to decrease the recurrence of papillomas and thus decrease the need for successive surgeries and associated operative risks.[13]

VZV infections have many complications, including cerebellitis. Treating the source infection has been shown to decrease the complication burden as well. A 2019 case report, for instance, describes a patient presenting with truncal ataxia. After intravenous acyclovir treatment, the patient was free of neurologic disability and his cerebellitis. [14] Similarly, paresis secondary to dermatomal herpes zoster infections has been shown to respond to oral acyclovir; this is a rare complication of herpes zoster when the virus affects motor nerve fibers in addition to/instead of the dorsal root ganglion.[15]

Acyclovir is an antiviral agent that incorporates itself into viral DNA preventing further synthesis. It inhibits DNA synthesis and viral replication after it is converted to acyclovir triphosphate by viral and cellular enzymes. Acyclovir is a synthetic purine nucleoside analog that demonstrates in vitro and in vivo inhibitory activity against both herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus.[16]

Acyclovir administration may be oral or intravenous.

For limited mucocutaneous lesions, acyclovir administration can be via the oral route. In cases in which there is disseminated, visceral, or CNS involvement, the acyclovir administration should be intravenous.[11]

When taken orally, acyclovir may be taken with or without food 2 to 5 times a day for 5 to 10 days as well as up to 12 months to prevent outbreaks of genital herpes.

Intravenous administration should be done via IV infusion only, over 1 hour, at a constant rate to prevent renal damage. Medication should be in a diluted D5W solution or 0.9% NaCl to a final concentration of less than or equal to 7 mg/mL.

The following is a non-exhaustive list of dosing regimens:

• HSV encephalitis - 10 mg/kg IV every 8 hours for 21 days; use ideal body weight for obese patients
• Genital HSV (immunocompetent patients):
  • Mild or moderate infection, initial episode - 400 mg orally three times daily for 7 to 10 days
  • Severe infection, first episode - 5 to 10 mg/kg IV every 8 hours for 10 days; use ideal body weight for obese patients
  • Recurring infection - 400 mg orally three times a day for 5 days. May also use 800 mg orally twice daily for 5 days 
• Genital HSV (immunocompromised patients):
  • Initial episode - 400 mg orally three times daily for 5 to 10 days
  • Recurring infection - 400 mg orally three times a day for 5 days. May also use 800 mg orally twice daily for 5 days
• Varicella-zoster - chickenpox:
  • Immunocompetent patients - 800 mg orally four to five times a day for 5 to 7 days
  • Immunocompromised patients - 800 mg orally 5 days daily for 7 days
• Varicella-zoster - shingles:
  • Immunocompetent patients - 800 mg orally five times a day for 7 days
  • Immunocompromised patients - 10 mg/kg IV every 8 hours for 7 days; use ideal body weight for obese patients

Most commonly, patients experience malaise.

Less commonly, patients experience inflammation or phlebitis at the infusion site, nausea, vomiting, transaminitis, and rash (including Steven-Johnson syndrome) when taken intravenously. Rotating infusion sites and decreasing final infusion concentration less than 10 mg/mL can help prevent inflammation/phlebitis at the infusion site.[17][18] Patients also may experience nausea, vomiting, diarrhea, headache when taken orally.

Least commonly, patients experience abdominal pain, aggression/confusion, agitation, alopecia, anaphylaxis, anemia, angioedema, anorexia, ataxia, coma, disseminated intravascular coagulation (DIC), dizziness, and fatigue.

In certain pediatric patients, acyclovir has been shown to decrease hemoglobin concentrations and the absolute neutrophil count.

The only absolute contraindication to acyclovir is hypersensitivity.

Cautions include renal failure/impairment, immunocompromised host, potential risk of thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS)).

Regarding pregnancy and lactation, acyclovir has been shown to cross the placenta. Acyclovir's manufacturer recommends caution with use during pregnancy as well as only using it when necessary and indicated, as there have only been a few studies conducted. Specifically, cases of HSV hepatitis have received treatment during pregnancy. Although rare, this condition can become disseminated and fatal in pregnant patients. Although all 56 patients studied had transaminitis, only 18.2% had a vesicular rash. For patients that were treated with acyclovir empirically, it conferred no risks to the fetus.[19] Acyclovir also has been shown to enter breast milk but is generally considered compatible with breastfeeding.[20]