What are the recommended oral dosing regimens of valacyclovir, famciclovir, and acyclovir for herpes simplex virus infections (primary, recurrent, and suppressive therapy) and varicella‑zoster in immunocompetent adults, and how should these doses be adjusted for impaired renal function?

Herpes Antiviral Dosing for Immunocompetent Adults

Herpes Simplex Virus (HSV) Infections

Primary Genital Herpes

For first-episode genital herpes, initiate acyclovir 400 mg orally three times daily for 7–10 days, or valacyclovir 1 g twice daily for 10 days. 1

• Both regimens achieve comparable clinical outcomes in controlling initial infection 1
• Treatment should begin as soon as the diagnosis is suspected, without waiting for laboratory confirmation 1

Recurrent Genital Herpes (Episodic Treatment)

Valacyclovir 500 mg twice daily for 5 days is the preferred episodic regimen, offering equivalent efficacy to acyclovir with superior convenience. 2

Alternative episodic regimens include:

• Acyclovir 400 mg orally five times daily for 5 days 1
• Famciclovir 1500 mg as a single oral dose 1

Treatment must be initiated during the prodromal phase or within 24 hours of lesion onset to achieve maximal benefit, as peak viral titers occur in the first 24 hours. 1

Suppressive Therapy for Recurrent Genital Herpes

For patients with ≥6 recurrences per year, daily suppressive therapy reduces outbreak frequency by ≥75%. 1, 3

Recommended suppressive regimens:

• Valacyclovir 500 mg once daily for patients with <10 recurrences per year 3
• Valacyclovir 1000 mg once daily for patients with ≥10 recurrences per year (500 mg once daily is less effective in this population) 3
• Acyclovir 400 mg twice daily (documented safety for up to 6 years of continuous use) 3
• Famciclovir 250 mg twice daily (documented safety for 1 year) 1, 3

After 1 year of continuous suppressive therapy, discuss discontinuation to reassess recurrence frequency, as outbreak rates often decline over time. 3

Herpes Labialis (Cold Sores)

Episodic Treatment

Valacyclovir 2 g twice daily for 1 day (doses separated by 12 hours) is the first-line treatment, reducing median episode duration by approximately 1 day compared to placebo. 1

Alternative episodic regimens:

• Famciclovir 1500 mg as a single oral dose 1
• Acyclovir 400 mg five times daily for 5 days (requires more frequent dosing, may reduce adherence) 1

Treatment must begin during prodromal symptoms (tingling, burning, itching) or within 24 hours of lesion appearance for optimal efficacy. 1

Suppressive Therapy for Recurrent Cold Sores

For patients with ≥6 recurrences per year, consider daily suppressive therapy:

• Valacyclovir 500 mg once daily (can increase to 1000 mg once daily for very frequent recurrences) 1
• Famciclovir 250 mg twice daily 1
• Acyclovir 400 mg twice daily 1

Severe Oral HSV (Gingivostomatitis)

For mild symptomatic gingivostomatitis, acyclovir 20 mg/kg (maximum 400 mg/dose) orally three times daily for 5–10 days is recommended. 1

For moderate to severe gingivostomatitis requiring hospitalization, initiate acyclovir 5–10 mg/kg IV three times daily until lesions begin to regress, then switch to oral acyclovir and continue until complete healing. 1

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Varicella-Zoster Virus (VZV) Infections

Herpes Zoster (Shingles)

For immunocompetent patients with herpes zoster, valacyclovir 1000 mg every 8 hours for 7 days is the preferred regimen. 4, 5

Alternative regimens with comparable efficacy:

• Famciclovir 500 mg three times daily for 7 days 4, 6
• Acyclovir 800 mg five times daily for 7 days 4, 7

Valacyclovir demonstrates superior efficacy over acyclovir in reducing the duration of zoster-associated pain and postherpetic neuralgia, despite similar efficacy for cutaneous lesion healing. 7

Treatment should ideally begin within 72 hours of rash onset, though observational data suggest benefit even when initiated later. 7

Herpes Zoster Ophthalmicus

Use the same dosing as for herpes zoster: valacyclovir 1000 mg every 8 hours for 7 days, famciclovir 500 mg three times daily for 7 days, or acyclovir 800 mg five times daily for 7 days. 4, 7

Severe VZV Disease (Acute Retinal Necrosis)

Initiate acyclovir 10 mg/kg IV three times daily for 10–14 days, followed by valacyclovir 1000 mg three times daily for 4–6 weeks. 5

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Renal Dose Adjustments

All three antivirals require dose adjustment in renal impairment; failure to adjust doses can lead to neurotoxicity and nephrotoxicity. 4, 5

Valacyclovir Renal Adjustments

• CrCl 30–49 mL/min: No reduction needed for suppressive therapy (500 mg daily) 3
• CrCl <30 mL/min: Mandatory dose reduction based on creatinine clearance 5
• Advise adequate hydration to minimize nephrotoxicity risk 3

General Renal Impairment Guidance

The National Kidney Foundation mandates dose adjustment for valacyclovir based on creatinine clearance in patients with impaired renal function. 5

For patients with severe renal impairment who cannot tolerate adjusted oral dosing, IV acyclovir with appropriate dose reduction may be necessary. 5

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Critical Clinical Considerations

Antiviral Resistance

Acyclovir resistance remains rare in immunocompetent patients (<0.5%), but rises to approximately 7% in immunocompromised individuals. 1

All acyclovir-resistant strains are cross-resistant to valacyclovir and famciclovir. 3

For confirmed acyclovir-resistant HSV, IV foscarnet 40 mg/kg every 8 hours until clinical resolution is the treatment of choice. 1, 3

Transmission Risk and Viral Shedding

Suppressive therapy reduces but does not eliminate asymptomatic viral shedding; transmission risk persists even during treatment. 1, 3

Patients remain contagious until all lesions are fully crusted. 1

Counsel patients to avoid direct contact (kissing, sexual activity) during active lesions or prodromal symptoms, and to use barrier protection with uninfected partners. 3

Common Pitfalls to Avoid

• Starting treatment after the first 24 hours markedly reduces efficacy 1
• Relying on topical antivirals, which provide only modest benefit and are substantially less effective than oral therapy 1
• Using once-daily valacyclovir 500 mg in patients with ≥10 recurrences per year (inadequate dosing) 3
• Failing to adjust doses in renal impairment, risking neurotoxicity 5
• Not counseling patients that suppressive therapy does not eliminate transmission risk 3

Tolerability

All three oral antivirals are well-tolerated, with headache (<10%), nausea (<4%), and diarrhea being the most common adverse events, typically mild to moderate in intensity. 1

High-dose valacyclovir (8 g/day) has been associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in immunocompromised patients, but this has not been reported at standard HSV suppression doses. 3, 8