How do I diagnose and manage primary and recurrent oral or genital herpes, including treatment dosing, suppressive therapy, counseling, and special considerations for pregnant or immunocompromised patients?

Diagnosis and Management of Herpes Simplex Virus Infection

Diagnosis

Diagnose genital herpes using type-specific molecular or virologic tests when genital ulcers are present, and type-specific serologic testing when lesions are absent. 1

• Type-specific testing is essential because HSV-1 and HSV-2 have different prognoses: HSV-1 causes 5-30% of first-episode genital herpes but recurs much less frequently than HSV-2, making strain identification critical for counseling 2
• Most genital herpes is unrecognized—only 13% of HSV-2–seropositive persons have been diagnosed 1
• Oral herpes (herpes labialis) is typically diagnosed clinically, though laboratory confirmation can be obtained during active lesions 3

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Treatment of First Clinical Episode

For first-episode genital or oral herpes, initiate valacyclovir 1 g orally twice daily for 7-10 days. 3

Alternative First-Episode Regimens (CDC-endorsed):

• Acyclovir 400 mg orally three times daily for 7-10 days 2
• Acyclovir 200 mg orally five times daily for 7-10 days 2
• Famciclovir 250 mg orally three times daily for 7-10 days 2

Key Treatment Principles:

• Extend treatment beyond 10 days if healing is incomplete 2
• For severe ulcerative disease, treat for at least 2 weeks to achieve complete clinical healing 2
• Topical acyclovir is substantially less effective than oral therapy and should not be used—it does not improve systemic symptoms, viremia, or viral shedding from the cervix, urethra, or pharynx 2, 3

Special Indication:

• For first-episode herpes proctitis, use acyclovir 400 mg orally five times daily for 10 days (higher dosing and longer duration required for rectal site) 2

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Treatment of Recurrent Episodes (Episodic Therapy)

Initiate episodic therapy at the first sign of prodrome or within 24 hours of lesion onset for maximal benefit. 2, 3

Recommended 5-Day Episodic Regimens:

• Valacyclovir 500 mg orally twice daily 2, 4
• Acyclovir 800 mg orally twice daily 2, 4
• Acyclovir 400 mg orally three times daily 2, 4
• Famciclovir 125 mg orally twice daily 2, 4

Critical Timing:

• Peak viral replication occurs in the first 24 hours—delaying treatment beyond this window substantially reduces efficacy 3
• Provide patients with a prescription to self-initiate treatment at the first prodromal sign 2, 3

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Suppressive (Daily) Therapy

Offer daily suppressive therapy to patients experiencing ≥6 recurrences per year, which reduces recurrence frequency by ≥75%. 2, 3, 4

Recommended Suppressive Regimens:

• Valacyclovir 500 mg orally once daily (for patients with <10 recurrences/year) 2
• Valacyclovir 1 g orally once daily (for patients with ≥10 recurrences/year) 2, 4
• Acyclovir 400 mg orally twice daily (safety documented up to 6 years) 2, 3
• Famciclovir 250 mg orally twice daily (safety documented up to 1 year) 2, 4

Long-Term Management:

• After 1 year of continuous suppressive therapy, discontinue temporarily to reassess recurrence frequency, as natural decline often occurs over time 2, 3
• Suppressive therapy significantly lowers asymptomatic viral shedding and transmission risk but does not eliminate either completely 2, 3
• Antiviral resistance remains extremely low (<0.5%) in immunocompetent patients even after prolonged use 3

Common Pitfall:

• Do not use valacyclovir 500 mg once daily in patients with ≥10 recurrences per year—it is less effective than higher-dose regimens 2

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Severe or Hospitalized Disease

For disseminated HSV infection, encephalitis, pneumonitis, hepatitis, or inability to tolerate oral medication, administer acyclovir 5-10 mg/kg IV every 8 hours for 5-7 days or until clinical resolution. 2, 3

Indications for IV Acyclovir:

• Central nervous system involvement 2
• Visceral organ involvement 2
• Extensive mucocutaneous disease preventing oral intake 2
• Immunocompromised status with severe presentation 2

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Management in Pregnancy

Administer antiviral prophylaxis from 36 weeks gestation until delivery to lower term-time recurrences and cesarean-delivery rates. 2

Cesarean Delivery Indications:

• Suspected or confirmed first-episode genital herpes at labor onset 2
• First episode occurring <6 weeks before delivery 2
• Prodrome or visible lesions at labor onset 2

Safety Considerations:

• Oral acyclovir may be used during pregnancy for first clinical episodes, though safety data remain limited 2
• Women receiving acyclovir or valacyclovir during pregnancy should be reported to the manufacturer's pregnancy registry 2

Neonatal Transmission Risk:

• 25-44% transmission risk with primary episode at delivery versus ≈1% with recurrent infection 2

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Management in Immunocompromised Patients

For immunocompromised patients, use higher doses: acyclovir 400 mg orally three to five times daily until clinical resolution. 2

Antiviral Resistance:

• Suspect acyclovir resistance if lesions fail to improve within 7-10 days of appropriate therapy 2, 4
• Confirm resistance with viral culture and susceptibility testing 2
• IV foscarnet 40 mg/kg every 8 hours is the treatment of choice for confirmed resistant HSV 2, 4
• Topical cidofovir, trifluridine, or imiquimod may be used for external lesions, requiring prolonged application (≈21-28 days) 2
• Resistance is uncommon in immunocompetent hosts but more frequent in immunocompromised patients, especially those with HIV on long-term suppressive therapy 2

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Management in HIV-Infected Patients

For HIV-infected patients on suppressive therapy, use valacyclovir 500 mg orally twice daily (not once daily) to achieve adequate viral control. 2

• For recurrent genital herpes in HIV-infected patients, famciclovir 500 mg twice daily for 7 days is recommended, reflecting increased viral replication 2
• Daily suppressive antiviral therapy reduces HIV RNA concentrations in plasma and genital secretions, though its impact on HIV transmission remains uncertain 2
• Suppressive therapy does not effectively decrease transmission risk among persons co-infected with HIV and HSV-2 2

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Renal Function Considerations

Assess renal function before starting and during antiviral therapy; adjust dosing frequency or total daily dose according to creatinine clearance to avoid toxicity. 2

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Patient Counseling (Essential Components)

Counsel patients that genital herpes is a chronic, incurable infection with potential for lifelong recurrences, and that asymptomatic viral shedding can occur even without visible lesions. 2, 4

Transmission Prevention:

• Abstain from all sexual activity when lesions or prodromal symptoms are present 2, 4
• Inform all sex partners about having genital herpes 2, 4
• Use condoms during all sexual encounters with new or uninfected partners, though condoms do not completely eliminate transmission risk 2, 4
• Suppressive therapy reduces transmission to uninfected partners in HIV-negative heterosexual couples but does not eliminate risk 2

Natural History Education:

• HSV-2 leads to more frequent asymptomatic shedding than HSV-1, particularly during the first 12 months after infection 2
• Antiviral medications control symptoms but do not eradicate the virus or prevent all recurrences 2, 4
• For oral HSV-1, prophylactic measures like sunscreen or zinc oxide application may help reduce UV-triggered recurrences 3

Addressing Stigma:

• Genital herpes is associated with significant stigma, which can be combatted by patient education about the natural history of infection 1
• HSV-2 increases HIV acquisition risk 3-fold compared to those without HSV-2 infection 1

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Common Pitfalls to Avoid

• Never use topical acyclovir as monotherapy—it is substantially less effective than systemic oral antivirals 2, 3, 4
• Do not delay episodic therapy beyond 24 hours of lesion onset—efficacy drops significantly 2, 3
• Avoid valacyclovir 8 g/day in immunocompromised patients—it is associated with hemolytic uremic syndrome/thrombotic thrombocytopenic purpura 4