What is the first‑line therapy for primary or recurrent genital or oral herpes simplex virus lesions in an otherwise healthy adult?

Treatment for Herpetic Lesions

First-Line Therapy for Otherwise Healthy Adults

For both genital and oral herpes simplex virus infections in immunocompetent adults, oral valacyclovir or acyclovir initiated within 24 hours of symptom onset represents the standard of care. 1, 2, 3

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Primary (Initial) Episode Treatment

Genital Herpes

• Valacyclovir 1 g orally twice daily for 7-10 days is the CDC-recommended first-line treatment for initial genital HSV infection 1
• Acyclovir 400 mg orally three times daily for 7-10 days serves as an effective alternative 1
• Treatment may be extended beyond 10 days if healing remains incomplete 1
• Therapy initiated more than 72 hours after symptom onset has not been proven effective 4

Oral Herpes (HSV-1)

• Valacyclovir 1 g orally twice daily for 7-10 days is recommended for initial HSV-1 infection 1
• Acyclovir 400 mg orally three times daily for 7-10 days is an alternative regimen 1
• Extension beyond 10 days may be necessary for incomplete healing 1

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Recurrent Episode Treatment (Episodic Therapy)

Critical Timing Principle

Treatment must be initiated during the prodrome or within 24 hours of lesion onset to achieve maximum efficacy. 1, 2, 3 Delaying treatment beyond 72 hours significantly reduces effectiveness and should be avoided 1, 3

Genital Herpes Recurrences

• Valacyclovir 500 mg orally twice daily for 5 days (CDC first-line recommendation) 2
• Alternative regimens include:
  • Acyclovir 400 mg orally three times daily for 5 days 2
  • Acyclovir 800 mg orally twice daily for 5 days 2
  • Famciclovir 125 mg orally twice daily for 5 days 2

Oral Herpes Recurrences (Cold Sores)

• Valacyclovir 500 mg orally twice daily for 5 days initiated at first sign of outbreak 1, 3
• Alternative regimens:
  • Acyclovir 400 mg orally three times daily for 5 days 1
  • Famciclovir 125 mg orally twice daily for 5 days 1

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Suppressive Therapy for Frequent Recurrences

Indications

Daily suppressive therapy should be considered for patients experiencing ≥6 recurrences per year, which reduces recurrence frequency by ≥75%. 1, 2, 3

Genital Herpes Suppression

• Valacyclovir 500 mg orally once daily (may be less effective with ≥10 episodes/year) 1, 2
• Valacyclovir 1 g orally once daily for more frequent recurrences 2
• Alternative: Acyclovir 400 mg orally twice daily 2
• Alternative: Famciclovir 250 mg orally twice daily 2

Oral Herpes Suppression

• Valacyclovir 500 mg orally once daily 1
• Valacyclovir 250 mg orally twice daily 1
• Alternative: Acyclovir 400 mg orally twice daily 1

Long-Term Safety

• Continuous acyclovir suppression has been documented as safe for up to 6 years of uninterrupted use 1, 2
• Valacyclovir suppression is documented as safe for up to 1 year 2
• After 1 year of suppressive therapy, consider discontinuation to reassess recurrence frequency, as episodes often decrease over time 1, 2

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Severe or Complicated Infections

HIV-Infected Patients

• Oral valacyclovir, famciclovir, or acyclovir for 5-10 days for orolabial lesions 5
• Oral therapy for 5-14 days for genital HSV 5
• Short-course therapy (1-3 days) should NOT be used in HIV-infected patients 5
• Severe mucocutaneous lesions require initial IV acyclovir with transition to oral therapy once lesions begin to regress 5

Treatment Failure and Resistance

• Suspect acyclovir resistance if lesions do not begin to resolve within 7-10 days of therapy 5, 2
• Obtain viral culture and susceptibility testing to confirm resistance 5
• IV foscarnet 40 mg/kg every 8 hours is the treatment of choice for acyclovir-resistant HSV 5, 2
• Resistance in immunocompetent patients remains extremely rare (<0.5%) even after prolonged use 1

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Critical Pitfalls to Avoid

• Never use topical acyclovir alone—it is substantially less effective than systemic therapy 1, 2, 3
• Do not delay treatment beyond 24 hours for recurrent episodes or beyond 72 hours for initial episodes 1, 2, 3, 4
• Avoid valacyclovir 8 g/day—associated with hemolytic uremic syndrome/thrombotic thrombocytopenic purpura in immunocompromised patients 2
• Do not use short-course (1-3 day) regimens in HIV-infected patients 5

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Patient Counseling Essentials

• HSV is a chronic, incurable infection with potential for lifelong recurrence 1, 2, 3
• Asymptomatic viral shedding can occur, allowing transmission even without visible lesions 1, 2
• Patients should abstain from sexual activity when lesions or prodromal symptoms are present 1, 2
• Consistent condom use reduces but does not eliminate transmission risk 5, 1
• Patients should receive a prescription for antiviral medication to self-initiate at the first sign of recurrence 1
• Suppressive therapy lowers but does not eliminate asymptomatic shedding and transmission risk 1