What are the key clinical features, diagnosis, treatment, and prevention strategies for herpes simplex virus type 1 (HSV‑1) and type 2 (HSV‑2)?

Herpes Simplex Virus (HSV-1 and HSV-2): Comprehensive Clinical Guide

Epidemiology and Transmission

HSV-1 and HSV-2 are among the most prevalent viral infections globally, with HSV-1 affecting approximately 47.8% and HSV-2 affecting 12.1% of the US population aged 14-49 years. 1

• HSV-1 traditionally causes orofacial infections but is increasingly responsible for genital herpes, particularly in developed countries where it now accounts for approximately half of new genital herpes cases 2, 3
• HSV-2 nearly exclusively causes genital disease and remains the primary cause of genital herpes worldwide 1
• Most HSV-2 infections are unrecognized—only 13% of HSV-2 seropositive persons have been diagnosed with genital herpes 1
• HSV-2 increases HIV acquisition risk 3-fold compared to HSV-2 negative individuals 1
• Transmission occurs through direct skin-to-skin contact, with viral shedding possible even without visible lesions 3

Clinical Manifestations

Orofacial HSV-1

• Typically manifests above the neck with lesions on lips, face, and oral mucosa 4
• Primary infections are generally the most severe manifestation when HSV-seronegative individuals acquire the virus 4
• Herpes gladiatorum affects wrestlers and other contact athletes, with lesions on exposed areas like face and forehead transmitted during skin-to-skin contact 4

Genital Herpes (HSV-1 or HSV-2)

• Presents as recurrent, self-limited genital ulcers 1, 5
• Primary episodes are typically more severe than recurrences 5
• Many infections remain asymptomatic or minimally symptomatic, yet viral shedding still occurs 3

Severe Manifestations

• HSV encephalitis can occur, particularly with HSV-1, causing fever, photophobia, and altered consciousness requiring intensive care 6
• Neonatal herpes is uncommon but serious, occurring when virus is present in the genital tract during delivery 1
• Immunocompromised patients experience more aggressive, persistent, and potentially life-threatening infections 7

Diagnosis

Use type-specific molecular or virologic tests when genital ulcers are present, and type-specific serologic tests to detect antibody when lesions are absent. 1

• Clinical diagnosis is neither sensitive nor specific—virological and type-specific serological tests should be used routinely 3
• PCR testing of lesion samples provides definitive diagnosis during active outbreaks 1
• Type-specific serology distinguishes HSV-1 from HSV-2 antibodies in asymptomatic patients 1

Coding Considerations

• Anogenital herpes codes (A60.0-A60.9) do not apply to facial or forehead HSV-1 lesions 4
• For non-genital, non-oral mucosal HSV-1 infections (e.g., forehead), use B00.9 (Herpesviral infection, unspecified) as ICD-10-CM does not distinguish primary from recurrent cutaneous infections 4

Treatment

Standard Antiviral Therapy

Acyclovir and its derivatives (valacyclovir, famciclovir) are the gold standard for HSV treatment and can be administered as either episodic therapy for outbreaks or daily suppressive therapy. 1, 7

Episodic Treatment

• Initiate within 24 hours of symptom onset for maximum benefit 4
• Valacyclovir 500 mg twice daily for 7 days reduces viral shedding duration by approximately 21% 4
• Decreases duration of symptoms and signs during outbreaks 5

Suppressive Therapy

• Daily antiviral medication prevents recurrences and reduces viral shedding 1
• Consider for patients with frequent recurrences or high-risk situations (e.g., contact athletes, discordant couples) 4
• Reduces risk of sexual transmission to partners when combined with condom use 3

Special Populations

Pregnancy

Women with a history of genital herpes should receive suppressive acyclovir (400 mg TID) or valacyclovir (500 mg BID) starting at 36 weeks' gestational age to decrease viral shedding, recurrences, and cesarean deliveries. 1

• Routine serologic screening for HSV during pregnancy is not recommended by ACOG due to lack of cost-effectiveness evidence 1
• Screen pregnant women for history of genital herpes 1
• Acyclovir remains pregnancy category B 1
• Caveat: A case-control study showed 4.7-fold increased odds of gastroschisis with antiherpes medications used between one month before conception through the third month of pregnancy, though significant confounders and recall bias were present 1

HIV Coinfection

Suppressive acyclovir should be considered for the first 6 months after starting ART among HSV-2 seropositive individuals to reduce genital ulcer disease risk, particularly those with CD4 count <200 cells/μL. 1

• Genital ulcer disease increases during the first 3 months after initiating ART 1
• Acyclovir reduces GUD risk by 58% (prevalence risk ratio 0.42) 1
• Valacyclovir and famciclovir may be reasonable alternatives though not specifically studied in this setting 1
• Suppressive antiherpesvirus therapy is not recommended to prevent HIV transmission among sexual partners of HIV/HSV-2 coinfected individuals 1

Athletes (Herpes Gladiatorum)

• Isolate from competition for 3-8 days to prevent outbreak spread 4
• Exclude athletes with active lesions until all lesions are fully crusted or physician confirms non-infectious status 4
• Consider suppressive antiviral therapy for wrestlers with recurrent outbreaks given high-risk contact environment 4

Acyclovir-Resistant HSV

For acyclovir-resistant HSV (primarily in immunocompromised patients), cidofovir and foscarnet serve as alternative treatments, though foscarnet exhibits limiting toxicity. 2, 7

• Resistance is uncommon in immunocompetent patients but occurs more frequently with long-term treatment and prophylaxis in immunocompromised individuals 7
• Helicase primase inhibitors (HPIs) are emerging as promising alternatives with high efficacy, novel mechanism of action, and potential to overcome resistance 2

Prevention Strategies

Sexual Transmission

• Antiviral treatment of infected partners combined with condom use reduces sexual transmission risk 3
• Counsel patients that transmission can occur during asymptomatic viral shedding 3
• Type-specific serologic testing of partners can guide counseling and prevention strategies 1

Neonatal Herpes Prevention

• Women acquiring genital herpes during pregnancy are at highest risk for transmission to infants 1
• Suppressive-dose acyclovir (400 mg TID) starting at week 36 prevents HSV recurrences requiring cesarean delivery at term 1
• Whether this approach reduces actual transmission risk remains under investigation 1

Vaccine Development

• Vaccine development has been challenging and remains an area of active research 2
• No effective vaccine is currently available 2

Counseling Essentials

Counseling on natural history, transmission, treatment, and management of sexual partners is an integral part of genital herpes management. 5

• Address the significant stigma associated with genital herpes through patient education about natural history 1
• Explain that HSV is a chronic, lifelong infection with potential for recurrent episodes 5
• Discuss asymptomatic viral shedding and transmission risk even without visible lesions 3
• Provide information about treatment options (episodic vs. suppressive therapy) based on outbreak frequency and patient preference 1
• Counsel on safer sex practices including condom use and disclosure to partners 3

Key Clinical Pitfalls

• Do not rely on clinical diagnosis alone—virological confirmation is essential as clinical diagnosis lacks sensitivity and specificity 3
• Do not delay antiviral therapy—initiate within 24 hours of symptom onset for optimal efficacy 4
• Do not assume all genital herpes is HSV-2—HSV-1 now causes approximately half of new genital herpes cases in developed countries 2, 3
• Do not overlook cardiac complications in severe HSV encephalitis—consider stress-induced cardiomyopathy in critically ill patients 6
• Do not use anogenital ICD-10 codes for non-genital HSV-1 infections—use appropriate anatomic codes or B00.9 for unspecified sites 4