Acyclovir vs. valacyclovir: Differences, similarities, and which is better for you

In this article:

• Main differences
• Conditions treated
• Efficacy
• Insurance coverage and cost
• Side effects
• Interactions
• Warnings
• FAQs

In this article

• Main differences
• Conditions treated
• Efficacy
• Insurance coverage and cost
• Side effects
• Interactions
• Warnings
• FAQs

Herpes simplex virus (HSV) is a viral infection that lasts a lifetime. It can greatly impact your quality of life, leading to cold sores, genital lesions, and dangerous eye infections. HSV is a virus that can remain latent or inactive for a long period of time, but then symptoms can reoccur suddenly and become problematic. 

There are two primary types of herpes simplex viruses, HSV-1 and HSV-2. HSV-1 is primarily responsible for oral cold sore lesions. HSV-2 is primarily responsible for genital and rectal lesions. HSV is contagious and affects a large portion of our population. The World Health Organization (WHO) estimates that for those under 50 years of age, HSV-1 affects about 64% of the global population, and HSV-2 affects about 13% of the global population. Acyclovir and valacyclovir are prescription antiviral medications that symptomatically treat HSV infections and prevent their spread to others.

What are the main differences between acyclovir and valacyclovir?

Acyclovir (Zovirax) is a prescription medication used to treat herpes simplex virus and varicella zoster virus (VZV). It belongs to a class of antiviral drugs known as nucleoside and nucleotide DNA polymerase inhibitor antivirals. Acyclovir fights viral infections by incorporating itself into the viral DNA and prohibiting viral DNA synthesis. Acyclovir is available in a variety of forms, including a topical cream and ointment, ophthalmic ointment, solution for injection, oral capsule, oral tablet, buccal tablet, and oral suspension. The oral acyclovir formulation has poor bioavailability because it is altered in first-pass metabolism, resulting in poor absorption from the gastrointestinal tract.

Valacyclovir (Valtrex) is also a prescription antiviral medication indicated for the treatment of HSV and VZV. Valacyclovir is the L-valyl ester of acyclovir. More simply put, it is considered the prodrug of acyclovir. First-pass metabolism removes most of the acyclovir from circulation, which is why the oral bioavailability of acyclovir is so low. In contrast, first-pass metabolism converts valacyclovir to acyclovir, which is then available to the body. The oral bioavailability of acyclovir is only 10-20%, while the oral bioavailability of valacyclovir is as high as 54%. The process of first-pass metabolism also creates differences in how often these drugs must be dosed. Acyclovir must be dosed three to five times daily, depending on the indication, and valacyclovir is typically once or twice daily, depending on the indication. Valacyclovir is only available as oral tablets in 500 mg and 1,000 mg strengths.

Conditions treated by acyclovir and valacyclovir

Acyclovir and valacyclovir are indicated for the treatment of HSV-1, HSV-2, and VZV. The most common viruses are cold sores, genital herpes, chickenpox, and shingles. These drugs also play an important role in the prophylaxis of these types of infections, such as recurrent genital herpes.

Acyclovir and valacyclovir are used off-label to prevent cytomegalovirus and treat ocular infections related to shingles. Off-label use refers to treating an indication not approved by the Food and Drug Administration (FDA).

Is acyclovir or valacyclovir more effective?

Acyclovir and valacyclovir were compared in treating the first episodes of genital herpes infections in an international, double-blind, randomized trial. Acyclovir was dosed five times daily, and valacyclovir was dosed only twice daily. It found no clinically significant difference in the lesion healing time, duration of pain, or time to loss of all symptoms. Given that, valacyclovir offers the advantage of a more convenient dosing regimen. This decreases the pill burden and increases the likelihood that patients will take the regimen as prescribed until completion. Your healthcare provider will determine what is best to treat genital herpes infection, but twice-daily valacyclovir dosing may offer an advantage.

In another randomized, double-blind clinical trial, acyclovir and valacyclovir oral tablet doses were compared for the treatment of a herpes zoster virus infection, otherwise known as shingles. This study showed that valacyclovir significantly accelerated the resolution of pain associated with a shingles rash. While the rash resolved at similar times with either treatment regimen, there were fewer ocular complications in those treated with valacyclovir. Another significant advantage of valacyclovir in this study is that it only needed to be dosed three times per day instead of five times per day for acyclovir. Ultimately, your prescriber can help determine which treatment option is best for you with an active herpes zoster infection.

Insurance coverage and cost comparison of acyclovir vs. valacyclovir

Acyclovir is a prescription medication covered by commercial and Medicare prescription insurance plans. The out-of-pocket price for acyclovir can be almost $100, but with a coupon from SingleCare, you could pay less than $10 at participating pharmacies.

 Valacyclovir is a prescription medication covered by commercial and Medicare drug insurance plans. The out-of-pocket price of one prescription can be more than $200. However, with a coupon from SingleCare, you could obtain valacyclovir for about $7.

Common side effects of acyclovir vs. valacyclovir

The manufacturer literature lists potential side effects for acyclovir and valacyclovir by indication and dosing. Dosing is dependent upon the type of viral infection being treated. Overall, post-marketing data is not provided by specific indications and does not give incidence rates. Given the chemical relationship and similarities of the drugs, the side effects are similar, as might be expected. Gastrointestinal effects, such as abdominal pain, nausea, vomiting, and diarrhea, can occur with either drug. A more serious concern is that both drugs have been linked to renal failure and an increase in liver (hepatic) enzymes. It is advised that a patient’s kidney and liver function statuses are assessed prior to initiating therapy with either drug. The following list is not intended to be a comprehensive list of side effects. Please consult your pharmacist or other healthcare professional for a more comprehensive list of adverse events.

Sources: DailyMed (Acyclovir); Dailymed (Valacyclovir)

Drug interactions of acyclovir vs. valacyclovir

Acyclovir and valacyclovir are known to have negative effects on both the kidneys and the liver. For this reason, both drugs may be dangerous to take with drugs that are also nephrotoxic or hepatotoxic. In some cases, the risk is so severe that the concurrent use of these drugs is contraindicated. This is the case with cidofovir. Other drugs are strongly discouraged from being used concomitantly with acyclovir or valacyclovir for the same concerns. These include capreomycin, foscarnet, and mannitol.

Vaccinations against varicella (chickenpox) and zoster (shingles) have significantly decreased outbreaks of these viruses. However, the administration of live attenuated vaccines depends on the body’s immune system and natural response to the vaccine to produce antibodies to be effective. Therefore, acyclovir and valacyclovir should not be taken within a specific window before and after getting these vaccines. Your healthcare provider can provide more specific information prior to your vaccine.

This is not intended to be a comprehensive list of all potential drug interactions. Please ask your doctor or pharmacist for more information and be sure they know all prescription drugs and supplements you are taking prior to beginning antiviral therapy.

Warnings of acyclovir and valacyclovir

Both acyclovir and valacyclovir are contraindicated in patients with a history of hypersensitivity to either drug. Caution should also be used if a patient has had a previous reaction to famciclovir, ganciclovir, penciclovir, or valganciclovir, as there is a chance for cross-sensitivity between these drugs. 

Acyclovir and valacyclovir should also be used cautiously in patients with renal dysfunction. Dose adjustments may be necessary to avoid central nervous system (CNS) toxicity. Signs of CNS toxicity include agitations, hallucinations, confusion, and delirium, which are more likely in the elderly. Good hydration is necessary to avoid precipitation of the drugs in the kidney tubules, which could lead to kidney damage.

Frequently asked questions about acyclovir vs. valacyclovir

Are acyclovir and valacyclovir the same?

Acyclovir and valacyclovir are closely related chemically but are not the same drug. Valacyclovir is the prodrug of acyclovir. During first-pass metabolism of the oral dosage form, valacyclovir is converted to acyclovir, allowing more active ingredients to be absorbed from oral administration and more time between doses.

Is acyclovir or valacyclovir better?

Acyclovir and valacyclovir are effective treatments for viral infections arising from the herpes simplex and varicella zoster virus strains. The most clinically significant difference between them may be seen when treating shingles, as valacyclovir leads to a shorter duration of pain and fewer complications related to the eyes. An important consideration when choosing between the two treatments is that valacyclovir is dosed fewer times per day than acyclovir, which decreases the pill burden for patients and may be easier to manage and remain compliant with treatment regimens.

Can I use acyclovir or valacyclovir while pregnant?

The acyclovir and valacyclovir pregnancy registries have followed outcomes for fetuses exposed to these drugs in utero. There have been no drug-associated risks of major birth defects in pregnant women. There is insufficient data for a link to miscarriages. There are, however, known risks to untreated HSV infections during pregnancy. Primary herpes infections during the first trimester can cause neonatal chorioretinitis, microcephaly, and skin lesions.

Can I use acyclovir or valacyclovir with alcohol?

While there is no contraindication to drinking alcohol while on acyclovir and valacyclovir, caution should be used because alcohol is processed by the liver, and acyclovir and valacyclovir have the risk of also having a negative effect on the liver. Additionally, alcohol can weaken the immune system and might make it harder to treat a viral infection.

Which is better for shingles: acyclovir or valacyclovir?

A randomized, double-blind, controlled clinical trial found that valacyclovir resolves pain symptoms associated with a shingles outbreak faster than acyclovir. Treatment with valacyclovir was also linked to fewer ocular complications from shingles, which can be damaging and difficult to treat.

What happens if you take acyclovir and valacyclovir together?

Taking acyclovir and valacyclovir together can lead to higher concentrations of acyclovir, the active form of both drugs, in the body and further increase the risk of renal toxicity and hepatotoxicity. Liver function may become impaired, and drug precipitate may form in the tubules of the kidneys. Permanent damage could be done to both organs.