Acyclovir
Brand names: Zovirax · Sitavig (buccal tablet for cold sores) · Generic widely available
What Is Acyclovir?
Acyclovir (also spelled aciclovir outside the United States) is a nucleoside analogue antiviral — a synthetic compound that mimics a building block of DNA in a way that disrupts viral replication. It was first approved by the FDA in 1982 and remains one of the most widely used antiviral drugs in the world, available in oral tablets, topical cream and ointment, intravenous infusion for serious infections, and as a buccal tablet (Sitavig) that dissolves against the gum for cold sore treatment. Generic versions are widely available and inexpensive.
Acyclovir is active against several members of the herpesvirus family: herpes simplex virus type 1 (HSV-1, which causes cold sores and some genital infections), herpes simplex virus type 2 (HSV-2, the primary cause of genital herpes), varicella-zoster virus (VZV, which causes chickenpox and shingles), and Epstein-Barr virus (EBV, though less effectively). It is not effective against cytomegalovirus (CMV), for which other antivirals such as ganciclovir are used. A closely related prodrug, valacyclovir (Valtrex), is converted to acyclovir in the body and offers better oral bioavailability.
What Is Acyclovir Used For?
Acyclovir treats a range of herpesvirus infections at varying degrees of severity, from mild cold sores to life-threatening encephalitis. The choice of formulation — topical, oral, or intravenous — depends on the infection type and its severity.
- Genital herpes (HSV-2): Shortens the duration and reduces the severity of initial and recurrent outbreaks; can be used as daily suppressive therapy to reduce outbreak frequency and transmission risk
- Oral herpes / cold sores (HSV-1): Oral or topical acyclovir accelerates healing; the Sitavig buccal tablet is applied directly to the affected area
- Chickenpox (varicella): Most beneficial when started early; reduces duration and severity of the rash and systemic symptoms
- Shingles (herpes zoster): Reduces pain, speeds healing, and may help prevent postherpetic neuralgia (chronic nerve pain following shingles) when started promptly
- Herpes encephalitis: Life-threatening brain infection requiring intravenous acyclovir; early treatment is critical for reducing mortality and neurological damage
- Herpes in immunocompromised patients: Prophylaxis and treatment of herpes infections in cancer patients, transplant recipients, and HIV-positive individuals, who are at higher risk for severe or disseminated disease
- Neonatal herpes: Serious herpes infection in newborns treated with intravenous acyclovir
How Does Acyclovir Work?
Acyclovir is a prodrug that requires activation inside infected cells to become effective. The key to its selectivity and safety lies in the first step of this activation: acyclovir is phosphorylated (converted to acyclovir monophosphate) by viral thymidine kinase — an enzyme that is present in herpes virus-infected cells but not in healthy human cells. This means the activation step occurs almost exclusively where the drug is needed, sparing normal tissues from the active compound.
Once activated by viral thymidine kinase, human cellular enzymes complete the conversion to acyclovir triphosphate, the active form. Acyclovir triphosphate works in two ways: it competitively inhibits the viral DNA polymerase enzyme (blocking it from building new viral DNA), and it is itself incorporated into the growing viral DNA chain — but because acyclovir lacks the chemical group needed to attach the next nucleotide, the DNA chain terminates right there. The result is that viral DNA replication stops completely. Acyclovir does not affect human DNA polymerases at therapeutic concentrations. Importantly, acyclovir treats active infections only — the latent virus hiding in nerve ganglia is transcriptionally silent and does not express thymidine kinase, so it is completely unaffected by acyclovir treatment.
Side Effects
Common Side Effects
- Oral: Nausea, vomiting, diarrhea, headache, dizziness, fatigue — generally mild and well tolerated
- Topical: Burning, stinging, or itching at the site of application; mild skin irritation
- IV (intravenous): Phlebitis (inflammation at the injection site); nausea; and more significant risks related to kidney and nervous system (see below)
Serious Side Effects
- Nephrotoxicity (kidney damage): Acyclovir can crystallize in the tubules of the kidneys, causing acute kidney injury (crystalluria). This risk is highest with IV administration and in patients who are dehydrated. Adequate hydration is essential during IV acyclovir therapy. Kidney function should be monitored.
- Neurotoxicity: Confusion, agitation, hallucinations, tremors, myoclonus (jerky movements), and seizures have been reported — most often in patients with renal impairment (since acyclovir is eliminated by the kidneys, impaired function leads to toxic accumulation). Symptoms typically resolve after stopping the drug.
- Thrombotic thrombocytopenic purpura / hemolytic uremic syndrome (TTP/HUS): A rare but serious blood disorder reported primarily in severely immunocompromised patients receiving high-dose IV acyclovir
- Phlebitis: IV infusion can cause inflammation and damage to the vein if the infusion is too concentrated or infused too rapidly
- Rash or allergic reaction: Seek medical attention for hives, difficulty breathing, or facial swelling
Drug Interactions
Acyclovir has a relatively limited drug interaction profile compared to many other medications. Most significant interactions relate to kidney function, since acyclovir is primarily eliminated by the kidneys and competes with other drugs for the same elimination pathways.
| Drug / Drug Class | Interaction | Clinical Significance |
|---|---|---|
| Probenecid | Probenecid blocks renal tubular secretion of acyclovir, reducing its elimination and substantially increasing acyclovir blood levels | Moderate — may increase acyclovir efficacy but also toxicity risk; monitor for signs of acyclovir toxicity |
| Nephrotoxic drugs (aminoglycosides, amphotericin B, cisplatin, cyclosporine, NSAIDs) | Additive risk of kidney damage when combined with IV acyclovir, which can already cause crystalluria and nephrotoxicity | Moderate-High — monitor kidney function carefully; ensure adequate hydration |
| Zidovudine (AZT, Retrovir) | Combined use has been reported to cause additive neurotoxicity — drowsiness, lethargy — in some HIV patients receiving both drugs | Moderate — monitor neurological status; combination may be unavoidable in HIV patients with herpes infections |
| Mycophenolate mofetil (CellCept) | Both acyclovir and mycophenolate compete for the same renal tubular secretion pathway, potentially increasing levels of both drugs | Low-Moderate — particularly relevant in transplant patients receiving both drugs; monitor renal function |
| Theophylline | Some evidence that acyclovir may increase theophylline levels, though the interaction is generally considered minor | Low — monitor theophylline levels if used concurrently; of greater concern at higher acyclovir concentrations |
Who Should Not Take Acyclovir?
- Patients with a known allergy to acyclovir or valacyclovir
- Patients with severe renal impairment — dose adjustment is required; if kidney function is severely compromised, acyclovir should be used only with careful monitoring and appropriate dose reduction to prevent toxic accumulation
- Patients who are dehydrated at the start of IV therapy — hydration must be ensured before and during IV acyclovir to prevent crystalluria
- Extreme caution in patients with neurological disorders or those taking other drugs that affect the nervous system when using IV acyclovir — monitor for signs of neurotoxicity
- Topical acyclovir should not be applied to the eyes (ophthalmic preparations are available separately for ocular herpes)
Frequently Asked Questions
Does acyclovir cure herpes?
No. Acyclovir treats active outbreaks of herpes by blocking viral replication, but it does not eliminate the herpes virus from the body. After a primary herpes infection, the virus travels to nerve ganglia — clusters of nerve cells near the spinal cord — where it establishes a permanent latent infection. In this dormant state, the virus does not replicate, does not express the thymidine kinase enzyme needed to activate acyclovir, and is completely unaffected by the drug. The virus can reactivate at any time to cause future outbreaks. No currently available medication can cure herpes or eliminate latent viral reservoirs.
Why is acyclovir safe for human cells but harmful to herpes viruses?
The key is the first activation step. To become active, acyclovir must be converted by an enzyme called thymidine kinase. Human cells contain a version of thymidine kinase, but it has very poor activity on acyclovir. Herpes viruses, however, encode their own viral thymidine kinase that is highly efficient at phosphorylating acyclovir. This means acyclovir is selectively activated primarily in virus-infected cells, where viral thymidine kinase is present — not in healthy surrounding tissue. This elegant selectivity is why acyclovir is generally well-tolerated at therapeutic levels while being effective against the virus.
What is the difference between acyclovir and valacyclovir?
Valacyclovir (Valtrex) is a prodrug of acyclovir — it is converted to acyclovir in the body after absorption. The key advantage of valacyclovir is dramatically better oral bioavailability: only about 10–20% of oral acyclovir is absorbed from the gut, while valacyclovir achieves 3–5 times higher blood levels of acyclovir after conversion. This allows valacyclovir to be taken less frequently than acyclovir for most indications. Both drugs produce the same active compound (acyclovir) in the body and have equivalent efficacy; the choice depends on cost, convenience, and clinical indication.
Why is hydration so important with IV acyclovir?
Intravenous acyclovir can crystallize inside the tiny tubules of the kidneys — a process called crystalluria — when the concentration in the urine becomes too high. These crystals can block urine flow through the tubules and cause acute kidney injury. Dehydration worsens this risk by concentrating the drug in the urine. To prevent crystalluria, patients receiving IV acyclovir must be well-hydrated before and throughout treatment, the infusion must be given over at least one hour (not rapidly), and kidney function should be monitored regularly. Patients on oral acyclovir at standard amounts face much lower but not zero risk and should also maintain adequate fluid intake.