Acyclovir Versus Valacyclovir – What’s the Difference?

When treating herpes simplex virus (HSV) or varicella-zoster virus (VZV), two antiviral agents commonly used are acyclovir and valacyclovir. While both medications are effective, understanding their pharmacokinetic profiles, dosage forms, and clinical uses can help healthcare providers make the best choice for each patient. In this blog post, I will highlight the most important differences when comparing acyclovir versus valacyclovir.

Oral Bioavailability and Patient Adherence

Acyclovir was the first of the two drugs to be developed and has long been a mainstay in antiviral therapy. Valacyclovir, on the other hand, is a prodrug of acyclovir—meaning it is converted to acyclovir in the body. Valacyclovir has an oral bioavailability of approximately 55%, compared to only about 10–20% for oral acyclovir. This is a big advantage for patient adherence. As a result, valacyclovir can be dosed less frequently and still adequately treat a viral infection.

Dosing varies depending on the indication and severity of the infection. For an initial HSV outbreak, acyclovir is typically dosed at 400 mg three times daily or 200 mg five times daily for 7 to 10 days, whereas valacyclovir is dosed at 1 g twice daily for the same duration. For recurrent HSV episodes, shorter regimens are often used—acyclovir at 400 mg three times daily for five days or valacyclovir at 500 mg twice daily for three days.

Dosage Form Availability – Acyclovir Versus Valacyclovir

When it comes to dosage forms, acyclovir offers greater flexibility. It is available as oral tablets, capsules, an oral suspension, and as an intravenous formulation. Valacyclovir, in contrast, is only available orally in 500 mg and 1 g tablet strengths. This makes acyclovir the preferred agent in hospitalized or immunocompromised patients who require IV therapy or for patients who cannot take tablets but can tolerate a liquid formulation. When treating pediatric patients or adults who have difficulty swallowing, the availability of an acyclovir suspension makes it the more versatile option.

Renal Accumulation and Toxicity

Both medications are eliminated primarily through the kidneys. However, dose adjustments are necessary in patients with renal impairment to prevent accumulation and potential neurotoxicity (important nugget to remember for board exams). The neurotoxicity risk will typically be greater with IV acyclovir because higher doses will typically be utilized to treat serious infections. I had a possible case of neurotoxicity donated to the blog many years ago. It was a good one – check it out here!

Summary – Acyclovir Versus Valacyclovir

In summary, both valacyclovir and acyclovir are effective antivirals with overlapping uses but distinct advantages. Valacyclovir offers improved bioavailability and convenience, making it ideal for most outpatient scenarios. Acyclovir, meanwhile, remains valuable for its lower cost, broader formulation options, and role in inpatient care. Understanding these differences helps clinicians tailor antiviral therapy to the individual needs of each patient.

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