Genital Herpes

Genital herpes is a recurrent, lifelong viral infection of the anogenital skin and mucosa caused by herpes simplex virus type 2 (HSV-2) or type 1 (HSV-1). It is one of the commonest sexually transmitted infections: global HSV-2 seroprevalence about 13% (491 million aged 15 to 49), and HSV-1 genital infections are increasing, now causing a majority of first episodes in young adults in many high-income countries (through oral-genital contact).

Virology and pathogenesis

• Enveloped double-stranded DNA alpha-herpesvirus. Infection of mucosal epithelium, then retrograde axonal transport to sensory ganglia (sacral dorsal root ganglia), where it establishes lifelong latency. Reactivation produces recurrent lesions or asymptomatic viral shedding.
• HSV-2 genital infection recurs more often (about 4 per year in the first year; frequency declines over time) than HSV-1 genital infection (about 1 recurrence per year).
• Asymptomatic shedding occurs on about 10 to 20% of days in HSV-2 seropositive people, and is the main route of transmission (70% of transmissions occur without lesions).
• Transmission and risk factors: sexual contact, perinatal (neonatal herpes), female sex (higher susceptibility), number of partners, age, HIV infection, other STIs, and low socioeconomic factors. Condoms reduce risk by about 30%, valaciclovir suppression in the infected partner reduces transmission by about 48% (to 50%).
• Interaction with HIV: HSV-2 increases the risk of HIV acquisition 2 to 3 fold and increases HIV shedding, while HIV leads to more severe, prolonged and atypical herpes.

Complications

• Aseptic meningitis (more common in women), sacral radiculopathy (urinary retention, constipation, neuralgia), autonomic dysfunction, transverse myelitis (rare), disseminated herpes (immunocompromised, pregnancy), eczema herpeticum, herpetic whitlow, proctitis, psychosocial morbidity, and neonatal herpes (the most serious consequence).
• Neonatal herpes: risk highest (30 to 50%) with a primary infection acquired in the third trimester near delivery, and about 1% or less with recurrent maternal infection. Outcomes: skin-eye-mouth disease, CNS disease, or disseminated disease, with mortality up to 30% in disseminated forms even with treatment.

Most infections are subclinical or unrecognised (up to 70 to 80% of seropositive people have no diagnosed genital herpes).

First episode (primary infection)

• Incubation 2 to 12 days. Painful grouped vesicles on an erythematous base that rapidly ulcerate, multiple tender ulcers on the vulva, vagina, cervix, penis, perineum, buttocks, perianal region, or thighs, lasting 2 to 3 weeks (average 12 to 20 days).
• Systemic features in primary infection (fever, headache, malaise, myalgia in 40 to 70%), tender inguinal lymphadenopathy, dysuria, urinary retention, vaginal or urethral discharge, and pharyngitis.
• Cervicitis is frequent in women (80%). Aseptic meningitis occurs in up to 10% of women.
• First episode non-primary (previous HSV-1 immunity and HSV-2 acquired) is milder.

Recurrent episodes

• Prodrome of tingling, burning, itching or shooting pains in the buttock, thigh or genitals (hours to 2 days before lesions).
• Fewer lesions, localised, which heal within 5 to 10 days (average 7 days), with no systemic symptoms. Recurrences are less frequent over years.
• Atypical presentations: fissures, redness, itching without vesicles, genital pain without lesions.
• Other presentations: herpetic proctitis (MSM: anorectal pain, tenesmus, discharge), urethritis, herpetic whitlow, ocular herpes, and extragenital lesions. In immunocompromised patients: chronic, persistent, hypertrophic, verrucous, or ulcerative lesions that may be resistant to aciclovir.
• Differential diagnosis: syphilis, chancroid, LGV, Behçet disease, aphthous ulcers, fixed drug eruption, trauma, candidiasis, folliculitis, lichen simplex, zoster, and irritant dermatitis.
• Red flags: neurological symptoms (retention, severe headache, neck stiffness, confusion), immunocompromise with persistent lesions, pregnancy near term, neonatal skin lesions, eye involvement, and suspected child abuse.

• Laboratory confirmation is recommended because clinical diagnosis is unreliable (sensitivity 40 to 60%).
• HSV PCR of lesion swab (unroof the vesicle and swab the base, or ulcer base): most sensitive (above 95%), specific, and distinguishes HSV-1 and HSV-2. Preferred test.
• Viral culture: specific, but less sensitive (50 to 70% for vesicles, decreasing in older lesions and recurrences), with 2 to 5 days to result.
• Direct fluorescent antibody and Tzanck smear (multinucleated giant cells): low sensitivity, not recommended.
• Type-specific serology (glycoprotein G-based IgG assays for HSV-1 and HSV-2): not helpful for acute diagnosis, but useful for recurrent genital symptoms with negative PCR, to evaluate partners of people with genital herpes, and in pregnancy (selected cases). Interpretation: HSV-2 seropositivity indicates anogenital infection. HSV-1 seropositivity cannot distinguish oral from genital infection. A window of 12 to 16 weeks after infection exists. Low index values (1.1 to 3.5) are often false positive, so confirm with a second assay (Biokit, Western blot).
• Screening is not recommended in asymptomatic general populations.
• Additional tests: HIV, syphilis serology, NAAT for gonorrhoea and chlamydia, hepatitis B and C, pregnancy test, and urine culture if retention. CSF analysis (lymphocytic pleocytosis, HSV PCR) for suspected meningitis or encephalitis. Neonatal evaluation: PCR on surface cultures (conjunctiva, mouth, nasopharynx, rectum), skin lesions, CSF and blood, plus liver enzymes.

Antivirals reduce symptom duration and shedding but do not eradicate latent infection.

First clinical episode

• Valaciclovir 1 g orally twice daily for 7 to 10 days, or aciclovir 400 mg orally three times daily for 7 to 10 days (200 mg five times daily alternative), or famciclovir 250 mg three times daily for 7 to 10 days. Extend if healing is incomplete.
• Severe disease (neurological involvement, inability to tolerate oral therapy, disseminated infection): aciclovir 5 to 10 mg/kg IV every 8 hours for 2 to 7 days (until clinical improvement), then oral therapy to complete at least 10 days. Meningitis: aciclovir 10 mg/kg IV every 8 hours for 5 to 7 days (then oral valaciclovir 1 g twice daily to complete 10 to 14 days).
• Supportive care: saline bathing or sitz baths, topical lidocaine 2 to 5% gel or ointment, analgesia (paracetamol, NSAIDs), loose clothing, petroleum jelly to the area during urination, and urinary catheterisation for retention. Avoid topical antivirals (little benefit).

Recurrent episodes

• Episodic therapy (start within 24 hours of prodrome or lesion onset): valaciclovir 500 mg twice daily for 3 days (or 1 g once daily for 5 days), aciclovir 800 mg three times daily for 2 days (or 400 mg three times daily for 5 days), famciclovir 1 g twice daily for 1 day (or 125 mg twice daily for 5 days). Patient-initiated therapy ("quick-start" packs).
• Suppressive therapy (for six or more recurrences per year, severe or distressing episodes, to reduce transmission to discordant partners, or in HIV): valaciclovir 500 mg to 1 g once daily (500 mg daily for fewer than 10 recurrences per year, 1 g daily or 500 mg twice daily for more), aciclovir 400 mg twice daily, or famciclovir 250 mg twice daily. Reduces recurrences by 70 to 80% and shedding by 90%. Reassess need after 12 months, with a trial of discontinuation. Safety data support continuous use for up to 10 years.

Special populations

• HIV infection: episodic therapy for 5 to 10 days (valaciclovir 1 g twice daily, aciclovir 400 mg three times daily, or famciclovir 500 mg twice daily). Suppression: valaciclovir 500 mg twice daily or aciclovir 400 to 800 mg two to three times daily. Antiretroviral therapy reduces frequency.
• Aciclovir-resistant HSV (immunocompromised, TK-deficient): foscarnet 40 mg/kg IV every 8 to 12 hours until healed (monitor renal function and electrolytes), cidofovir 5 mg/kg IV weekly, topical cidofovir 1% gel or trifluridine 1%, or helicase-primase inhibitor (pritelivir 100 mg daily). Cross-resistance with famciclovir and valaciclovir.
• Pregnancy: first episode in pregnancy: valaciclovir 500 mg to 1 g twice daily or aciclovir 400 mg three times daily for 7 to 10 days (IV for severe). Suppression from 36 weeks of gestation: aciclovir 400 mg three times daily or valaciclovir 500 mg twice daily, until delivery, to reduce lesions at term and caesarean rates. Caesarean section is recommended for women with active lesions or prodromal symptoms at the onset of labour (and for primary infection acquired in the third trimester, within 6 weeks of delivery, in some guidelines). Breastfeeding is safe unless lesions on the breast.
• Neonatal herpes: aciclovir 20 mg/kg IV every 8 hours for 14 days (skin-eye-mouth disease) or 21 days (CNS or disseminated), with CSF PCR clearance before stopping, and suppressive oral aciclovir 300 mg/m2 three times daily for 6 months afterwards. Ophthalmology review.

Prevention and counselling

• Education about natural history (recurrences decline with time), asymptomatic shedding, and triggers (stress, illness, menstruation, sun, friction). Disclosure to partners, condom use during all sexual contact (reduces transmission by 30%), avoidance of sexual contact from prodrome until lesions heal, and suppressive therapy for discordant couples. Screening of partners with type-specific serology.
• Psychological support for stigma, anxiety and depression, with peer support. Advise about the low risk to neonates with appropriate obstetric management.
• Vaccines are in development, none licensed. Voluntary medical male circumcision lowers HSV-2 acquisition by about 30%.
• Vaginal microbicides (tenofovir gel) show a modest effect.

Follow-up

Review at 1 to 2 weeks for severe first episode. Annual review of suppression, screening for other STIs, and HIV test. Specialist referral for resistant or complicated disease.