What are the causes and management of herpes simplex virus (HSV) infection?

Causes and Management of Herpes Simplex Virus Infection

Causative Agents and Transmission

Herpes simplex virus (HSV) infection is caused by two distinct viral serotypes—HSV-1 and HSV-2—that are transmitted through direct contact with infected secretions or lesions, with most genital infections caused by HSV-2 and most oral infections by HSV-1, though HSV-1 is increasingly causing genital disease. 1

Viral Etiology

• HSV-1 traditionally causes orolabial disease (cold sores) and is acquired through oral contact 1
• HSV-2 predominantly causes genital infections and is transmitted sexually 1
• HSV-1 now accounts for 5-30% of first-episode genital herpes cases, particularly in well-resourced settings 1

Transmission Mechanisms

• Sexual transmission is the primary route for genital HSV-2 infection, with antibodies rarely found before onset of sexual activity 2
• Asymptomatic viral shedding allows transmission even when lesions are absent, making many infected persons unaware they are transmitting the virus 1
• Most cases are transmitted by persons who don't know they have the infection or are asymptomatic at the time of transmission 1
• Vertical transmission occurs when infants are delivered vaginally to women with active genital infection 3

Epidemiology

• 47.8% of the US population aged 14-49 years is seropositive for HSV-1 1
• 12.1% of the US population aged 14-49 years is seropositive for HSV-2 1
• Only 13% of HSV-2-seropositive persons have been diagnosed with genital herpes 1
• At least 45 million persons in the United States have genital HSV-2 infection 1

Pathophysiology and Natural History

Viral Latency Mechanism

• The virus establishes lifelong latency in sensory ganglia, persisting in a dormant, non-multiplying episomal form within neuronal nuclei that cannot be eradicated by the immune system or current antiviral medications 4
• During latency, the virus remains inactive and causes no symptoms but retains the ability to reactivate 4

Reactivation Process

• Lesions typically recur at the same anatomical location as primary infection because the virus returns via the same nerve pathway 4
• Triggers for reactivation include menstruation and immunosuppression 4
• Recurrence frequency varies from once every few years to several times per month 4
• Episodes typically last less than 10 days but may be prolonged by secondary bacterial infection or immunosuppression 4

Clinical Manifestations

• Primary infection occurs at some time in almost every member of the population, especially among those in crowded, unsanitary conditions 5
• Many primary infections are subclinical or self-limited 5
• In newborns, patients with eczema, or immunocompromised patients, primary infection may become severe, generalized, and life-threatening 5
• Recurrent episodes follow the classic progression: prodrome → erythema → papule → vesicle → pustule → ulceration → crusting 4

Management Approach

First Clinical Episode of Genital Herpes

For first-episode genital herpes, initiate systemic antiviral therapy immediately with one of three FDA-approved regimens for 7-10 days, as these drugs partially control symptoms but do not eradicate latent virus. 1

Recommended First-Line Regimens

• Acyclovir 400 mg orally three times daily for 7-10 days 1, 6
• OR Acyclovir 200 mg orally five times daily for 7-10 days 1
• OR Famciclovir 250 mg orally three times daily for 7-10 days 1, 7
• OR Valacyclovir 1 g orally twice daily for 7-10 days 1, 8

Key Management Principles

• Treatment may be extended if healing is incomplete after 10 days 1
• Topical acyclovir is substantially less effective than systemic therapy and should not be used 1
• Identification of HSV type (HSV-1 vs HSV-2) has prognostic importance, as HSV-1 genital infections recur much less frequently 1

Recurrent Episodes

For recurrent genital herpes, episodic therapy should be initiated at the first sign or symptom of an episode, ideally during the prodrome or within 24 hours of lesion onset. 8

Episodic Treatment Considerations

• Most immunocompetent patients with recurrent disease do not benefit significantly from treatment unless initiated very early 1
• There are no data on effectiveness of treatment initiated more than 24 hours after onset of recurrent episode symptoms 8
• Peak viral titers occur within the first 24 hours after lesion onset, making early treatment critical 4

Suppressive Therapy

Suppressive therapy with daily oral antivirals reduces recurrence frequency by ≥75% in patients with six or more episodes per year, but does not eliminate the latent viral reservoir. 4

Suppressive Regimens

• Famciclovir 250 mg orally twice daily 1
• Safety and effectiveness data support suppressive therapy for up to 1 year in otherwise healthy patients 8
• In HIV-infected patients, safety and effectiveness data support suppressive therapy for up to 6 months 8

Herpes Labialis (Cold Sores)

For recurrent herpes labialis, initiate treatment at the earliest symptom (tingling, itching, or burning) with famciclovir 1500 mg as a single dose or valacyclovir with two doses taken 12 hours apart. 8, 7

• There are no data on effectiveness of treatment initiated after development of clinical signs (papule, vesicle, or ulcer) 8
• Treatment should not exceed 1 day (2 doses) 8

Special Populations

HIV-Infected Patients

• HIV-infected patients may require longer courses of therapy 1
• Episodes are usually longer and more severe in immunocompromised patients 4, 9
• For recurrent orolabial or genital herpes in HIV-infected adults: famciclovir 500 mg orally twice daily for 7 days 7

Pregnant Women

• Acyclovir is Pregnancy Category B; use only if potential benefit justifies potential risk 6
• A prospective registry of 749 pregnancies with first-trimester acyclovir exposure showed birth defect rates approximating the general population 6
• Valacyclovir and famciclovir safety data in pregnancy are more limited 8, 7

Renal Impairment

• Dosage adjustment is mandatory in patients with renal impairment to prevent acute renal failure 6, 7
• Adequate hydration should be maintained during therapy 6, 8

Critical Patient Counseling Points

Disease Education

• Patients must understand that HSV infection is incurable with current therapies because the latent viral reservoir in neurons is inaccessible to both immune surveillance and antiviral medications 4, 6, 8
• Genital herpes is frequently transmitted through asymptomatic viral shedding even when no lesions are present 8
• Patients should avoid contact with lesions or intercourse when lesions/symptoms are present 6, 8

Transmission Prevention

• Sex partners of infected persons should be advised they might be infected even if asymptomatic 8
• Type-specific serologic testing of asymptomatic partners can determine whether risk for HSV-2 acquisition exists 8
• Valacyclovir has not been shown to reduce transmission of sexually transmitted infections other than HSV-2 8
• Safer sex practices should be used in combination with suppressive therapy 8

Common Pitfalls to Avoid

• Do not use topical acyclovir—it is substantially less effective than oral therapy 1
• Do not delay treatment initiation—effectiveness decreases dramatically if treatment is not started within 24-72 hours of symptom onset 8
• Do not prescribe standard doses in renal impairment—this can cause acute renal failure 6, 7
• Do not tell patients antivirals will cure the infection—they only suppress viral replication and do not affect latent virus 1, 4
• Do not assume absence of lesions means non-infectiousness—asymptomatic shedding is a major source of transmission 1, 8