What is the recommended first‑line oral antiviral treatment and dosing for symptomatic herpes simplex virus infection in an immunocompetent adult, and when should suppressive therapy be initiated?

First-Line Oral Antiviral Treatment for Herpes Simplex Virus Infection

For symptomatic HSV infection in immunocompetent adults, valacyclovir 1 g orally twice daily for 7–10 days is the recommended first-line treatment, with suppressive therapy initiated when patients experience ≥6 recurrences per year. 1

Initial Episode Treatment

• Valacyclovir 1 g orally twice daily for 7–10 days is the CDC-recommended first-line regimen for initial HSV-1 or HSV-2 infection 1
• Acyclovir 400 mg orally three times daily for 7–10 days is an effective alternative with the longest documented safety record 1
• Famciclovir 250 mg orally twice daily for 7–10 days offers comparable efficacy with more convenient dosing than acyclovir 2
• Treatment may be extended beyond 10 days if healing remains incomplete or new lesions continue to form 1

Critical Timing Principle

• Antiviral therapy is most effective when initiated during the prodromal period or within 24 hours of lesion onset, as peak viral replication occurs in the first 24 hours 1
• Delaying treatment beyond 72 hours significantly reduces effectiveness 1

Recurrent Episode Treatment (Episodic Therapy)

• Valacyclovir 500 mg orally twice daily for 5 days is the preferred episodic regimen for recurrent HSV 1
• Acyclovir 400 mg orally three times daily for 5 days is an alternative option 1
• Famciclovir 125 mg orally twice daily for 5 days is also effective 1
• For herpes labialis specifically, famciclovir 1500 mg as a single dose is FDA-approved and reduces healing time by approximately 1.3 days compared to placebo 2
• For genital herpes recurrences, famciclovir 1000 mg twice daily for 1 day is FDA-approved when initiated within 6 hours of symptom onset 2

Patient Self-Management Strategy

• Patients should receive a prescription for antiviral medication to self-initiate at the first sign of recurrence 1
• Treatment initiated during the prodrome or within the first 24 hours provides maximum benefit 1

Suppressive Therapy Indications and Regimens

Suppressive therapy should be initiated when patients experience ≥6 recurrences per year, as it reduces recurrence frequency by ≥75%. 1, 3

Recommended Suppressive Regimens

• Valacyclovir 500 mg orally once daily for patients with <10 recurrences per year 3, 4
• Valacyclovir 1 g orally once daily for patients with ≥10 recurrences per year (the 500 mg dose is less effective in this high-frequency group) 3
• Acyclovir 400 mg orally twice daily has the longest documented safety record, with efficacy maintained for up to 6 years of continuous use 3
• Famciclovir 250 mg orally twice daily is an acceptable alternative 3, 2

Reassessment and Duration

• After one year of continuous suppressive therapy, treatment should be temporarily discontinued to reassess the patient's recurrence rate, as episode frequency often decreases naturally over time 3
• Acyclovir has demonstrated safety for up to 6 years of uninterrupted use 3, 5
• Suppressive therapy has not been associated with clinically significant acyclovir resistance in immunocompetent patients 3

Critical Pitfalls to Avoid

• Do not use topical acyclovir alone—it is substantially less effective than systemic treatment and does not address systemic symptoms 1, 6
• Do not use valacyclovir 500 mg once daily in patients with ≥10 recurrences per year; the 1 g dose is required 3
• Do not continue suppressive therapy indefinitely without periodic reassessment, as recurrence frequency often decreases over time 3
• Avoid delaying episodic treatment beyond 72 hours, as effectiveness diminishes significantly 1

Transmission Counseling

• Suppressive therapy reduces but does not eliminate asymptomatic viral shedding, so transmission risk persists even while on therapy 3
• Patients should abstain from sexual activity when lesions or prodromal symptoms are present 1
• Asymptomatic viral shedding occurs less frequently with HSV-1 than HSV-2, but transmission can still occur during asymptomatic periods 1
• All sexual partners should be informed about the HSV infection and counseled on transmission risks 1

Comparative Effectiveness

• Valacyclovir and famciclovir offer more convenient dosing schedules than acyclovir (once or twice daily versus three to five times daily), which may improve long-term adherence 1, 7, 8
• All three agents demonstrate comparable clinical efficacy when dosed appropriately 1, 7
• Valacyclovir achieves higher serum acyclovir concentrations than oral acyclovir due to superior bioavailability 7, 8