Herpes Simplex Virus (HSV) Empiric Therapy

Although lesions caused by herpes simplex virus (HSV) subtypes HSV-1 and HSV-2 differ in rates of recurrence and subclinical shedding, they are treated with the same antiviral regimens, based on the site of infection. ^{[1, 2, 3, 4]}

Genital herpes

First episode

Previously, treatment was recommended in all patients, as symptoms could be severe and/or prolonged. ^{[1, 3, 4]} The latest guidelines state that oral antiviral drugs should be administered to patients presenting within 5 days of the start of the episode or while new lesions are still forming. The recommended regimens, all with a treatment duration of 5-10 days, are as follows: ^[5]

• Acyclovir 400 mg TID or
• Acyclovir 200 mg 5 times daily or
• Famciclovir 250 mg TID or
• Valacyclovir 500 mg BID

Topical agents are not recommended, as they are less effective than oral agents and easily generate resistance.

Recommended initial doses in HIV-positive patients are as follows:

• Acyclovir 400 mg 5 times a day for 7-10 days
• Valacyclovir 500-1000 mg BID for 10 days
• Famciclovir 250-500 mg TID for 10 days

First episode during pregnancy: Daily suppressive acyclovir 400 mg TID from 36 weeks’ gestation may prevent HSV lesions at term and hence the need for delivery via Caesarean section.

Regimens in adults and adolescents with a first clinical episode of genital HSV infection are as follows: ^[6]

• Acyclovir 400 mg PO TID for 10 days (standard dose) or
• Acyclovir 200 mg PO 5 times daily for 10 days or
• Valacyclovir 500 mg PO BID for 10 days or
• Famciclovir 250 mg PO TID for 10 days

Recurrent episodes

Initiate treatment during prodrome or within 24 hours of lesion appearance to ensure effectiveness. ^{[1, 3, 4]} Regimens are as follows:

• Acyclovir 400 mg PO TID for 5 days or
• Acyclovir 800 mg PO BID for 5 days or
• Acyclovir 800 mg PO TID for 2 days or
• Famciclovir 1000 mg PO BID for 1 day or
• Famciclovir 125 mg PO BID for 5 days or
• Famciclovir 500 mg PO once, followed by 250 mg PO BID for 2 days or
• Valacyclovir 500 mg PO BID for 3 days or
• Valacyclovir 1000 mg PO once daily for 5 days

Recurrent genital herpes  ^[5]

Oral acyclovir, valacyclovir, and famciclovir are effective at reducing the duration and severity of recurrent genital herpes. The reduction in duration is a median of 1-2 days.

Short-course therapies should be tried in the first instance, as follows:

• Acyclovir 800 mg TID for 2 days or
• Famciclovir 1 g BID for 1 day or
• Valacyclovir 500 mg BID for 3 days

Alternative longer 5-day courses include the following:

• Acyclovir 400 mg TID for 3-5 days or
• Acyclovir 200 mg 5 times daily or
• Valacyclovir 500 mg BID or
• Famciclovir 125 mg BID

Management of HIV-positive pregnant women with recurrent HSV infection: Women who are HIV antibody–positive and have a history of genital herpes should be offered daily suppressive acyclovir 400 mg TID from 32 weeks’ gestation to reduce the risk of HIV-1 transmission, especially if vaginal delivery is planned.

Recurrent clinical episode of genital HSV infection  ^[6]

Dosages for adults, adolescents, and pregnant women are as follows:

• Acyclovir 400 mg PO TID for 5 days, 800 mg BID for 5 days, or 800 mg TID for 2 days or
• Valacyclovir 500 mg PO BID for 3 days or
• Famciclovir 250 mg BID for 5 days

Dosages for people living with HIV and people who are immunocompromised are as follows:

• Acyclovir 400 mg PO TID for 5 days or
• Valacyclovir 500 mg PO BID for 5 days or
• Famciclovir 500 mg PO BID for 5 days

Episodic infection in immunocompromised patients/those with HIV infection

Recommended regimens for episodic infection in immunocompromised patients including those with HIV infection ^[1] are as follows:

• Acyclovir 400 mg PO TID for 5-10 days or
• Famciclovir 500 mg PO BID for 5-10 days or
• Valacyclovir 1000 mg PO BID for 5-10 days

Recommendations for HSV treatment in adult HSV‐seropositive solid-organ transplant recipients are as follows: ^[7]

• Acyclovir 400 mg TID
• Valacyclovir 1000 mg BID
• Famciclovir 500 mg BID
• Acyclovir 5 mg/kg IV q8h (if unable to take PO or more extensive disease)

Because prompt initiation of therapy is associated with improved outcomes, therapy should be started based on clinical diagnosis, pending laboratory confirmation. Therapy should be continued until all lesions are completely healed or at least 5‐7 days. ^[7]

Suppressive therapy

Daily suppressive antiviral therapy reduces the rate of outbreaks and of subclinical shedding. Use of once-daily valacyclovir has been demonstrated to reduce the rate of transmission to HSV-2–seronegative partners. ^{[1, 3, 8, 4]}

Suppressive therapy reduces the frequency of genital herpes recurrences by 70%-80% in patients who have frequent recurrences. ^[9]

In adults and adolescents with recurrent clinical episodes of genital HSV infection that are frequent (eg, 4-6 times per year or more), that are severe, or that cause distress, the WHO sexually transmitted infection (STI) guidelines suggest suppressive therapy over episodic therapy and reassessment after one year. ^[6]

The optimal total daily dose of suppressive acyclovir therapy is 800 mg. ^[5]

Recommended doses for adults, adolescents, and pregnant women are as follows: ^{[5, 6]}

• Acyclovir 400 mg BID (for all frequencies of disease recurrence)
• Valacyclovir 500 mg daily (if fewer than 10 recurrences per year)
• Valacyclovir 1 g daily (if more than 10 recurrences per year)
• Famciclovir 250 mg PO BID

Second-stage therapy for poorly controlled cases are as follows: ^[5]

• Acyclovir 400 mg TID
• Valacyclovir 250 mg BID
• Valacyclovir 500 mg BID
• Acyclovir 200 mg QID

Recommended drug regimens for daily suppressive treatment in immunocompromised/HIV-positive patients are as follows: ^{[6, 5, 1]}

• Acyclovir 400-800 mg PO BID to TID
• Valacyclovir 500 mg PO BID
• Famciclovir 500 mg PO BID

If these options do not adequately control disease, the first option should be to double the dose. If control is still not achieved, famciclovir 500 mg PO BID can be tried. ^[5]

Antiviral-resistant HSV infection

If lesions persist or recur in a patient receiving antiviral treatment, HSV resistance should be suspected and a viral isolate obtained for sensitivity testing. ^[9]

All acyclovir-resistant strains are also resistant to valacyclovir, and most are resistant to famciclovir. ^[9]

Treatment for acyclovir-resistant genital herpes: ^[9] Foscarnet (40-80 mg/kg IV q8h until clinical resolution is attained) is a DNA polymerase inhibitor unrelated to acyclovir and its congeners that is available only for intravenous use and has been compounded for topical use.

Alternatives are as follows: ^{[9, 10]}

• Cidofovir 5 mg/kg once weekly, an acyclic nucleoside phosphonate, is also available intravenously and can be formulated for topical use or
• Imiquimod is a topical alternative, as is topical cidofovir gel 1%, applied to the lesions once daily for 5 consecutive days.
• Pritelivir, a new helicase-primase inhibitor that is unaffected by thymidine kinase deficiency and is available in oral form, is currently under study.

The following are regimens for acyclovir‐resistant HSV in adult HSV‐seropositive solid organ transplant recipients: ^[7]

• Foscarnet 80‐120 mg/kg/day IV in 2‐3 divided doses
• Cidofovir 5 mg/kg IV once a week with probenecid
• Topical cidofovir (1% gel qd)
• Topical trifluridine

Resistance should be laboratory‐confirmed, although empiric therapy can be started. Reduce immunosuppression, if possible. ^[7]

Herpes labialis

Episodic therapy

Initiate treatment within 48 hours of symptom onset. ^{[3, 11, 12, 4, 13]} Regimens include the following:

• Acyclovir 400 mg PO 5 times daily for 5 days or
• Famciclovir 1500 mg PO as a single dose or
• Valacyclovir 2000 mg PO BID for 1 day or
• Docosanol Cream 10% (Abreva; available without prescription), applied topically 5 times daily until healed, for up to 10 days or
• Acyclovir cream 5%, applied topically 5 times a day for 4 days or
• Penciclovir cream 1%, applied topically q2h while awake for 4 days

Episodic treatment for recurrent herpes labialis in immunocompetent patients is as follows: ^[14]

• Acyclovir 200-400 mg PO 5 times a day for 5 days or
• Valacyclovir 2000 mg PO q12h for 1 day or
• Famciclovir 1500 mg PO as a single dose

Episodic treatment for recurrent herpes labialis in HIV-infected/immunocompromised patients is as follows: ^[14]

• Acyclovir 400 mg PO TID for 5-10 days or
• Valacyclovir 1000 mg PO BID for 5-10 days or
• Famciclovir 500 mg PO BID for 5-10 days

Suppressive therapy

Regimens include the following: ^{[3, 11, 4, 13]}

• Acyclovir 400 mg PO BID or
• Valacyclovir 500 mg PO once daily

Long-term suppressive therapy should be considered in patients with frequent and severe infections, specifically patients with herpes-associated erythema multiforme or eczema herpeticum. ^[14]

Long-term suppressive therapy for recurrent herpes labialis in immunocompetent patients is as follows: ^[14]

• Acyclovir 400 mg PO BID or
• Valacyclovir 500-1000 mg PO daily

Stomatitis  ^[15]

• Acyclovir 400 mg PO TID for 7-10 days
• Acyclovir 200 mg PO 5 times daily for 7-10 days
• Famciclovir 250 mg PO q8h for 7-10 days
• Valacyclovir 1 g PO BID for 7-10 days

Herpes labialis prophylaxis  ^[15]

• Acyclovir 400 mg PO BID
• Famciclovir 250 mg PO BID
• Valacyclovir 250 mg PO BID
• Valacyclovir 500 mg PO once daily
• Valacyclovir 1000 mg PO once daily

Esophagitis:  Duration typically 7-10 days ^[15]

• Acyclovir 400-800 mg PO 5 times daily
• Valacyclovir 1 g PO BID
• Famciclovir 500 mg PO BID or TID
• Acyclovir 5 mg/kg IV q8h

A systematic review and meta-analysis of 4 studies showed that patients receiving topical corticosteroids in addition to antiviral therapy had a significantly lower recurrence rate of ulcerative lesions compared with those in the placebo group (OR, 0.50; 95% CI, 0.39-0.66; P< 0.001) and the antiviral treatment alone group (OR, 0.73, 95% CI, 0.58-0.92; P = 0.007). The healing time was also significantly shorter in combined therapy compared with placebo (P< 0.001). ^[16]

Severe HSV disease

Disseminated HSV disease or severe symptoms in the immunocompromised patient ^[1] : Acyclovir 5-10 mg/kg IV q8h for 2-7 days until clinical improvement is observed, followed by oral antiviral therapy, to complete at least 10 days total of therapy

HSV meningoencephalitis ^{[3, 17]} : Acyclovir 10-20 mg/kg IV q8h for 14-21 days should be given early to prevent extensive replication and subsequent CNS damage.

Early treatment should be started in any of the following situations: ^[18]

• Before loss of consciousness
• Within 24 hours of symptom onset
• Glasgow Coma Scale score of 9-15

Encephalitis ^[15] : Acyclovir 10 mg/kg IV q8h for 14-21 days

Acute meningitis ^[15] : Acyclovir 10 mg/kg IV q8h for 7-10 days

Benign recurrent lymphocytic meningitis ^[15] : Acyclovir 10 mg/kg IV q8h for 7-10 days

Severe, visceral/disseminated/CNS disease in adult HSV‐seropositive solid organ transplant recipients, as follows: ^[7]

• Acyclovir 10 mg/kg IV q8h; intravenous therapy should be continued until disease resolution or 14 days, at which time oral medication may be given
• For CNS infection, 21 days of intravenous therapy may be considered.
• For disseminated or CNS infection, continue for 21 days.

Neonatal HSV ^{[3, 17, 19]} : Acyclovir 20 mg/kg IV q8h

Duration of therapy is determined by the disease classification, as follows ^[20]

• Skin, eye, mouth (SEM) disease: 14 days
• CNS or disseminated disease: At least 21 days

After completion of the recommended 14- or 21-day treatment course with intravenous acyclovir determined by patient's classification of neonatal HSV disease, patients are transitioned to oral acyclovir (300 mg/m²/dose TID) to complete a 6-month course of suppressive therapy. ^[20]

All infants with CNS involvement require repeat lumbar puncture to assess for clearance of the virus prior to termination of intravenous therapy. ^[20]

If HSV PCR continues to show viral DNA at approximately day 21 of therapy, intravenous acyclovir should be extended an additional week and a repeat lumbar puncture performed to obtain CSF for HSV PCR testing. ^[20]

See Herpes Simplex Viruses: Test Your Knowledge, a Critical Images slideshow, for more information on clinical, histologic, and radiographic imaging findings in HSV-1 and HSV-2.