Approach Considerations
Most herpes simplex virus (HSV) infections are self-limited and treatment is not always indicated or necessary. However, antiviral therapy shortens the course of the symptoms and may prevent dissemination and transmission.
Intravenous, oral, and topical antiviral medications are available for treatment of HSV infection and are most effective if used at the onset of symptoms. Oral therapy can be given at the time of the episode or as long-term suppressive therapy.
Treatment of herpes labialis and herpes genitalis generally consists of episodic courses of oral acyclovir, valacyclovir, and famciclovir. Oral antiviral medications may be used (off label) as therapy for other uncomplicated HSV conditions (eg, herpetic whitlow), and the same doses as those used for herpes genitalis treatment are commonly recommended.
Complicated HSV infections, cutaneous and/or visceral dissemination, neonatal HSV infection, and severe infections in those who are immunocompromised should be treated promptly with intravenous acyclovir.
In patients who are immunocompromised and have recurrent HSV infections, acyclovir-resistant HSV strains have been identified, and treatment with intravenous foscarnet or cidofovir may be used.
Medical Care
The treatment of herpes simplex virus (HSV) infections depends on multiple factors, including the location and severity of the disease, immune status, pregnancy, primary or recurrent disease, and frequency of recurrences.
Management
Herpes labialis
Primary infection with HSV-1 commonly presents a gingivostomatitis in children. Treatment should be started within 72 hours of suspected primary HSV-1 gingivostomatitis. Treatment with acyclovir decreases the duration of fever, oral lesions, eating/drinking difficulties, and viral shedding. [51] The duration of oral lesions is reduced by 6 days in patients treated with acyclovir in comparison to those treated with placebo (median 4 d vs 10 d). [51] The duration of treatment for primary HSV-1 infection is 7-10 days.
Recurrences are typically less severe than primary infections and are often heralded by a prodrome of burning pain or stinging prior to the herpetic eruption. Episodic treatment should be initiated at the first sign of recurrence. Treatments with acyclovir, valacyclovir, and famciclovir have all been shown to reduce the duration of lesions by 1-2 days. A study of 701 patients comparing famciclovir to placebo showed a median time to resolution of 4-4.5 days in the famciclovir groups in comparison to 6.2 days in the placebo group. [52] The dosing of valacyclovir and famciclovir is less cumbersome and more convenient, and both offer greater bioavailability.
Episodic treatment for recurrent herpes labialis in immunocompetent patients is as follows:
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Acyclovir 200-400 mg PO 5 times a day for 5 days
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Valacyclovir 2000 mg PO every 12 hours for 1 day
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Famciclovir 1500 mg PO as a single dose
Episodic treatment for recurrent herpes labialis in HIV-infected/immunocompromised patients is as follows:
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Acyclovir 400 mg PO 3 times a day for 5-10 days
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Valacyclovir 1000 mg PO twice daily for 5-10 days
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Famciclovir 500 mg PO twice daily for 5-10 days
Long-term suppressive therapy should be considered in patients with frequent and severe infections, specifically patients with herpes-associated erythema multiforme or eczema herpeticum. Long-term suppressive therapy has been shown to reduce the number of recurrences and prolong the time to first recurrence. [53]
Long-term suppressive therapy for recurrent herpes labialis in immunocompetent patients is as follows:
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Acyclovir 400 mg PO twice daily
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Valacyclovir 500-1000 mg PO daily
Genital herpes
Genital herpes is a chronic disease characterized by intermittent recurrences. The majority of cases are caused by HSV-2, and, like HSV-1, the primary infection is typically more severe. On average, patients experience four recurrences per year and 38% of patients have six or more recurrences during the first year. [54] Approximately 90% of patients experience a recurrence in the first year and some have a prodrome of tingling, pain, or paresthesias. [54, 55] The duration of lesions and viral shedding is shorter in recurrent episodes of genital herpes. Lesions may be asymptomatic, and many patients may be unaware when transmission occurs. [48] Primary genital herpes infections are typically more severe and may last 3 weeks if untreated. Treatment with systemic antivirals helps to decrease the duration and severity of both primary and recurrent genital herpes, but it does not eliminate the virus. Thus, the chronicity of the disease and preventive strategies are important aspects of management. [48]
Treatment for primary infection of genital herpes is as follows:
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Acyclovir 200-400 mg PO 3 times per day for 7-10 days
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Valacyclovir 1000 mg PO twice daily for 7-10 days
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Famciclovir 250 mg PO 3 times per day for 7-10 days
Systemic antivirals may be given for episodic disease recurrence or as long-term suppressive therapy. Episodic treatment can be considered for patients with few recurrences and those who experience a prodrome of symptoms signifying the need for initiation of systemic antivirals. Patients with multiples recurrences (6 or more) per year and those with unaffected partners may benefit from long-term suppressive therapy. Long-term suppressive therapy leads to a 70-80% reduction in the frequency of recurrences and decreases the rate of transmission. [48] Valacyclovir administered as long-term suppressive therapy has been shown to reduce transmission by 48%. [56] Recommendations for the episodic treatment of genital herpes and long-term suppressive therapy in immunocompetent and immunocompromised patients have been developed by the US Centers for Disease Control and Prevention (CDC) and are summarized below. [48]
Episodic treatment of recurrent genital herpes is as follows:
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Acyclovir 400 mg PO 3 times per day for 5 days
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Acyclovir 800 mg PO twice daily for 5 days
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Acyclovir 800 mg PO 3 times per day for 2 days
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Valacyclovir 1000 mg PO daily for 5 days
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Famciclovir 125 mg PO twice daily for 5 days
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Famciclovir 1000 mg PO twice daily for 1 day
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Famciclovir 500 mg PO once, then 250 mg PO twice daily for 2 days
Episodic treatment of recurrent genital herpes in patients with HIV infection is as follows:
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Acyclovir 400 mg PO 3 times per day for 5-10 days
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Valacyclovir 1000 mg PO twice daily for 5-10 days
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Famciclovir 500 mg PO twice daily for 5-10 days
Long-term suppressive therapy for recurrent genital herpes is as follows:
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Acyclovir 400 mg PO twice daily
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Valacyclovir 500-1000 mg PO once daily
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Famciclovir 250 mg PO twice daily
Long-term suppressive therapy for recurrent genital herpes in patients with HIV infection is as follows:
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Acyclovir 400-800 mg PO 2-3 times per day
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Valacyclovir 500 mg PO twice daily
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Famciclovir 500 mg PO twice daily
Treatment with systemic antivirals leads to faster healing and resolution of symptoms by 1-2 days. Viral shedding is also reduced as a result of treatment. All of the systemic antivirals have similar efficacy. A study that compared famciclovir 1000 mg twice daily for a single day and valacyclovir 500 mg twice daily for 3 days found no difference in the reduction in healing time. [57] Similar results with regard to long-term suppressive therapy have been observed among the systemic antivirals.
Special considerations
Acyclovir-resistant HSV
Acyclovir resistance is not common but does occur at higher rates in immunocompromised patients. [58] Acyclovir resistance can be attributed to thymidine kinase mutations and confers cross-resistance among the antiviral nucleoside analogs (acyclovir, valacyclovir, famciclovir, and penciclovir). [58] Agents that inhibit HSV-DNA polymerase (foscarnet and cidofovir) can be used in cases in which acyclovir resistance is suspected. Acyclovir resistance should be suspected in cases with persistent lesions or recurrences in patients on treatment. [48] Treatment with either intravenous foscarnet or cidofovir is effective for such cases. Additionally, a compounded topical preparation of cidofovir 1% gel applied once daily for 5 days may be a useful adjunctive or alternative treatment. [48, 59, 60] Resiquimod is an agonist of Toll-like receptors 7 and - that has been studied in patients with recurrent genital herpes. Topical resiquimod 0.01% gel applied twice weekly for 3 weeks increased the number of days to healing by 6-8 days and was associated significantly more erythema and erosions in comparison with vehicle. [61]
Pregnancy
Transmission rates of HSV to neonates during pregnancy are low in women with nonprimary HSV infections, but they approach 50% in women with primary infections. [62] Routine screening for HSV in pregnancy is not indicated, and diagnostic testing should be performed in suspected cases of genital herpes. [62] Management of genital herpes in pregnancy is accomplished through careful history and physical examination, especially during delivery. Vaginal delivery can be performed in the absence of signs or symptoms of genital herpes infection. [48] However, cesarean delivery should be performed in women with primary or recurrent genital herpes at the time of labor to reduce the risk of neonatal transmission. [48] Systemic antivirals can be used safely during pregnancy and can reduce the need for cesarean delivery. [48] However, neonatal transmission is still possible. [48]
Suppressive therapy for recurrent genital herpes in pregnancy is as follows:
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Acyclovir 400 mg PO 3 times per day (starting at 36 weeks’ gestation)
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Valacyclovir 500 mg PO twice daily (starting at 36 weeks’ gestation)
Topical antivirals
Acyclovir is available as a 5% ointment or cream and can be applied 5-6 times per day for either 4 or 7 days for the treatment of herpes labialis or genital herpes, respectively. The cream formulation should be avoided in cases of genital herpes. The benefit of topical acyclovir in the treatment of herpes simplex infections is modest at best. Despite statistically significant benefits in clinical trials, clinically significant results are not appreciable. In a study that compared acyclovir 5% cream with vehicle in the treatment of herpes labialis, a reduction in the duration of recurrence by one half day was noted in the acyclovir group. [63] A combination of 5% acyclovir and 1% hydrocortisone is available and can be applied topically 5 times per day at the earliest sign of cold sore recurrence. It has been shown to prevent progression in comparison to acyclovir and placebo. [64] Penciclovir is another topical antiviral available as a 1% cream that can be applied every 2 hours for herpes labialis. The clinical efficacy of topical penciclovir is similar to topical acyclovir. Docosanol 10% cream is available over the counter and can be applied 5 times a day for up to 10 days. In a study that compared docosanol with placebo, the average resolution time was approximately 4 days, or 18 hours shorter than placebo. [65] As stated, topical treatments for herpes simplex are much less effective than systemic antivirals. The CDC recommends avoidance of topical antivirals, owing to a lack of clinical benefit. [48]
Other cutaneous HSV infections
Localized cutaneous HSV infections may result from mucocutaneous or cutaneous contact with infectious sources. Herpes gladiatorum, herpetic whitlow, and other localized cutaneous herpetic infections can typically be managed with similar treatment strategies for primary and recurrent herpes labialis or genitalis.
Eczema herpeticum
Eczema herpeticum is an acute HSV infection that occurs in patients with chronic severe atopic dermatitis. It is characterized by erythematous vesicles, erosions, and crusting that occur in areas affected by atopic dermatitis. [66] Dissemination can occur and may be associated with fever, pain, and lymphadenopathy. [66] Prompt initiation of systemic antivirals is indicated.
Erythema multiforme
HSV is the most common cause of erythema multiforme, and recurrences of erythema multiforme parallel recurrences of herpes simplex. Long-term suppressive therapy can be used for patients with six or more episodes per year or for those with severe recurrences. Long-term suppressive therapy with acyclovir has been shown to suppress recurrences of erythema multiforme in approximately 60% of patients. [67] Dosing of systemic antivirals for recurrent herpes labialis or genitalis can be used, as the majority of evidence is derived from small studies and case reports.
Consultations
Consult a dermatologist and an infectious diseases specialist in cases of complicated or acyclovir-resistant herpes simplex virus (HSV) infections.
Activity
Avoidance of known triggers of herpes simplex recurrences, such as ultraviolet (UV) light and smoking, may diminish the number of outbreaks experienced by an individual.
Prevention
Herpes simplex virus (HSV) viral shedding is greatest during clinically evident outbreaks; however, transmission from individuals who are seropositive to their partners who are seronegative usually occurs during asymptomatic periods of viral shedding. Therefore, preventing transmission requires more than abstaining from intimate contact during outbreaks.
The prevention of herpes labialis is focused on the avoidance of triggers and prophylaxis in certain scenarios. UV light exposure, specifically UVB, can lead to recurrences of herpes labialis, and sunscreen can help prevent recurrences. [68] Laser resurfacing has been shown to cause recurrences in 2.2% of patients, and prophylaxis with systemic antivirals may reduce the risk of recurrence. [69, 70]
Barrier methods, such as condoms, confer 10-15% protection against the transmission of genital herpes, as transmission can occur to and from uncovered mucocutaneous surfaces or if the integrity of the barrier is compromised. Condoms have also been shown to be more effective in protecting women than men.
Various HSV vaccines have been and continue to be under investigation for the treatment and prevention of herpes genitalis, although most have not been shown to be effective. [71] A trivalent glycoprotein C, D, and E vaccine has been evaluated in guinea pigs, and a 50% reduction in the frequency of recurrences and vaginal shedding of HSV was observed. [72] Double-blind randomized trials of a glycoprotein D HSV-2 vaccine revealed that the vaccine conferred protection against the virus in women who were serologically negative for both HSV-1 and HSV-2. However, it did not prevent HSV infection in men, despite their serostatus, or in women who were positive for HSV-1 but negative for HSV-2. [73] In 2017, a glycoprotein D monoclonal antibody that can block in vitro cell-to-cell spread of HSV was developed, with implications for the prevention and treatment of HSV infection. [74]
Long-term suppressive therapy for genital herpes has been shown to decrease asymptomatic HSV shedding, and long-term valacyclovir therapy significantly decreased HSV transmission to susceptible partners of individuals who were HSV-2 positive by 50-77%. [75] Acyclovir and famciclovir have been shown to be as effective as valacyclovir for suppression of recurrences. Considerations for placing a patient on long-term suppressive therapy include frequent and/or severe outbreaks, infection in a patient who is immunocompromised, the patient’s sex, the patient’s HSV serostatus, and the reproductive capability of the patient’s partner.
HIV infection of an HSV patient or his or her seronegative partner should also be considered a possible indication for suppression, given the proposed increase in HIV viral load, although HSV suppressive therapy has not been shown to have an effect on HIV-1 viral shedding. [76, 77, 78]
Women who are HSV-2 negative should be counseled to abstain from intercourse during the third trimester of pregnancy with partners who could be seropositive because primary HSV infection during this time places the fetus at highest risk of infection.
The most common approach in attempting to prevent vertical transmission is to have women with clinically apparent HSV lesions during labor undergo cesarean delivery. However, cesarean delivery does not prevent all cases of neonatal infection because in utero infection occurs and antepartum HSV cultures are not a good predictor of neonatal infections.
Use of acyclovir 400 mg PO thrice daily during the third trimester of pregnancy has been proven to be safe and effective in preventing neonatal herpes and in eliminating the need for cesarean deliveries. [79]
A large nationwide cohort study in Denmark did not find any association between first trimester in utero antiviral drug (ie, acyclovir, valacyclovir, famciclovir) exposure and congenital anomalies. In 1804 pregnancies exposed to an antiviral drug during the first trimester, 40 infants (2.2%) were diagnosed with a major birth defect, compared with 19,920 (2.4%) unexposed pregnancies. [80] A 2017 review also reports that prophylactic acyclovir reduces active genital lesions at delivery. [81]
The American College of Obstetricians and Gynecologists (ACOG) has released guidelines on expedited partner therapy for chlamydial and gonorrheal sexually transmitted diseases (STDs). [82, 83] While designed to prevent reinfection with chlamydia and gonorrhea, the recommendations can also be applied to other STDs. The ACOG recommendations include the following:
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Expedited partner therapy to prevent reinfection, with legalization of expedited partner therapy
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Counsel partners to undergo screening for HIV infection and other STDs
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Expedited partner therapy contraindicated in cases of suspected abuse or compromised patient safety; pretreatment evaluation for abuse potential recommended
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Expedited partner therapy medications and protocols based on CDC, state, and/or local guidelines
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Characteristic cluster of vesicles on an erythematous base. Photo courtesy of Dr. John Reeves.
