HSV Prophylaxis in the Setting of Resistance
For acyclovir-resistant HSV, foscarnet 40 mg/kg IV every 8 hours is the treatment of choice, and once resistance develops, patients require foscarnet for all future prophylaxis during periods of immunosuppression. 1
Understanding Acyclovir Resistance
Prevalence and Risk Factors
- Acyclovir resistance is rare (<1%) in immunocompetent patients but significantly elevated in immunocompromised hosts, particularly hematopoietic stem cell transplant recipients 2
- All acyclovir-resistant strains are also resistant to valacyclovir, and most are resistant to famciclovir due to shared mechanisms of action targeting viral DNA polymerase 1
- Resistance should be suspected when lesions persist despite standard acyclovir therapy 1
Key Clinical Pitfall
The critical error is continuing acyclovir or switching to valacyclovir/famciclovir when resistance is present—these drugs share cross-resistance and will fail 1
Treatment Algorithm for Proven or Suspected Resistance
First-Line: Foscarnet
- Foscarnet 40 mg/kg IV every 8 hours until clinical resolution is the FDA-approved regimen for acyclovir-resistant mucocutaneous HSV in immunocompromised patients 3
- Alternative dosing: 60 mg/kg IV every 12 hours 3, 4
- Treatment duration: Continue for 2-3 weeks or until complete healing 3, 4
- Mandatory hydration and renal monitoring are required due to nephrotoxicity risk 3
Second-Line: Cidofovir
- Topical cidofovir gel 1% applied once daily for 5 consecutive days for accessible mucocutaneous lesions 1
- Intravenous cidofovir is reserved for foscarnet failure 4
Third-Line: Trifluorothymidine
- Topical trifluorothymidine (as ophthalmic solution) applied 3-4 times daily for accessible lesions when foscarnet is contraindicated 4
Prophylaxis Strategy After Resistance Develops
Critical Management Principle
Once a patient develops acyclovir-resistant HSV requiring treatment, they need alternative prophylaxis (foscarnet) during all future episodes of neutropenia or immunosuppression. 1
Prophylaxis Regimens
- Standard acyclovir prophylaxis (acyclovir 400 mg PO twice daily, valacyclovir 500 mg PO twice daily, or famciclovir 250 mg PO twice daily) is contraindicated in patients with documented resistance 1
- For patients receiving CMV prophylaxis with ganciclovir or foscarnet, additional HSV prophylaxis is unnecessary as these agents cover HSV 1
- However, patients on letermovir for CMV require separate HSV prophylaxis as letermovir lacks HSV activity 1
High-Risk Populations Requiring Prophylaxis
- HSV-seropositive patients receiving chemotherapy for acute leukemia during neutropenia 1
- Allogeneic and autologous HCT recipients during neutropenia and beyond, especially those with GVHD 1
- Patients with hematologic malignancies on high-dose corticosteroids or T-cell–depleting agents (fludarabine, alemtuzumab) 1
- Alemtuzumab-treated patients require prophylaxis until ≥2 months post-therapy AND CD4 count ≥200 cells/mcL 1
Special Populations
HIV-Infected Patients
- Higher doses are required: acyclovir 400 mg PO 3-5 times daily for immunocompromised patients 1
- Famciclovir 500 mg twice daily has demonstrated efficacy in reducing recurrences and subclinical shedding in HIV patients 1
- Valacyclovir doses of 8 g/day are contraindicated due to risk of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura 1
Pregnancy
- Acyclovir prophylaxis is not routinely recommended for pregnant women with recurrent genital herpes 1
- For frequent, severe recurrences, acyclovir prophylaxis may be considered with no documented pattern of adverse pregnancy outcomes 1
- Foscarnet use in pregnancy should be reserved for life-threatening maternal HSV infection when acyclovir resistance is documented 1
Monitoring and Follow-Up
Essential Monitoring
- Obtain HSV cultures and acyclovir susceptibility testing when resistance is suspected 4
- Monitor renal function closely with foscarnet therapy, adjusting doses for creatinine clearance 3
- Discontinue foscarnet if creatinine clearance falls below 0.4 mL/min/kg until renal function recovers 3