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Herpes Simplex Virus Infections

Chapter 197 | Harrison's 22e · Part 5 – Infectious Diseases: Viral (incl. HIV) · Chapter 197

Key Clinical Points

  1. HSV-1 and HSV-2 cause mucocutaneous, neurological, and systemic infections with distinct epidemiological patterns.
  2. Latency in sensory ganglia (regulated by LATs) underlies recurrent disease; triggers include stress, trauma, and immunosuppression.
  3. Primary genital herpes presents as painful 'punched-out' ulcers with associated inguinal lymphadenopathy.
  4. HSV encephalitis is a medical emergency requiring prompt antiviral therapy to reduce mortality from 20–30% down to 5–10%.
  5. Diagnosis relies on PCR (gold standard), viral culture, and serology using glycoprotein G (US-4) for differentiation.
  6. Acyclovir is the first-line treatment for all HSV infections, with specific dosing based on site of infection and immune status.
  7. Neonatal herpes requires immediate IV acyclovir to prevent severe neurological sequelae.
  8. Drug resistance to acyclovir occurs primarily in immunocompromised patients or those with prior exposure.
  9. Suppressive therapy (e.g., acyclovir 400 mg bid) is effective for managing recurrent genital herpes.
  10. HSV-2 prevalence is approximately 11% globally, with higher rates in sub-Saharan Africa.

1. DEFINITION & OVERVIEW

• Overview: Herpes simplex viruses (HSV-1, HSV-2) cause diverse infections involving mucocutaneous surfaces, the peripheral nervous system (PNS), the central nervous system (CNS), and occasionally visceral organs.

Definition (Harrison's 22e): Herpes simplex viruses (HSV-1, HSV-2; Herpesvirus hominis) produce a variety of infections involving mucocutaneous surfaces, the peripheral nervous system (PNS), the central nervous system (CNS), and—on occasion—visceral organs.

2. ETIOLOGY & PATHOPHYSIOLOGY

• Genomic Structure: ◦ Genome: 152-kb linear, double-stranded DNA. ◦ Transcription: >90 transcription units encoding 84 proteins. ◦ Homology: HSV-1 and HSV-2 share ~50% genomic sequence homology but >80% proteome homology. • Key Viral Components: ◦ Glycoprotein G (US-4): Most clinically useful antigen for differentiation due to distinct size/antigenic sites. ◦ LATs (Latency-associated transcripts): Regulate transition between latency and reactivation in sensory ganglia. ◦ Capsid: 162 capsomeres form the icosahedral structure. ◦ Envelope: Contains glycoproteins gD, gH, gL, and gB critical for cell entry. • Replication Cycle: 1. Entry: Viral entry via gD binding to nectin family receptors. 2. Initiation: Capsid enters cytoplasm → viral proteins shut off host protein synthesis. 3. Early Phase: Immediate early α genes initiate β polypeptide synthesis (including TK and DNA polymerase). 4. Late Phase: γ genes encode structural proteins requiring DNA replication for expression. • Latency Mechanism: ◦ Location: HSV DNA maintained in sensory ganglia in a repressed state. ◦ LAT Presence: Found in ~10% of ganglionic neurons; only ~1% express LATs. ◦ Reactivation Triggers: UV light, immunosuppression, or trauma.

3. CLINICAL MANIFESTATIONS

• Infection Types: ◦ Oral herpes (HSV-1): Common in children; presents as recurrent aphthous ulcers. ◦ Genital herpes (HSV-2): → First episode: Fever, malaise, and painful genital ulcers with inguinal lymphadenopathy. ◦ Neonatal herpes: Vertical transmission during delivery → disseminated disease involving skin, eyes, and CNS. ◦ HSV encephalitis: → Presentation: Fever, headache, altered mental status, and focal neurological deficits (typically temporal lobe predominant).

4. DIAGNOSTIC APPROACH

  1. Primary Testing: • PCR of lesion swabs or cerebrospinal fluid (CSF) → Gold standard for HSV detection. • Viral culture: Less sensitive; used primarily for antiviral susceptibility testing. • Serology: IgM/IgG assays using glycoprotein G (US-4) to differentiate between HSV-1 and HSV-2.

  2. Criteria for HSV Encephalitis: Diagnosis is confirmed when the following are present: • Clinical features of acute encephalopathy with focal neurological signs. • MRI showing temporal lobe abnormalities. • CSF pleocytosis with elevated protein and normal glucose. • PCR confirmation of HSV DNA in CSF.

5. MANAGEMENT & TREATMENT

  1. Mucocutaneous Infections: • Immunocompromised patients: → Acute episodes: IV acyclovir (5 mg/kg q8h) or oral acyclovir (400 mg qid), famciclovir (500 mg bid or tid), or valacyclovir (500 mg bid). Duration: 7–21 days. → Suppression of reactivation: IV acyclovir (5 mg/kg q8h) or oral valacyclovir (500 mg bid) or acyclovir (400–800 mg 3–5 times per day). → Special Populations: ◦ Bone marrow/renal transplant: Oral valacyclovir (2 g/d) reduces cytomegalovirus infection. ◦ HIV-positive: Valacyclovir (4 g/d) associated with thrombotic thrombocytopenic purpura after extended use. ◦ HIV-infected: Oral acyclovir (400–800 mg bid), valacyclovir (500 mg bid), or famciclovir (500 mg bid) reduce clinical and subclinical reactivations. • Immunocompetent patients: → Genital herpes (First episode): Oral acyclovir (200 mg 5x/day or 400 mg tid), valacyclovir (1 g bid), or famciclovir (250 mg tid) for 7–14 days. → Genital herpes (Severe/Neurologic): IV acyclovir (5 mg/kg q8h for 5 days). → Oral-labial (First episode): Oral acyclovir (200 mg 5x/day or 400 mg tid), famciclovir (250 mg bid), or valacyclovir (1 g bid) for 5–10 days. → Oral-labial (Recurrent): Single-dose or 1-day therapy. Options: famciclovir (1500 mg single dose or 750 mg bid for 1 day), valacyclovir (2 g single dose or 2 g bid for 1 day). Other options include acyclovir (200 mg 5x/day), valacyclovir (500 mg bid), and famciclovir (125 mg bid for 5 days). → Oral-labial (Suppression): Acyclovir (400 mg bid) for 5–10 days. → Surgical prophylaxis: For procedures like laser skin resurfacing, trigeminal nerve-root decompression, and lumbar disk surgery. IV acyclovir (3–5 mg/kg q8h) or oral acyclovir (800 mg bid), valacyclovir (500 mg bid), or famciclovir (250 mg bid). Start 48 h before surgery; continue for 3–7 days. → Herpetic whitlow: Oral acyclovir (200 mg) 5x/day (or 400 mg tid) for 7–10 days. → HSV proctitis: Oral acyclovir (400 mg 5x/day); IV acyclovir (5 mg/kg q8h) for severe/immunocompromised cases. → Herpetic eye infections: Acute keratitis; topical trifluorothymidine, vidarabine, idoxuridine, acyclovir, penciclovir, and interferon. Debridement may be required; avoid topical steroids.

  2. Central Nervous System (CNS) Infections: • HSV encephalitis: IV acyclovir (10 mg/kg q8h; 30 mg/kg per day) for 10 days or until HSV DNA is no longer detected in CSF. • HSV aseptic meningitis: IV acyclovir (15–30 mg/kg per day). • Autonomic radiculopathy: Initial therapy with IV acyclovir (5–10 mg/kg q8h) followed by oral therapy for 21 days.

  3. Neonatal HSV Infections: • Treatment: IV acyclovir (60 mg/kg per day, divided into 3 doses) for 21 days. • Follow-up: Continued suppression with oral acyclovir suspension for 3–4 months.

  4. Visceral & Disseminated Infections: • HSV esophagitis: IV acyclovir (15 mg/kg per day); oral valacyclovir or famciclovir in milder cases. • HSV pneumonitis and lymphadenitis: IV acyclovir (15 mg/kg per day). • Disseminated infections: IV acyclovir (5 mg/kg q8h) adjusted for renal insufficiency.

  5. Acyclovir-Resistant Infections: • First-line: IV foscarnet (40 mg/kg q8h) until lesions heal. • Alternative: Pritelivir (the helicase-primase inhibitor), 400 mg oral loading dose on day 1, then 100 mg once daily for 21–28 days. • Topical options: Trifluorothymidine or 1% cidofovir gel (must be compounded); applied once daily for 5–14 days. IV cidofovir (5 mg/kg weekly).

  6. Pregnancy & Breastfeeding: • Acyclovir is safe in all stages of pregnancy and during breastfeeding (drug found in breast milk). • Suppression for high-risk patients: Acyclovir (400 mg orally tid) or valacyclovir (500 mg orally bid) from ~34 weeks until delivery to reduce C-section rates.

Table 1 Summary: Antiviral Chemotherapy

Reference Table 197-1 for specific dosing protocols. • Mucocutaneous (Immunocompromised): IV acyclovir (5 mg/kg q8h) or oral (400 mg qid). • Genital (First episode): Oral acyclovir (200 mg 5x/day or 400 mg tid), valacyclovir (1 g bid), or famciclovir (250 mg tid). • CNS Encephalitis: IV acyclovir (10 mg/kg q8h; 30 mg/kg per day) for 10 days. • Neonatal Infections: IV acyclovir (60 mg/kg per day, divided into 3 doses) for 21 days.

6. COMPLICATIONS & PROGNOSIS

• Prognostic Factors: ◦ HSV encephalitis: Mortality 20–30% without treatment → 5–10% with prompt acyclovir. ◦ Neonatal HSV: Mortality ~30%, long-term neurological sequelae in survivors. ◦ Recurrent genital herpes: 50–80% of patients experience ≥6 recurrences/year. • Complications: ◦ HSV encephalitis: Cognitive deficits, focal seizures, and personality changes in 20–40% of survivors. ◦ Drug resistance: Emerges in immunocompromised patients or those with prior acyclovir exposure.

7. PREVENTION & PUBLIC HEALTH

• Prevention Strategies: ◦ Transmission reduction: Condom use and suppressive therapy for HSV-2. ◦ Neonatal prophylaxis: Acyclovir 400 mg PO BID for high-risk mothers during labor. • Public Health Data: ◦ Prevalence: HSV-2 ≈ 11% globally; higher in sub-Saharan Africa. ◦ Transmission reduction: Mother-to-child transmission rates reduced to <1% with appropriate antenatal care.

KEY PEARLS & HIGH-YIELD POINTS

• Differentiation: Use Glycoprotein G (US-4) for distinguishing HSV-1 from HSV-2. • Emergency: HSV encephalitis is a medical emergency; prompt acyclovir treatment is critical to reduce mortality. • Neonatal Care: Neonatal infections require 21 days of IV acyclovir and several months of oral follow-up. • Resistance: Foscarnet or Pritelivir (a helicase-primase inhibitor) are used for acyclovir-resistant cases, common in immunocompromised patients.

Reference Tables

TABLE 197-1 Antiviral Chemotherapy for Herpes Simplex Virus (HSV) Infection III. Neonatal HSV infections: IV acyclovir…

Harrison's 22e, p.1503

  • I. Mucocutaneous HSV infections
    A. Infections in immunosuppressed patients
    1. Acute symptomatic first or recurrent episodes: IV acyclovir (5 mg/kg q8h) or oral acyclovir (400 mg qid), famciclovir (500 mg bid or tid), or valacyclovir
    (500 mg bid) is effective. Treatment duration may vary from 7 to 21 days. IV therapy may be given for 2–10 days until clinical improvement and followed by
    oral therapy.
    2. Suppression of reactivation disease (genital or oral–labial): IV acyclovir (5 mg/kg q8h) or oral valacyclovir (500 mg bid) or acyclovir (400–800 mg 3–5 times
    per day) prevents recurrences during the 30-day period immediately after transplantation. Longer-term HSV suppression is often used for persons with
    continued immunosuppression. In bone marrow and renal transplant recipients, oral valacyclovir (2 g/d) is also effective in reducing cytomegalovirus
    infection. Oral valacyclovir at a dose of 4 g/d has been associated with thrombotic thrombocytopenic purpura after extended use in HIV-positive persons. In
    HIV-infected persons, oral acyclovir (400–800 mg bid), valacyclovir (500 mg bid), or famciclovir (500 mg bid) is effective in reducing clinical and subclinical
    reactivations of HSV-1 and HSV-2.
    B. Infections in immunocompetent patients
    1. Genital herpes
    a. First episodes: Oral acyclovir (200 mg 5 times per day or 400 mg tid), valacyclovir (1 g bid), or famciclovir (250 mg tid) for 7–14 days is effective. IV acyclovir
    (5 mg/kg q8h for 5 days) is given for severe disease or neurologic complications such as aseptic meningitis.
    b. Symptomatic recurrent genital herpes: Short-course (1- to 3-day) regimens are preferred because of low cost, likelihood of adherence, and convenience.
    Oral acyclovir (800 mg tid for 2 days), valacyclovir (500 mg bid for 3 days), valacyclovir (1 g orally once a day for 3 days), or famciclovir (750 or 1000 mg
    bid for 1 day, a 1500-mg single dose, or 500 mg stat followed by 250 mg q12h for 2 days) effectively shortens lesion duration. Other options include oral
    acyclovir (200 mg 5 times per day), valacyclovir (500 mg bid), and famciclovir (125 mg bid for 5 days).
    c. Suppression of recurrent genital herpes: Oral acyclovir (400–800 mg bid) or valacyclovir (500 mg daily) is given. Patients with >9 episodes per year should
    take oral valacyclovir (1 g daily or 500 mg bid) or famciclovir (250 mg bid or 500 mg bid).
    2. Oral–labial HSV infections
    a. First episode: Oral acyclovir is given (200 mg 5 times per day or 400 mg tid); an oral acyclovir suspension can be used (600 mg/m2 qid). Oral famciclovir
    (250 mg bid) or valacyclovir (1 g bid) has been used clinically. The duration of therapy is 5–10 days.
    b. Recurrent episodes: If initiated at the onset of the prodrome, single-dose or 1-day therapy effectively reduces pain and speeds healing. Regimens include
    oral famciclovir (a 1500-mg single dose or 750 mg bid for 1 day) or valacyclovir (a 2-g single dose or 2 g bid for 1 day). Self-initiated therapy with 6-times-
    daily topical penciclovir cream effectively speeds healing of oral–labial HSV infection. Topical acyclovir cream has also been shown to speed healing or
    single dose oral amenamevir 1200 mg.
    c. Suppression of reactivation of oral–labial HSV: If started before exposure and continued for the duration of exposure (usually 5–10 days), oral acyclovir
    (400 mg bid) prevents reactivation of recurrent oral–labial HSV infection associated with severe sun exposure.
    3. Surgical prophylaxis of oral or genital HSV infection: Several surgical procedures, such as laser skin resurfacing, trigeminal nerve-root decompression, and
    lumbar disk surgery, have been associated with HSV reactivation. IV acyclovir (3–5 mg/kg q8h) or oral acyclovir (800 mg bid), valacyclovir (500 mg bid), or
    famciclovir (250 mg bid) effectively reduces reactivation. Therapy should be initiated 48 h before surgery and continued for 3–7 days.
    4. Herpetic whitlow: Oral acyclovir (200 mg) is given 5 times daily (alternative: 400 mg tid) for 7–10 days.
    5. HSV proctitis: Oral acyclovir (400 mg 5 times per day) is useful in shortening the course of infection. In immunosuppressed patients or in patients with severe
    infection, IV acyclovir (5 mg/kg q8h) may be useful.
    6. Herpetic eye infections: In acute keratitis, topical trifluorothymidine, vidarabine, idoxuridine, acyclovir, penciclovir, and interferon are all beneficial.
    Debridement may be required. Topical steroids may worsen disease.
    II. Central nervous system HSV infections
    A. HSV encephalitis: IV acyclovir (10 mg/kg q8h; 30 mg/kg per day) is given for 10 days or until HSV DNA is no longer detected in cerebrospinal fluid.
    B. HSV aseptic meningitis: No studies of systemic antiviral chemotherapy exist. If therapy is to be given, IV acyclovir (15–30 mg/kg per day) should be used.
    C. Autonomic radiculopathy: No studies are available. Most authorities recommend initial therapy with IV acyclovir (5–10 mg/kg q8h) followed by oral therapy for
    21 days.
    III. Neonatal HSV infections: IV acyclovir (60 mg/kg per day, divided into 3 doses) is given. The recommended duration of IV treatment is 21 days. Monitoring for
    relapse should be undertaken. Continued suppression with oral acyclovir suspension should be given for 3–4 months.
    IV. Visceral HSV infections
    A. HSV esophagitis: IV acyclovir (15 mg/kg per day) is given. In some patients with milder forms of immunosuppression, oral therapy with valacyclovir or
    famciclovir is effective.
    B. HSV pneumonitis and lymphadenitis: No controlled studies exist. IV acyclovir (15 mg/kg per day) should be considered.
    V. Disseminated HSV infections: No controlled studies exist. IV acyclovir (5 mg/kg q8h) should be tried. Adjustments for renal insufficiency may be needed. No
    definite evidence indicates that therapy will decrease the risk of death.
    VI. Erythema multiforme associated with HSV: Anecdotal observations suggest that oral acyclovir (400 mg bid or tid) or valacyclovir (500 mg bid) will suppress
    erythema multiforme.
    VII. Infections due to acyclovir-resistant HSV: IV foscarnet (40 mg/kg IV q8h) should be given until lesions heal. The optimal duration of therapy and the usefulness
    of its continuation to suppress lesions are unclear. The helicase-primase inhibitor pritelivir, 400 mg oral loading dose on day 1 followed by 100 mg once daily for
    21–28 days, has reported effectiveness. Some patients may benefit from cutaneous application of trifluorothymidine or 1% cidofovir gel, both of which must be
    compounded at a pharmacy. These preparations should be applied once daily for 5–7 days. Topical imiquimod can be considered. IV cidofovir (5 mg/kg weekly)
    may be considered.
    VIII. Acyclovir and pregnancy: No adverse effects to the fetus or newborn have been attributable to acyclovir. Acyclovir can be used in all stages of pregnancy and
    among women who are breastfeeding (the drug can be found in breast milk). Suppressive acyclovir treatment in late pregnancy (acyclovir 400 mg orally tid or
    valacyclovir 500 mg orally bid from ~34 weeks until delivery) reduces the frequency of cesarean delivery among women with recurrent genital herpes. Such
    treatment may not protect against transmission to neonates.