What are the treatment options for Herpes Simplex Virus (HSV) infections?

HSV Diagnosis and Treatment

Diagnosis

For suspected HSV infection, obtain viral culture from active lesions or use type-specific serologic testing when available, though most commercially available antibody tests do not accurately discriminate between HSV-1 and HSV-2. 1

Clinical Diagnosis

• Most HSV-2 infections are diagnosed clinically based on characteristic vesicular or ulcerative genital lesions 1
• Many infected persons never recognize signs of genital herpes, and some have symptoms only after initial infection 1
• Asymptomatic viral shedding occurs, meaning transmission can happen without visible lesions 2

Laboratory Confirmation

• Viral culture should be obtained from suspected lesions, particularly when considering acyclovir resistance (if lesions persist beyond 7-10 days of treatment) 1, 2
• Susceptibility testing should be performed if virus is isolated and resistance is suspected 1
• Type-specific serologic assays may become useful for future intervention strategies, though current antibody tests have limitations 1

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Treatment of First Clinical Episode

For first-episode genital herpes, start valacyclovir 1 g orally twice daily for 7-10 days, which offers convenient dosing with proven efficacy. 2, 3

Oral Regimen Options (All Equally Effective)

• Valacyclovir 1 g orally twice daily for 7-10 days (preferred for convenience) 2, 3
• Acyclovir 400 mg orally three times daily for 7-10 days 2, 3
• Acyclovir 200 mg orally five times daily for 7-10 days 1, 2
• Famciclovir 250 mg orally three times daily for 7-10 days 2, 3

Important Considerations

• Treatment may be extended beyond 10 days if healing is incomplete 2, 3
• Topical acyclovir is substantially less effective than oral therapy and should not be used 1, 3
• For first-episode herpes proctitis, use acyclovir 400 mg orally 5 times daily for 10 days 1

Severe Disease Requiring Hospitalization

• For severe disease with complications (disseminated infection, pneumonitis, hepatitis, meningitis, or encephalitis), use IV acyclovir 5-10 mg/kg every 8 hours for 5-7 days until clinical resolution. 1, 4
• Monitor renal function at initiation and once or twice weekly during IV treatment 1, 2

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Treatment of Recurrent Episodes

For recurrent genital herpes, use valacyclovir 500 mg orally twice daily for 5 days, starting at the first sign of prodrome or within 1 day of lesion onset for maximum benefit. 2, 3

Episodic Therapy Options

• Valacyclovir 500 mg orally twice daily for 5 days (preferred) 2, 3
• Acyclovir 400 mg orally three times daily for 5 days 2, 3
• Acyclovir 800 mg orally twice daily for 5 days 1, 2
• Famciclovir 125 mg orally twice daily for 5 days 3

Critical Timing

• Treatment must be initiated during prodrome or within 1 day of lesion onset for effectiveness 2, 3
• Delayed treatment beyond 72 hours significantly reduces effectiveness 3
• Most immunocompetent patients do not benefit if treatment starts after 2 days of lesion onset 1

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Suppressive Therapy

For patients with frequent recurrences (≥6 episodes per year), prescribe daily suppressive therapy with valacyclovir 1 g once daily, which reduces recurrence frequency by ≥75% and decreases transmission risk. 2, 3

Suppressive Regimen Options

• Valacyclovir 1 g orally once daily (for ≥10 episodes/year) 2
• Valacyclovir 500 mg orally once daily (for <10 episodes/year) 2
• Acyclovir 400 mg orally twice daily 1, 2, 3
• Famciclovir 250 mg orally twice daily 3

Benefits and Monitoring

• Reduces recurrences by at least 75% 1, 2
• Reduces asymptomatic viral shedding and may decrease transmission to sexual partners 2, 3
• After 1 year of continuous therapy, discontinue to reassess recurrence rate 1, 2
• No laboratory monitoring needed unless substantial renal impairment exists 1, 2

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Special Populations

HIV-Infected Patients

HIV-infected patients require higher doses and longer treatment duration: use valacyclovir 500 mg twice daily for suppressive therapy (not once daily). 1, 2

• For recurrent episodes, use acyclovir 400 mg orally 3-5 times daily until clinical resolution 1
• Famciclovir 500 mg twice daily is effective for reducing recurrences and subclinical shedding 1
• Do NOT use short-course therapy (1-3 days) in HIV-infected patients 2
• Monitor closely as healing may be slower and treatment failures can occur 1
• For severe cases, IV acyclovir 5 mg/kg every 8 hours may be required 1

Critical Warning: High-dose valacyclovir (8 g/day) has been associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in HIV-infected patients, but standard doses for HSV treatment are safe 1

Pregnant Women

For HSV infections during pregnancy, use acyclovir as first-line therapy based on decades of safety data showing no increased risk of birth defects. 1, 2

Treatment During Pregnancy

• Episodic therapy for first-episode and recurrent HSV can be offered during pregnancy 1, 2
• Acyclovir is the preferred agent (most safety data) 1, 2
• Standard suppressive therapy is NOT routinely recommended during pregnancy unless frequent/severe recurrences occur 2

Late Pregnancy Considerations

• Consider suppressive therapy starting at 36 weeks gestation to reduce HSV shedding at delivery and decrease need for cesarean delivery 2
• Cesarean delivery is mandatory for women with visible genital lesions or prodromal symptoms at labor onset 1, 2
• Maternal genital HSV shedding at delivery is the primary risk for neonatal transmission 1, 2

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Treatment Failure and Resistance

If lesions do not begin to resolve within 7-10 days of antiviral therapy, suspect acyclovir resistance, obtain viral culture with susceptibility testing, and switch to IV foscarnet 40 mg/kg every 8 hours. 1, 2

Identifying Resistance

• Acyclovir resistance should be suspected if no improvement after 7-10 days of therapy 1, 2
• Resistance is rare (<0.5%) in immunocompetent patients but more common in immunocompromised hosts 5, 6
• All acyclovir-resistant strains are also resistant to valacyclovir, and most to famciclovir 1

Alternative Treatments for Resistant HSV

• IV foscarnet 40 mg/kg every 8 hours until clinical resolution (treatment of choice) 1, 2
• Topical cidofovir gel 1% applied once daily for 5 consecutive days (for external lesions) 1
• Topical trifluridine or imiquimod may be used for external lesions, though prolonged application (21-28 days) may be required 1

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Transmission Prevention Counseling

Counsel all patients to abstain from sexual activity when lesions or prodromal symptoms are present, and recommend consistent condom use during all sexual exposures, which reduces transmission risk by approximately 50%. 2, 3, 5

• Asymptomatic viral shedding occurs even without visible lesions 1, 2
• Suppressive therapy reduces but does not eliminate asymptomatic shedding 1, 2
• Most genital herpes transmission occurs from persons who are unaware of their infection or asymptomatic at time of contact 1
• Sex partners should be evaluated, counseled, and encouraged to self-examine for future lesions 1

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Common Pitfalls to Avoid

• Do not use topical acyclovir - it is substantially less effective than oral therapy 1, 3
• Do not delay episodic treatment - must start within 1 day of lesion onset for benefit 2, 3
• Do not use once-daily valacyclovir for suppression in HIV-infected patients - requires twice-daily dosing 1, 2
• Do not use high-dose valacyclovir (>2 g/day) in HIV-infected patients - risk of TTP/HUS 1
• Do not forget renal dose adjustment - particularly important for IV acyclovir and in elderly patients 4