What alternative or next‑step therapy should be used for a patient with recurrent HSV who is not adequately controlled on valacyclovir 1000 mg daily?

Alternative Therapy for Valacyclovir-Resistant HSV Suppression

If valacyclovir 1000 mg daily fails to suppress recurrent HSV, first confirm adequate dosing and adherence, then suspect antiviral resistance and switch to intravenous foscarnet 40 mg/kg every 8 hours until clinical resolution. 1

Step 1: Verify Treatment Failure and Rule Out Inadequate Dosing

Before assuming resistance, confirm the patient is truly failing suppressive therapy:

• Ensure the patient is receiving the correct dose for their recurrence frequency: valacyclovir 1000 mg once daily is appropriate only for patients with ≥10 recurrences per year; those with fewer recurrences may be adequately controlled on 500 mg daily. 1
• Verify medication adherence and confirm the patient is taking the medication consistently, as poor adherence is a more common cause of breakthrough recurrences than true resistance. 1
• If lesions persist despite appropriate valacyclovir treatment for 7–10 days, suspect HSV resistance and proceed to resistance testing. 1, 2

Step 2: Confirm Antiviral Resistance

• Obtain viral culture from active lesions and request susceptibility testing if virus is isolated, because clinical suspicion alone is insufficient to diagnose resistance. 1, 2
• Recognize that all acyclovir-resistant HSV strains are also resistant to valacyclovir due to shared mechanisms of action, so switching to higher-dose valacyclovir will not overcome resistance. 1, 2
• Resistance rates in immunocompetent patients remain below 0.5% despite more than 20 years of widespread valacyclovir use, making true resistance rare in this population. 1
• In immunocompromised patients (HIV-infected, transplant recipients, or those on chronic immunosuppression), resistance rates rise to approximately 5–7%, so maintain a higher index of suspicion in these populations. 1, 2

Step 3: Switch to Foscarnet for Confirmed or Suspected Resistance

• For proven or suspected acyclovir-resistant HSV, intravenous foscarnet 40 mg/kg every 8 hours until complete clinical resolution is the treatment of choice. 1, 2
• All acyclovir-resistant strains are also resistant to valacyclovir, and the majority exhibit cross-resistance to famciclovir, making foscarnet the only reliably effective option. 1
• Topical cidofovir gel 1% applied once daily for 5 consecutive days is an alternative when foscarnet is unavailable or contraindicated, though evidence is more limited. 1

Step 4: Monitor for Foscarnet Toxicity

• Assess baseline renal function before initiating foscarnet and monitor creatinine at least once or twice weekly throughout treatment, because foscarnet is markedly more nephrotoxic than acyclovir. 1
• Ensure aggressive hydration and monitor electrolytes—particularly calcium and magnesium—regularly to mitigate renal injury and electrolyte disturbances. 1

Step 5: Consider Alternative Oral Antivirals if Resistance Is Not Confirmed

If viral culture does not confirm resistance, consider these alternatives:

• Acyclovir 400 mg twice daily is an effective alternative for suppressive therapy, with documented safety for up to 6 years of continuous use. 1, 2
• Famciclovir 250 mg twice daily provides efficacy comparable to acyclovir for suppressive therapy, though it requires twice-daily dosing. 1, 3
• For HIV-infected patients with CD4+ ≥100 cells/mm³, valacyclovir 500 mg twice daily (not once daily) is the recommended regimen, as once-daily dosing is inadequate in this population. 1, 2

Critical Pitfalls to Avoid

• Do not use topical acyclovir for resistant HSV infections, because it is substantially less effective than systemic therapy and does not overcome resistance. 1
• Do not prescribe valacyclovir doses of 8 grams per day in immunocompromised patients, as this has been linked to thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome. 1, 4
• Do not assume treatment failure equals resistance in immunocompetent patients without viral culture confirmation, because resistance is exceedingly rare (<0.5%) in this group. 1
• Do not continue standard valacyclovir dosing when renal function declines; promptly adjust the regimen according to creatinine clearance to avoid neurotoxicity. 1

Reassessment After One Year of Suppressive Therapy

• After 1 year of continuous suppressive therapy, discuss discontinuation with the patient and reassess recurrence frequency, because outbreak rates often decline with prolonged infection and many individuals experience a natural reduction in recurrence frequency over time. 1, 2