What are the recommended treatment regimens and dosing for herpes simplex virus infection in otherwise healthy adults, including genital and oral lesions?

Treatment of Herpes Simplex Virus Infection

Oral Herpes (Herpes Labialis/Cold Sores)

Episodic Treatment for Acute Outbreaks

For acute cold sores, initiate valacyclovir 2 g twice daily for 1 day (doses separated by 12 hours) at the first sign of prodromal symptoms or within 24 hours of lesion onset. 1

Alternative first-line episodic regimens include:

• Famciclovir 1500 mg as a single dose 1, 2
• Acyclovir 400 mg five times daily for 5 days 1

Timing is critical: Peak viral titers occur within the first 24 hours after lesion appearance, making early intervention essential for blocking viral replication. 1 Treatment initiated after 24 hours shows markedly diminished efficacy with longer lesion duration and reduced symptom relief. 1

The single-day high-dose valacyclovir regimen reduces median episode duration by approximately 1 day compared to placebo and offers superior convenience and adherence compared to multi-day regimens. 1 Famciclovir's single-dose option provides comparable efficacy. 1 While acyclovir remains effective, its five-times-daily dosing reduces patient compliance. 1

Suppressive Therapy for Frequent Recurrences

For patients with six or more recurrences per year, initiate daily suppressive therapy with valacyclovir 500 mg once daily. 1

Alternative suppressive regimens:

• Famciclovir 250 mg twice daily 1
• Acyclovir 400 mg twice daily 1, 3

Daily suppressive therapy reduces recurrence frequency by ≥75% in patients with frequent outbreaks. 1 Safety and efficacy have been documented for acyclovir for up to 6 years and for valacyclovir and famciclovir for 1 year of continuous use. 1 After 1 year of suppressive therapy, consider a trial discontinuation to reassess recurrence frequency, as outbreak frequency naturally decreases over time in many patients. 1

Important caveat: Topical antivirals are ineffective for suppressive therapy because they cannot reach the site of viral reactivation in sensory ganglia. 1

Severe Oral HSV (Gingivostomatitis)

For mild symptomatic gingivostomatitis:

• Acyclovir 400 mg (or 20 mg/kg, maximum 400 mg/dose) orally three times daily for 5-10 days 1

For moderate to severe gingivostomatitis requiring hospitalization:

• 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

Genital Herpes

First Episode (Primary Infection)

For first-episode genital herpes, prescribe acyclovir 400 mg orally three times daily for 7-10 days. 1

Alternative first-episode regimens:

• Valacyclovir 1 g twice daily for 10 days 1
• Acyclovir 200 mg orally five times daily for 7-10 days 4

For herpes proctitis, increase the dose to acyclovir 400 mg orally five times daily for 10 days. 4

Systemic (oral or IV) acyclovir shortens viral shedding time, reduces time to complete healing, decreases new lesion formation, and alleviates symptoms of HSV urethritis and cervicitis more effectively than topical preparations. 5

Recurrent Episodes

For recurrent genital herpes, use episodic therapy with one of three equivalent regimens:

• Acyclovir 800 mg twice daily for 5 days 4
• Acyclovir 400 mg three times daily for 5 days 4
• Acyclovir 200 mg five times daily for 5 days 4

The higher-dose, less-frequent regimens (800 mg twice daily) improve adherence while maintaining equivalent efficacy. 4

Suppressive Therapy for Recurrent Genital Herpes

For patients with more than 5 episodes per year, severe recurrences, or unrecognizable prodromes:

• Valacyclovir 500 mg once daily 6, 7
• Famciclovir 250 mg twice daily 2
• Acyclovir 400 mg twice daily 8

Once-daily valacyclovir 500 mg prevents or delays 85% of recurrences that would occur without treatment, with 69% of patients remaining recurrence-free after 16 weeks compared to only 9.5% on placebo. 7

Special Populations

Immunocompromised Patients

Episodes in immunocompromised individuals are typically longer, more severe, and may involve extensive oral cavity involvement or facial spread. 1 These patients require higher doses or longer treatment durations. 1

Critical consideration: Acyclovir resistance rates are substantially higher in immunocompromised patients (approximately 7%) compared to immunocompetent hosts (<0.5%). 1

For HIV-infected patients with recurrent orolabial or genital herpes:

• Famciclovir 500 mg twice daily for 7 days 2

Acyclovir-Resistant HSV

For confirmed acyclovir-resistant HSV infection, administer foscarnet 40 mg/kg IV three times daily. 1 Acyclovir-resistant strains are routinely cross-resistant to ganciclovir. 8

Critical Clinical Considerations

Transmission Risk and Contagiousness

Patients remain contagious until all lesions are fully crusted. 1 Active vesicular and ulcerative lesions are highly contagious; avoid direct contact (kissing, oral sex) and sharing items that contact the mouth. 1

Important caveat: HSV can be transmitted during asymptomatic periods without visible lesions. 1 Suppressive antiviral therapy reduces but does not eliminate asymptomatic viral shedding. 8, 1 Even with optimal antiviral therapy, viral shedding persists for approximately 6.4 days with valacyclovir compared to 8.1 days without treatment. 1

Preventive Measures

Counsel patients to identify and avoid personal triggers:

• UV light exposure: Apply sunscreen (SPF ≥15) or zinc oxide to lips before sun exposure to prevent UV-triggered recurrences. 1
• Other triggers: Fever, psychological stress, and menstruation. 1

Renal Impairment

All antiviral agents require dose adjustment based on creatinine clearance in patients with renal impairment. 1, 9 Ensure adequate hydration throughout treatment to prevent acyclovir crystalluria. 4

Common Pitfalls to Avoid

• Do not rely on topical antivirals: Topical preparations provide only modest clinical benefit and are substantially less effective than oral therapy. 1
• Do not delay treatment: Efficacy decreases significantly when treatment begins after the first 24 hours of symptom onset. 1
• Do not use inadequate dosing: Short-course, high-dose therapy (e.g., valacyclovir 2 g twice in one day) is more effective than traditional longer courses with lower doses. 1
• Do not assume antivirals eradicate latent virus: Treatment does not prevent future recurrences after discontinuation. 4