Three prescription antiviral medications are used to treat herpes: acyclovir, valacyclovir, and famciclovir. All three work against both oral herpes (HSV-1) and genital herpes (HSV-2), and none of them cure the virus. What they do is shorten outbreaks, reduce symptoms, and lower the chance of spreading herpes to a partner. For cold sores specifically, there’s also an over-the-counter topical cream called docosanol (sold as Abreva).
The Three Main Antiviral Medications
Acyclovir is the oldest of the three and has been around since the 1980s. It’s effective and inexpensive, but it needs to be taken more frequently throughout the day. For a first genital herpes outbreak, the typical regimen is 400 mg taken three times daily for 7 to 10 days. A five-times-daily dosing schedule also works but isn’t generally recommended because it’s hard to stick with.
Valacyclovir is essentially a newer form of acyclovir that your body absorbs more efficiently. The practical benefit is fewer pills per day. For a first outbreak, it’s taken as 1 gram twice daily for 7 to 10 days. It’s the most commonly prescribed option today because of its convenience.
Famciclovir works through a similar mechanism and is taken as 250 mg three times daily for 7 to 10 days during a first episode. It’s equally effective but tends to be prescribed less often, partly out of habit and partly because valacyclovir dominates the market.
All three medications can be extended beyond 10 days if sores haven’t fully healed.
How These Drugs Actually Work
These antivirals are all classified as nucleoside analogs, which means they mimic one of the building blocks the herpes virus needs to copy its DNA. Once inside an infected cell, the drug gets activated by an enzyme the virus itself produces. This is what makes these medications so targeted: uninfected cells barely activate the drug at all, so healthy tissue is largely left alone.
Once activated, the drug tricks the virus’s DNA-copying machinery into incorporating it into the growing DNA strand. But because it’s a fake building block, it terminates the strand and locks up the viral copying enzyme. The virus can’t replicate, the outbreak stalls, and your immune system cleans up the rest.
Episodic vs. Daily Suppressive Therapy
There are two main strategies for using these medications, and which one fits you depends on how often you get outbreaks.
Episodic therapy means taking medication only when an outbreak starts. You keep a prescription on hand, and at the first sign of tingling, burning, or sores, you begin a short course. The earlier you start, the shorter and milder the outbreak tends to be. This approach works well for people who get outbreaks infrequently, perhaps a few times a year or less.
Daily suppressive therapy means taking a lower dose of antiviral medication every single day, whether or not you have symptoms. This approach significantly reduces the number of outbreaks per year and also lowers viral shedding, which is when the virus is present on the skin without visible sores. Reduced shedding means a lower risk of transmitting herpes to a sexual partner. Suppressive therapy is typically recommended for people who experience six or more outbreaks per year, or for those in relationships with an uninfected partner who want to minimize transmission risk.
Over-the-Counter Options for Cold Sores
Docosanol is the only FDA-approved nonprescription antiviral for oral herpes. Sold as a cream (most commonly under the brand name Abreva), it works by blocking the virus from fusing with healthy skin cells. You apply it five times a day to the affected area until the sore heals.
The key with docosanol is timing. It works best when applied at the very first sensation of a cold sore, the tingling or burning stage before a blister appears. It won’t dramatically shorten an outbreak that’s already fully developed. It’s also only meant for use around the mouth, not on the genitals or near the eyes. Compared to prescription antivirals taken by mouth, topical treatments are generally less effective, but for occasional cold sores, docosanol can take the edge off.
Common Side Effects
For most people, these antivirals are well tolerated, especially at the doses used for herpes. The most frequently reported side effects of valacyclovir include headache, nausea, tiredness, and mood changes like irritability or feeling down. Acyclovir and famciclovir have similar profiles.
The one area that requires real attention is kidney function. All three drugs are cleared through the kidneys, and in people with existing kidney disease or reduced kidney function (which becomes more common with age), doses often need to be adjusted. Staying well hydrated while taking these medications helps your kidneys process them efficiently. Serious side effects like changes in mental alertness, difficulty breathing, or blood in the urine are rare but warrant immediate medical attention.
Long-term daily use for suppressive therapy has been studied extensively and is considered safe for most people, even over years of continuous use.
When Standard Medications Don’t Work
In rare cases, the herpes virus can develop resistance to acyclovir and its related drugs. This happens almost exclusively in people with weakened immune systems, such as organ transplant recipients or those undergoing chemotherapy. The resistance occurs when the virus stops producing the enzyme needed to activate the drug inside infected cells.
For these patients, treatment options become more limited. Foscarnet, given intravenously multiple times per day with IV fluids, is the standard second-line treatment. It works through a different mechanism that bypasses the enzyme the virus has stopped making. Cidofovir is another IV option, and a compounded topical version is sometimes applied directly to stubborn sores, though complete resolution with topical cidofovir alone happens only about 30% of the time.
A newer drug called pritelivir has shown promise in phase 3 clinical trials for these difficult-to-treat cases. It works by blocking a completely different part of the virus’s replication machinery, the helicase-primase complex, making it effective even against strains resistant to all existing antivirals. In immunocompromised patients with resistant herpes, pritelivir demonstrated better lesion healing and fewer side effects than current alternatives.