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

Drug overview & main differences | Conditions treated | Efficacy | Insurance coverage and cost comparison | Side effects | Drug interactions | Warnings | FAQ

Herpes simplex virus (HSV) is a viral infection that lasts for a lifetime. It can greatly impact your quality of life as it leads 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 virus, 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 HSV-1 affects two-thirds of the global population, and HSV-2 affects over 500 million people. Acyclovir and valacyclovir are two prescription antiviral medications that have impacted our ability to symptomatically treat HSV infections and prevent their spread to others.

What are the main differences between acyclovir vs. valacyclovir

Acyclovir (Zovirax) is a prescription medication used in the treatment of herpes simplex virus and varicella-zoster virus (VZV). It belongs to a class of antiviral drugs known as synthetic purine deoxynucleoside analogues. This class is also sometimes referred to as nucleoside and nucleotide DNA polymerase inhibitor antivirals. Acyclovir fights viral infections by incorporating itself into the viral DNA and then prohibiting viral DNA synthesis. Acyclovir is available in a variety of forms including topical cream and ointment, ophthalmic ointment, solution for injection, oral capsules, oral tablets, oral dissolving tablets, 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 also indicated in 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, and this is why the oral bioavailability is so low for acyclovir. In contrast, first-pass metabolism converts valacyclovir to acyclovir which is then available to the body. The oral bioavailability when taking 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 in oral tablets in 500 mg and 1,000 mg strengths.

Main differences between acyclovir and valacyclovir

Conditions treated by acyclovir and valacyclovirt

Acyclovir and valacyclovir are indicated in the treatment of herpes simplex virus type 1 and type 2, as well as varicella-zoster virus. The most common of these types of 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 for the prevention of cytomegalovirus and treatment of ocular infections related to shingles. Off-label use refers to use for treatment in an indication not approved by the Food and Drug Administration (FDA).

Is acyclovir or valacyclovir more effective?

Acyclovir and valacyclovir were compared in the treatment of 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 twice-daily dosing. This decreases pill burden and increases the likelihood that patients will take the regimen as prescribed until completion. Your doctor will determine what is best to treat a genital herpes infection, but twice-daily dosing may offer an advantage for valacyclovir.

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

Coverage and cost comparison of acyclovir vs. valacyclovir

Acyclovir is a prescription medication that is covered by both commercial and Medicare prescription insurance plans. The out-of-pocket price for acyclovir can average more than $50, but with a coupon from SingleCare, you could pay less than $10 at participating pharmacies. 

Valacyclovir is a prescription medication that is covered by both commercial and Medicare drug insurance plans. The out-of-pocket price of valacyclovir can be more than $200 for one prescription. With a coupon from SingleCare, you could obtain valacyclovir for approximately $13.

Common side effects of Acyclovir vs. valacyclovir

The manufacturer literature lists 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 indication 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. Some of the more serious concerns are the fact 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 functions status 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.

Source: 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 with 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 depend on the body’s immune system and natural response to the vaccine to produce antibodies in order to be effective. For that reason, acyclovir and valacyclovir should not be administered within a specific window before and after administering 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. Cautions 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. These are more likely in the elderly population. Good hydration is necessary to avoid precipitation of the drugs in the tubules of the kidneys.

Frequently asked questions about Acyclovir vs. valacyclovir

What is acyclovir?

Acyclovir is a prescription antiviral medication. It belongs to a class of antiviral drugs known as synthetic purine deoxynucleoside analogues. It is prescribed to treat viral infections arising from infections with the herpes simplex virus (HSV) and varicela zoster (VZV). These may include oral cold sores, genital herpes, shingles, and chickenpox. Acyclovir is available in a topical cream and ointment, ophthalmic ointment, solution for injection, oral capsules, oral tablets, oral dissolving tablets, and oral suspension.

What is valacyclovir?

Valacyclovir is a prescription antiviral medication. It also belongs to the class of antiviral drugs known as synthetic purine deoxynucleoside analogues. Like acyclovir, it is prescribed to treat viral infections arising from infections with the herpes simplex virus (HSV) and varicela-zoster (VZV). These may include oral cold sores, genital herpes, shingles, and chickenpox. Valacyclovir is available only in oral tablets including 500 mg and 1,000 mg strengths.

Are acyclovir and valacyclovir the same?

Acyclovir and valacyclovir are closely related chemically, but they 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 also allowing more time between doses.

Is acyclovir or valacyclovir better?

Acyclovir and valacyclovir are both 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 to 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 has been no drug-associated risk 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.

Which is better for shingles: acyclovir or valacyclovir?

A randomized, double-blind, controlled clinical trial found that valacyclovir leads to the resolution of 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 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.

What should I avoid while taking valacyclovir?

It is important to avoid other drugs which have the potential for nephrotoxicity (renal toxicity) when taking valacyclovir. This includes other antivirals such as adefovir, cidofovir, and tenofovir as well as aminoglycoside antibiotics. Live vaccines against viruses like varicella (chickenpox) and zoster (shingles) should not be given while a patient is being treated with valacyclovir.