What is the recommended antiviral prophylaxis regimen for immunocompromised patients exposed to herpes simplex virus (HSV)?

Antiviral Prophylaxis for Herpes Simplex Virus Exposure in Immunocompromised Patients

For immunocompromised patients exposed to HSV, acyclovir, valacyclovir, or famciclovir should be initiated as prophylaxis, with the specific agent, dose, and duration determined by the type and degree of immunosuppression. 1

Risk Stratification and Prophylaxis Indications

High-Risk Populations Requiring Prophylaxis

HSV-seropositive patients undergoing the following treatments require antiviral prophylaxis:

• Acute leukemia patients receiving induction or consolidation chemotherapy during the entire period of neutropenia (60-80% reactivation risk without prophylaxis) 1

• Allogeneic HCT recipients during neutropenia and potentially longer depending on degree of immunosuppression, particularly those with GVHD or frequent pre-transplant HSV reactivations 1

• Autologous HCT recipients during the neutropenic period 1

• Alemtuzumab-treated patients (for chronic lymphocytic leukemia) until at least 2 months after completion of therapy AND until CD4 counts ≥200 cells/mcL 1

Intermediate-Risk Populations to Consider for Prophylaxis

• Patients with hematologic malignancies experiencing prolonged neutropenia 1

• Patients receiving high-dose corticosteroids 1

• Patients receiving T-cell–depleting agents (e.g., fludarabine) 1

• Any patient with prior HSV reactivation requiring treatment should receive prophylaxis during ALL future episodes of neutropenia induced by cytotoxic therapy 1

• HSV-seropositive children undergoing immunosuppressive therapy 1

Prophylactic Regimens

First-Line Agents

Choose one of the following:

• Acyclovir 400 mg orally twice daily 1, 2
• Valacyclovir 500 mg orally once or twice daily 1
• Famciclovir at appropriate prophylactic doses 1

All three agents demonstrate equivalent efficacy for HSV prophylaxis, with valacyclovir and famciclovir offering less frequent dosing schedules that may improve adherence 3, 4

Special Considerations for Concurrent CMV Prophylaxis

• If receiving ganciclovir or foscarnet for CMV prophylaxis: Additional acyclovir is NOT necessary as these agents are active against HSV 1

• If receiving letermovir for CMV prophylaxis: Acyclovir, valacyclovir, or famciclovir MUST be added as letermovir lacks activity against HSV 1

Duration of Prophylaxis

Timing varies by clinical scenario:

• Acute leukemia: Throughout the entire neutropenic period during induction and consolidation chemotherapy 1

• Allogeneic HCT: Minimum during neutropenia, with extension considered for patients with ongoing GVHD or continued systemic immunosuppression 1

• Alemtuzumab therapy: Minimum 2 months post-therapy AND until CD4 ≥200 cells/mcL 1

• Patients with prior HSV reactivation: During every subsequent neutropenic episode 1

Post-Exposure Prophylaxis for Varicella-Susceptible Patients

For immunocompromised patients who are varicella-susceptible and exposed to active varicella zoster infection:

First-Line Approach (Within 96 Hours)

• Varicella zoster immunoglobulin (VZIG) or intravenous immunoglobulin within 96 hours of exposure 1, 5, 6

Alternative Approach (If VZIG Unavailable or >96 Hours Post-Exposure)

• Acyclovir orally for 7 days, beginning 7-10 days after varicella exposure 1, 5, 6

This delayed initiation timing (7-10 days post-exposure) targets the incubation period when viral replication begins but before clinical disease manifests 6

Management of Acyclovir-Resistant HSV

For documented or suspected acyclovir resistance (rare in immunocompetent hosts, more common with prolonged immunosuppression):

• Foscarnet 40 mg/kg IV every 8 hours is the treatment of choice 1, 7

• All acyclovir-resistant strains are also resistant to valacyclovir, and most are resistant to famciclovir 8, 7

• Topical cidofovir gel 1% once daily for 5 consecutive days may be considered for accessible mucocutaneous lesions 8, 7

Critical Clinical Pitfalls

Common errors to avoid:

• Do NOT rely on clinical diagnosis alone in immunocompromised patients with atypical presentations; obtain laboratory confirmation 5

• Do NOT assume CMV prophylaxis covers HSV if the patient is receiving letermovir—separate HSV prophylaxis is required 1

• Do NOT discontinue prophylaxis prematurely in allogeneic HCT recipients who develop GVHD or require ongoing immunosuppression 1

• Do NOT use topical antivirals as they are substantially less effective than systemic therapy 1, 5

• HSV reactivation in immunocompromised patients is associated with increased mucosal damage, pain, impaired oral intake, and increased risk of bacterial and fungal superinfections—early prophylaxis prevents these complications 1