In an otherwise healthy adult with a first episode of genital herpes, what antiviral regimen is recommended for primary infection, for recurrent outbreaks, and when should suppressive therapy be used?

Antiviral Management of Genital Herpes in Otherwise Healthy Adults

For a first episode of genital herpes, initiate valacyclovir 1 g orally twice daily for 7–10 days, starting within 48 hours of symptom onset for maximal benefit. 1

---

Primary (First Episode) Infection

Treatment should begin as soon as possible—ideally within 48 hours of lesion onset—to reduce viral replication, accelerate healing, and minimize systemic symptoms. 1, 2

Recommended Regimens (CDC-endorsed, all equally effective):

• Valacyclovir 1 g orally twice daily for 7–10 days 1, 2
• Acyclovir 400 mg orally three times daily for 7–10 days 1
• Acyclovir 200 mg orally five times daily for 7–10 days 1
• Famciclovir 250 mg orally three times daily for 7–10 days 1

Key Clinical Principles:

• Extend therapy beyond 10 days if lesions have not completely healed, as primary episodes can be prolonged, especially in women. 1
• Topical acyclovir is substantially less effective than oral therapy and should never be used as monotherapy, because it does not reduce systemic symptoms, viremia, or viral shedding from the cervix, urethra, or pharynx. 1
• Primary genital herpes is characterized by bilateral, multiple painful ulcerative lesions, systemic symptoms (fever, malaise, myalgia in 67%), dysuria (63%), and tender inguinal adenopathy (80%), with a mean lesion duration of 19 days if untreated. 3

---

Recurrent Episodes (Episodic Therapy)

Initiate treatment at the first sign of prodrome (tingling, itching, burning) or within 24 hours of lesion onset, when viral replication peaks. 1

Recommended 5-Day Regimens (CDC-endorsed):

• Valacyclovir 500 mg orally twice daily for 5 days 1
• Acyclovir 800 mg orally twice daily for 5 days 1
• Acyclovir 400 mg orally three times daily for 5 days 1
• Famciclovir 125 mg orally twice daily for 5 days 1

Alternative Short-Course Regimen:

• Valacyclovir 500 mg twice daily for 3 days is FDA-approved for recurrent episodes and offers comparable efficacy with improved convenience. 2

Critical Counseling Points:

• Patients should be provided with a prescription or medication supply to self-initiate therapy at the first prodromal symptom, as delaying treatment beyond 24 hours significantly reduces efficacy. 1
• Recurrent episodes are typically unilateral, localized, and last a mean of 10 days, with systemic symptoms uncommon (present in <25% of recurrences). 3
• Approximately 25% of recurrent episodes are asymptomatic, yet viral shedding still occurs, posing transmission risk. 3

---

Suppressive (Chronic) Therapy

Daily suppressive therapy is recommended for patients experiencing ≥6 recurrences per year, reducing recurrence frequency by ≥75%. 1

Recommended Daily Regimens (CDC-endorsed):

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

Long-Term Management Strategy:

• After 1 year of continuous suppressive therapy, discontinue temporarily to reassess recurrence frequency, as the natural rate of recurrences often declines over time. 1
• Suppressive therapy reduces but does not eliminate asymptomatic viral shedding, so transmission risk persists even on daily therapy. 4, 1
• Valacyclovir 500 mg once daily is less effective in patients with ≥10 recurrences per year; use the 1 g daily dose in this population. 1

Transmission Reduction:

• For HIV-negative heterosexual couples in which one partner has genital herpes, valacyclovir 500 mg once daily reduces transmission to the uninfected partner but does not eliminate risk. 1
• Condom use should be advised for all sexual encounters with new or uninfected partners, though condoms do not completely eliminate transmission. 1

---

Special Populations and Severe Disease

HIV-Infected Patients:

• For suppressive therapy in HIV-infected patients with CD4+ ≥100 cells/mm³, use valacyclovir 500 mg orally twice daily (not once daily) to achieve adequate viral control. 1, 2
• Daily suppressive therapy reduces HIV RNA concentrations in plasma and genital secretions, though its impact on HIV transmission remains uncertain. 1

Severe or Complicated 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. 1
• Indications for IV acyclovir include CNS involvement, visceral organ involvement, extensive mucocutaneous disease preventing oral intake, or severe immunocompromise. 1

Pregnancy:

• Antiviral prophylaxis from 36 weeks gestation until delivery is recommended for women with a history of genital herpes to reduce term recurrences and cesarean delivery rates. 1
• Women receiving acyclovir or valacyclovir during pregnancy should be reported to the manufacturer's pregnancy registry. 1

---

Antiviral Resistance

Acyclovir resistance is extremely rare in immunocompetent patients (<0.5%) but occurs more frequently in immunocompromised individuals receiving prolonged suppressive therapy. 1, 5

Management of Suspected Resistance:

• Suspect resistance if lesions fail to improve within 7–10 days of appropriate therapy. 1
• Confirm resistance with viral culture and susceptibility testing. 1
• IV foscarnet 40 mg/kg every 8 hours is the treatment of choice for confirmed acyclovir-resistant HSV. 1
• Topical cidofovir, trifluridine, or imiquimod may be used for external lesions, requiring prolonged application (≈21–28 days). 1

---

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 neurotoxicity and nephrotoxicity. 1

---

Essential Patient Counseling

• Genital herpes is a chronic, incurable infection with potential for lifelong recurrences. 1, 5
• Asymptomatic viral shedding can occur even without visible lesions, allowing transmission to partners. 1, 3
• Patients must abstain from all sexual activity when lesions or prodromal symptoms are present. 1
• All sexual partners should be informed of the genital herpes diagnosis. 1
• HSV-2 causes more frequent asymptomatic shedding than HSV-1, particularly during the first 12 months after infection. 1
• Neonatal transmission risk is 25–44% with a primary episode at delivery versus ≈1% with recurrent infection. 1

---

Common Pitfalls to Avoid

• Do not use valacyclovir 500 mg once daily in patients with ≥10 recurrences per year; it is inadequate for this population. 1
• Do not delay episodic therapy; starting treatment during prodrome or within 1 day of lesion onset maximizes efficacy. 1
• Do not use topical acyclovir as monotherapy; it is substantially less effective than systemic therapy. 1, 5
• Do not discontinue primary episode therapy at exactly 7 days if lesions remain active; extend treatment until complete healing. 1