What's the next step for a patient with persistent cold sores who hasn't responded to valacyclovir (Valtrex) treatment?

Management of Persistent Cold Sores Despite Valacyclovir Treatment

If cold sores have not resolved after a few weeks of valacyclovir therapy, you should suspect acyclovir-resistant HSV and obtain viral culture with susceptibility testing, then initiate IV foscarnet 40 mg/kg every 8 hours as the treatment of choice for confirmed resistance. 1

When to Suspect Treatment Failure

• Suspect antiviral resistance if lesions do not begin to resolve within 7-10 days after initiating therapy 1, 2
• A patient taking valacyclovir for "a few weeks" with persistent cold sores clearly meets criteria for suspected treatment failure 1
• Treatment failure in immunocompetent patients is uncommon but does occur, particularly with prolonged or repeated antiviral exposure 2

Diagnostic Workup for Suspected Resistance

• Obtain viral culture from the active lesion and request susceptibility testing to confirm drug resistance 1
• All acyclovir-resistant HSV strains are also resistant to valacyclovir, and most are resistant to famciclovir, making susceptibility testing critical for guiding therapy 1
• This step is essential before escalating to alternative therapy, as it confirms the diagnosis and guides management 1

Treatment of Acyclovir-Resistant HSV

• IV foscarnet 40 mg/kg every 8 hours until clinical resolution is the treatment of choice for proven or suspected acyclovir-resistant HSV 1, 2
• Foscarnet is often effective even when oral antivirals have failed 1
• Continue treatment until lesions have completely healed 1
• Topical cidofovir gel 1% applied once daily for 5 consecutive days is an alternative option 1

Important Considerations Before Assuming Resistance

• Verify the patient was taking adequate doses: For orolabial HSV (cold sores), standard treatment is valacyclovir 2 g twice daily for 1 day, NOT prolonged therapy 2, 3, 4
• If the patient has been taking standard episodic dosing (2 g twice daily for 1 day) repeatedly without success, this differs from continuous therapy and may indicate either resistance or need for suppressive therapy 2, 4
• Assess immune status: Immunocompromised patients (HIV, transplant recipients, chemotherapy) are at higher risk for resistant HSV and may require higher doses or longer treatment courses 1

Alternative Explanation: Frequent Recurrences vs. Non-Healing Lesions

• If the patient is experiencing frequent new outbreaks (rather than one non-healing lesion), this is different from treatment failure and warrants suppressive therapy 2
• Daily suppressive therapy with valacyclovir 500 mg once daily reduces recurrence frequency by ≥75% 2, 5
• For patients with very frequent recurrences (≥10 episodes per year), valacyclovir 1 g once daily is more effective than 500 mg once daily 2, 5

Common Pitfalls to Avoid

• Do not continue ineffective oral antiviral therapy indefinitely—if lesions persist beyond 7-10 days, escalate care 1, 2
• Do not use topical acyclovir—it is substantially less effective than oral therapy and should not be used 2
• Do not assume all treatment failures are due to resistance—verify proper dosing, timing of initiation, and consider whether the patient needs suppressive rather than episodic therapy 2, 3
• Resistance is rare in immunocompetent patients, so also consider alternative diagnoses if lesions are atypical 2

Monitoring During Foscarnet Therapy

• Monitor renal function at initiation and once or twice weekly during treatment, as foscarnet requires dose adjustment for renal impairment 1
• Ensure adequate hydration during therapy 3

Consultation Recommendation

• Patients with proven or suspected acyclovir-resistant HSV should be managed in consultation with an infectious disease specialist 1