What are the recommended valacyclovir dosing regimens for an immunocompetent adult with primary genital herpes, recurrent genital herpes, suppressive therapy, and herpes zoster, including renal dose adjustments and considerations for pregnancy, breastfeeding, contraindications, adverse effects, and alternative antivirals?

Valacyclovir Dosing and Clinical Management

Primary Genital Herpes (First Episode)

For immunocompetent adults with primary genital herpes, valacyclovir 1 gram orally twice daily for 7-10 days is the recommended regimen, initiated within 48 hours of symptom onset for maximum benefit. 1, 2

• Treatment may be extended beyond 10 days if healing remains incomplete 1, 2
• Alternative regimens include acyclovir 400 mg three times daily or 200 mg five times daily for 7-10 days, or famciclovir 250 mg three times daily for 7-10 days 1
• Note that 5-30% of first-episode genital herpes cases are caused by HSV-1, which has significantly fewer recurrences than HSV-2, making viral typing prognostically important 1, 2

Recurrent Genital Herpes (Episodic Treatment)

Valacyclovir 500 mg orally twice daily for 3 days is the first-line episodic treatment for recurrent genital herpes, but must be initiated during prodrome or within 24 hours of lesion onset. 3

• Efficacy drops significantly if treatment is delayed beyond 24 hours of symptom onset 3
• Alternative regimens include acyclovir 400 mg three times daily for 5 days, acyclovir 800 mg twice daily for 5 days, or famciclovir 125 mg twice daily for 5 days 3
• Avoid topical acyclovir entirely—it is substantially less effective than oral therapy and provides minimal clinical benefit 3

Suppressive Therapy for Recurrent Genital Herpes

For immunocompetent patients with frequent recurrences (≥6 episodes per year), valacyclovir 1 gram orally once daily is the standard suppressive dose. 4, 3

Dosing by Recurrence Frequency:

• Patients with <10 recurrences per year: Valacyclovir 500 mg once daily is acceptable 4, 5
• Patients with ≥10 recurrences per year: Valacyclovir 1 gram once daily is required, as 500 mg once daily is less effective in this population 4, 5
• HIV-infected patients with CD4+ count ≥100 cells/mm³: Valacyclovir 500 mg twice daily 1, 4, 5

Clinical Benefits and Duration:

• Suppressive therapy reduces recurrence frequency by ≥75% 4, 3
• Safety and efficacy documented for up to 1 year with valacyclovir and up to 6 years with acyclovir 4
• After 1 year of continuous suppressive therapy, discuss discontinuation to reassess recurrence frequency, as outbreak rates often decline over time 4
• Suppressive therapy reduces but does not eliminate asymptomatic viral shedding, meaning transmission risk persists 4, 3
• No laboratory monitoring is needed unless substantial renal impairment exists 4

Herpes Zoster (Shingles)

For immunocompetent adults with herpes zoster, valacyclovir 1 gram orally three times daily (every 8 hours) for 7 days is the standard regimen. 5, 6

• Valacyclovir is significantly more effective than acyclovir in reducing the duration of zoster-associated pain and postherpetic neuralgia, particularly in patients ≥50 years of age 6
• Initiate therapy as early as possible, ideally within 72 hours of rash onset 6

Herpes Labialis (Cold Sores)

For herpes labialis in patients ≥12 years, valacyclovir 2 grams orally twice daily for 1 day (two doses taken 12 hours apart) is the recommended regimen. 3, 5

• Therapy must be initiated at the earliest symptom (tingling, itching, or burning) 3, 5

Renal Dose Adjustments

Dosage adjustment is mandatory for patients with reduced renal function to prevent neurotoxicity. 5

Creatinine Clearance-Based Adjustments:

For Recurrent Genital Herpes (500 mg twice daily regimen):

• CrCl 30-49 mL/min: No reduction needed 5
• CrCl 10-29 mL/min: 500 mg every 24 hours 5
• CrCl <10 mL/min: 500 mg every 24 hours 5

For Suppressive Therapy (1 gram once daily regimen):

• CrCl 30-49 mL/min: No reduction needed 5
• CrCl 10-29 mL/min: 500 mg every 24 hours 5
• CrCl <10 mL/min: 500 mg every 24 hours 5

For Herpes Zoster (1 gram three times daily regimen):

• CrCl 30-49 mL/min: 1 gram every 12 hours 5
• CrCl 10-29 mL/min: 1 gram every 24 hours 5
• CrCl <10 mL/min: 500 mg every 24 hours 5

For Hemodialysis Patients:

• Administer the recommended dose after hemodialysis 5
• Approximately one-third of acyclovir is removed during a 4-hour hemodialysis session 5

For Peritoneal Dialysis:

• No supplemental doses required following CAPD or CAVHD, as removal is less pronounced than with hemodialysis 5

Pregnancy Considerations

Acyclovir is the first-choice antiviral for HSV infections during pregnancy, as it has the most extensive safety data. 1

• Episodic therapy for first-episode HSV and recurrences can be offered during pregnancy 1
• Suppressive therapy in late pregnancy (starting at 36 weeks) suppresses genital herpes outbreaks and reduces the need for Cesarean delivery in HIV-seronegative women, and likely has similar efficacy in HIV-seropositive women 1
• Current registry findings do not indicate an increased risk for major birth defects after acyclovir treatment compared to the general population 4
• Cesarean delivery is recommended for women with genital herpes prodrome or visible HSV genital lesions at the onset of labor 1
• The safety of valacyclovir therapy in pregnant women has not been fully established, though no pattern of adverse pregnancy outcomes has been reported after acyclovir exposures 1, 4

Breastfeeding

While the evidence does not provide specific guidance on valacyclovir use during breastfeeding, acyclovir (the active metabolite) is generally considered compatible with breastfeeding based on its safety profile 1

Contraindications and Precautions

Avoid valacyclovir doses of 8 grams per day in immunocompromised patients due to risk of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). 4, 2, 7

• High-dose valacyclovir (8 g/day) in patients with advanced HIV disease has been associated with increased mortality and more gastrointestinal complaints 7
• TTP/HUS has been reported in immunocompromised patients receiving high-dose prophylactic valacyclovir for prolonged periods 7
• Close monitoring for symptoms of TTP/HUS is indicated in all immunocompromised patients receiving high-dose valacyclovir 7
• Central neurological toxicity is frequently observed with high doses but regresses on withdrawal 8

Adverse Effects

Valacyclovir is generally well tolerated at standard doses, with a safety profile similar to acyclovir or placebo. 6, 9

• Headache is the most commonly reported adverse effect 7
• Gastrointestinal complaints (nausea, abdominal pain) occur more frequently at higher doses 7
• Neurotoxicity (confusion, hallucinations, seizures) can occur, particularly in patients with renal impairment or those receiving high doses 8, 10

Treatment Failure and Resistance

If lesions persist after 7-10 days of appropriate valacyclovir therapy, consider HSV resistance. 4, 2

• All acyclovir-resistant HSV strains are also resistant to valacyclovir 4, 2
• For acyclovir-resistant HSV, IV foscarnet 40 mg/kg every 8 hours until clinical resolution is the treatment of choice 1, 4, 2
• Topical trifluridine, cidofovir, and imiquimod have been used successfully for resistant lesions on external surfaces, though prolonged application for 21-28 days or longer may be required 1
• Resistance rates remain below 0.5% in immunocompetent patients despite more than 20 years of widespread clinical use 4
• In HIV-infected and other immunocompromised patients, resistance rates are higher at approximately 5-7% 4

Alternative Antivirals

Acyclovir and famciclovir are effective alternatives to valacyclovir for all HSV indications. 1

Acyclovir Regimens:

• First-episode genital herpes: 400 mg three times daily or 200 mg five times daily for 7-10 days 1
• Recurrent genital herpes: 400 mg three times daily, 800 mg twice daily, or 200 mg five times daily for 5 days 1, 3
• Suppressive therapy: 400 mg twice daily 1, 4
• Herpes zoster: 800 mg five times daily for 7 days 6

Famciclovir Regimens:

• First-episode genital herpes: 250 mg three times daily for 7-10 days 1
• Recurrent genital herpes: 125 mg twice daily for 5 days 3
• Suppressive therapy: 250 mg twice daily 1, 4

Comparative Considerations:

• Valacyclovir provides significantly better oral bioavailability than acyclovir (54% vs. 20%), allowing for less frequent dosing 7, 6, 10
• Valacyclovir is the only antiviral approved for once-daily suppressive therapy and for a 3-day episodic treatment regimen 9
• Less frequent dosing with valacyclovir may contribute to increased patient adherence 9
• Safety and efficacy documented for up to 6 years with acyclovir suppressive therapy 4

Critical Pitfalls to Avoid

• Never use topical acyclovir for genital herpes—it is substantially less effective than oral therapy 3
• Always adjust doses for renal impairment to prevent neurotoxicity 5, 8
• Never use 8 grams per day of valacyclovir in immunocompromised patients due to TTP/HUS risk 4, 2, 7
• Counsel patients that antivirals control symptoms but do not eradicate latent virus or prevent all future recurrences 3
• Emphasize that asymptomatic viral shedding can lead to transmission even without visible lesions 4, 3
• Initiate episodic treatment within 24 hours of symptom onset for maximum benefit 3