What is the recommended suppressive antiviral regimen for genital herpes simplex virus type 2, including first‑line dosing, renal dose adjustments, and pregnancy considerations?

HSV-2 Suppressive Therapy

For HSV-2 suppression, valacyclovir 500 mg twice daily is the first-line regimen for HIV-infected patients, while immunocompetent patients should receive valacyclovir 500 mg once daily for infrequent recurrences or 1000 mg once daily for frequent recurrences (≥10 episodes per year). 1, 2

First-Line Suppressive Regimens

Immunocompetent Patients

• Valacyclovir 500 mg once daily is recommended for patients with infrequent recurrences (<10 episodes per year), with documented safety and efficacy for up to 1 year 2, 3
• Valacyclovir 1000 mg once daily should be used for patients with very frequent recurrences (≥10 episodes per year), as 500 mg once daily is less effective in this population 2, 3
• Acyclovir 400 mg twice daily is an effective alternative with documented safety for up to 6 years of continuous use 1, 2, 4
• Famciclovir 250 mg twice daily provides comparable efficacy to acyclovir but requires twice-daily dosing 2

HIV-Infected Patients

• Valacyclovir 500 mg twice daily is the recommended regimen for HIV-infected persons with CD4+ count ≥100 cells/mm³ 1, 2
• Twice-daily regimens with acyclovir or famciclovir should be used rather than once-daily dosing in this population 1
• Daily suppressive therapy in HIV-infected persons results in decreased HIV concentration in plasma and genital secretions, though clinical benefit remains uncertain 1

Clinical Benefits and Expectations

• Suppressive therapy reduces recurrence frequency by ≥75% among patients with frequent episodes 1, 2
• The option for suppressive therapy should be discussed with every HSV-2-infected patient 1
• Suppressive therapy reduces but does not eliminate asymptomatic viral shedding, meaning transmission risk persists 2
• After 1 year of continuous suppressive therapy, consider discussing discontinuation to reassess recurrence frequency, as recurrences may decrease over time 2

Renal Dose Adjustments

• No dose reduction is needed for creatinine clearance 30-49 mL/min 2
• For significant renal impairment (CrCl <30 mL/min), dose adjustments are necessary to prevent nephrotoxicity 2
• Adequate hydration should be maintained to minimize nephrotoxicity risk 2
• No laboratory monitoring is needed for patients on suppressive therapy unless they have substantial renal impairment 2

Pregnancy Considerations

• Acyclovir is the first choice for HSV therapy during pregnancy, as it has the most reported experience and appears safe 1
• Suppressive therapy is not used routinely during pregnancy, though episodic therapy for first-episode disease and recurrences can be offered 1
• Use of acyclovir in late pregnancy suppresses genital herpes outbreaks and reduces the need for cesarean delivery in HIV-seronegative women, with likely 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 2
• The safety of valacyclovir therapy in pregnant women has not been fully established 2

Treatment Failure and Resistance

• If lesions persist despite appropriate valacyclovir treatment, suspect HSV resistance 2
• All acyclovir-resistant strains are also resistant to valacyclovir 2
• For acyclovir-resistant HSV, IV foscarnet 40 mg/kg every 8 hours until clinical resolution is the treatment of choice 1, 2
• Resistance rates remain below 0.5% in immunocompetent patients despite 20+ years of widespread use 2
• In immunocompromised patients, resistance rates are higher at approximately 5-7% 2

Critical Pitfalls to Avoid

• Avoid valacyclovir doses of 8 g per day in immunocompromised patients due to risk of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome 2
• Do not use topical acyclovir alone, as it is substantially less effective than systemic therapy 1
• Valacyclovir 500 mg once daily is inadequate for patients with ≥10 recurrences per year—these patients require 1000 mg once daily 2, 3
• HIV-infected patients require twice-daily dosing (500 mg BID), not once-daily regimens 1, 2