Genital Herpes (HSV)

1. Clinical Overview

Summary

Genital herpes is a chronic, lifelong sexually transmitted infection caused by herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2). It is characterized by painful genital ulceration during primary and recurrent episodes, with the virus establishing latency in sacral nerve root ganglia (S2-S5) between outbreaks. Asymptomatic viral shedding occurs in the majority of infected individuals, enabling transmission even in the absence of visible lesions. [1,2,3]

HSV-2 has historically been the predominant cause of genital herpes, but HSV-1 now accounts for approximately 40-50% of new cases in high-income countries due to changing patterns of oral-genital sexual contact. [4,5] The infection poses significant challenges including psychological morbidity, risk of neonatal transmission, and facilitation of HIV acquisition and transmission. [6,7,8]

Key Facts

Clinical Pearls

• Primary vs Recurrent: Primary infection typically presents with severe, bilateral, extensive lesions and systemic symptoms; recurrent episodes are milder, unilateral, and shorter in duration
• Asymptomatic Shedding: Transmission occurs primarily during asymptomatic viral shedding, which happens even in individuals unaware of their infection status
• HSV-1 vs HSV-2 Recurrence: HSV-1 genital infection recurs significantly less frequently than HSV-2 (important for prognostic counseling)
• Neonatal Herpes Prevention: Risk is highest with primary maternal infection in the third trimester (30-50% transmission risk vs less than 1% with recurrent disease)
• Type-Specific Serology Limitations: Cannot distinguish timing of infection or anatomical site; HSV-1 IgG may represent oral or genital infection
• HIV Co-infection: HSV-2 increases HIV acquisition risk 2-3 fold and increases HIV viral shedding in co-infected individuals
• Partner Counseling: Suppressive antiviral therapy reduces transmission to seronegative partners by approximately 50%

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2. Epidemiology

Global Burden

Exam Detail: The shift toward HSV-1 causing genital herpes reflects changing sexual practices (increased oral-genital contact) and declining HSV-1 seroprevalence in childhood (due to improved hygiene). This has important prognostic implications: HSV-1 genital infection recurs less frequently than HSV-2, but primary HSV-1 genital infection can be clinically indistinguishable from HSV-2. [12]

Regional Variations

Risk Factors

High-Risk Populations

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3. Pathophysiology

Molecular Virology

Herpes Simplex Virus (HSV) Classification:

• Family: Herpesviridae
• Subfamily: Alphaherpesvirinae
• Genus: Simplexvirus
• Species: Human alphaherpesvirus 1 (HSV-1), Human alphaherpesvirus 2 (HSV-2)

Exam Detail: HSV Structure:

• Envelope: Lipid bilayer with glycoproteins (gB, gC, gD, gE, gH, gL, gK)
  • gD: Essential for viral entry (binds HVEM, nectin-1, 3-O-sulfated heparan sulfate)
  • gB and gH/gL: Mediate membrane fusion
• Tegument: Protein layer containing virion host shutoff (vhs) protein and VP16 transcriptional activator
• Capsid: Icosahedral, 162 capsomeres
• Core: Linear double-stranded DNA genome (~152 kb)

Replication Cycle:

1. Attachment via glycoprotein interactions with cell surface receptors
2. Fusion and entry into cytoplasm
3. Capsid transport to nucleus along microtubules
4. DNA release and circularization
5. Immediate-early (α), early (β), and late (γ) gene expression
6. DNA replication via viral DNA polymerase
7. Capsid assembly in nucleus
8. Acquisition of tegument and envelope by budding through nuclear/cytoplasmic membranes
9. Egress and cell-to-cell spread

Infection and Latency Establishment

PRIMARY INFECTION
         ↓
Mucosal/Epidermal Inoculation (genital epithelium)
         ↓
Local Viral Replication → Cytopathic Effect
         ↓
Vesicle Formation (intraepithelial vesicles with multinucleated giant cells)
         ↓
         ├──→ Local Spread (skin, mucosa)
         │    • Clinical lesions (vesicles → ulcers → crusts)
         │    • Inflammatory response
         │
         └──→ Retrograde Axonal Transport
              ↓
              Sacral Dorsal Root Ganglia (S2-S5)
              ↓
              LATENCY ESTABLISHMENT
              • Viral DNA persists as episomes in neuronal nuclei
              • Latency-associated transcripts (LAT) expressed
              • No viral protein expression (immune evasion)
              • Lifelong persistence

              ↓ (Reactivation Triggers)

REACTIVATION
         ↓
Viral Replication in Ganglia
         ↓
Anterograde Axonal Transport to Mucosal Surface
         ↓
         ├──→ Asymptomatic Shedding (60-70% of reactivations)
         │    • Subclinical viral replication
         │    • No visible lesions
         │    • Primary transmission mechanism
         │
         └──→ Clinical Recurrence (30-40% of reactivations)
              • Vesiculoulcerative lesions
              • Milder than primary infection
              • Shorter duration (5-10 days)

Exam Detail: Immune Evasion Mechanisms:

• ICP47: Inhibits TAP (transporter associated with antigen processing), preventing MHC class I antigen presentation
• ICP34.5: Prevents host protein synthesis shutoff; antagonizes PKR antiviral response
• gE-gI Complex: Fc receptor function; protects infected cells from antibody-mediated attack
• Latency-Associated Transcripts (LAT): Inhibit apoptosis; maintain latency; modulate reactivation frequency
• Cell-to-Cell Spread: Avoids antibody neutralization by direct intercellular spread

Reactivation Triggers (proposed mechanisms):

• Physical/Emotional Stress → Corticosteroid release → Immune modulation → Decreased T-cell surveillance
• UV Radiation → Local immunosuppression → Keratinocyte damage
• Menstruation → Hormonal fluctuations → Altered local immune environment
• Fever/Intercurrent Illness → Immune distraction → Reduced ganglionic surveillance
• Trauma/Surgery → Nerve manipulation → Altered neuronal environment

Immunology

Clinical Pearl: Why antibodies don't cure herpes: HSV establishes latency in neurons, which have limited MHC class I expression and are shielded from antibody penetration. Reactivation occurs via direct cell-to-cell spread along axons, bypassing extracellular virus neutralization. Control of latency and reactivation is primarily mediated by cellular immunity (CD8+ T cells), not humoral immunity.

HSV-1 vs HSV-2 Differences

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4. Clinical Presentation

Classification of Clinical Episodes

Primary Genital Herpes

Incubation Period: 2-14 days (mean 4 days) after exposure [13]

Exam Detail: Primary Infection Complications:

Recurrent Genital Herpes

Prodrome: Localized tingling, burning, or itching 24-48 hours before lesion appearance (occurs in 40-50% of recurrences)

Clinical Pearl: Natural History of Recurrences:

• Frequency is highest in the first year after primary infection
• Recurrence rate gradually declines over years
• 20-25% of individuals experience ≥10 recurrences per year
• Prodromal symptoms become more recognizable over time, allowing early self-initiated treatment

Atypical and Variant Presentations

Asymptomatic Viral Shedding

Critical Epidemiological Concept:

Exam Detail: Landmark Studies:

• Wald et al. (2000): Daily genital swabs in asymptomatic HSV-2 seropositive individuals demonstrated viral shedding on 28% of days in the first 3 months after symptomatic primary infection, declining to 20% of days in subsequent months [PMID: 10688204]
• Mark et al. (2008): Frequent sampling study showed subclinical shedding episodes were brief (median 13 hours) and occurred throughout the genital area [PMID: 18520462]

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5. Clinical Examination

Systematic Genital Examination

Lesion Morphology

Classical Evolution:

1. Erythematous macule/papule (early)
2. Vesicle (clear fluid on erythematous base, 2-4 mm diameter, grouped/clustered)
3. Pustule (cloudy fluid, inflammatory)
4. Ulcer (shallow, round/oval, red base, irregular borders after vesicle rupture)
5. Crust (healing phase, dry crust formation)
6. Re-epithelialization (complete healing without scarring in most cases)

Clinical Pearl: Exam Tip - Distinguishing Features:

• Grouped vesicles on erythematous base = pathognomonic for HSV
• Lesions at different stages of evolution in the same area (vesicles + ulcers + crusts) = recurrent HSV
• Unilateral distribution = recurrent episode
• Bilateral, extensive = primary episode

Differential Diagnosis

Exam Detail: Viva Question: "How would you differentiate syphilis from herpes on clinical grounds?"

Model Answer: "The classical teaching is that syphilitic chancre is painless, whereas herpetic ulcers are painful. However, this is not absolute. Key differentiating features include:

However, definitive diagnosis requires laboratory testing. I would perform:

• HSV PCR from ulcer swab (gold standard for herpes)
• Dark-field microscopy (if available) or PCR for Treponema pallidum
• Syphilis serology (RPR/VDRL and treponemal test)

Co-infection occurs in 5-10% of cases in high-prevalence settings, so testing for both is essential." [16]

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6. Investigations

Diagnostic Tests

Clinical Pearl: Specimen Collection Technique:

• Vesicles: Unroof vesicle with sterile needle; swab base vigorously
• Ulcers: Swab base and edges vigorously (multiple rotations)
• Use dacron or flocked swab (NOT cotton - inhibits PCR)
• Place in viral transport medium immediately
• Sensitivity decreases with lesion age (highest in first 48 hours)

Type-Specific Serological Testing

Available Assays:

• HSV-1 IgG and HSV-2 IgG (distinguish between types)
• Glycoprotein G-based assays (gG1 for HSV-1, gG2 for HSV-2): most type-specific

Interpretation of Serology:

Exam Detail: Limitations of Type-Specific Serology:

1. Does NOT distinguish anatomical site: HSV-1 IgG may represent oral or genital infection
2. Does NOT indicate timing: Cannot distinguish recent from remote infection
3. Does NOT predict clinical manifestations: Many seropositive individuals are asymptomatic
4. Window period: Seroconversion takes 2-12 weeks after primary infection
5. False positives: Low positive predictive value in low-prevalence populations (consider confirmatory Western blot for index values less than 3.5)
6. IgM testing NOT recommended: Cross-reactive, poor sensitivity/specificity, does NOT distinguish primary from recurrent infection [17]

Viva Question: "When would you use type-specific serology in genital herpes diagnosis?"

Model Answer: "Type-specific HSV serology has limited but specific roles:

Appropriate Uses:

• Asymptomatic sexual partner of person with known genital herpes (assess serostatus for counseling)
• Patient with recurrent genital symptoms but negative PCR/culture (lesions may have healed before swabbing)
• Patient presenting late after lesions have healed
• Screening in pregnancy when partner has known genital herpes
• Research/epidemiological studies

NOT recommended for:

• Routine STI screening in asymptomatic individuals (low positive predictive value)
• Diagnosis of active genital lesions (use PCR instead)
• Distinguishing primary from recurrent infection

The key limitation is that serology cannot tell you the anatomical site or timing of infection, and most seropositive individuals have unrecognized infection." [18]

Baseline Investigations for Confirmed Genital Herpes

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7. Management

Principles of Management

1. Antiviral Therapy: Reduce viral replication, shorten symptom duration, accelerate healing
2. Symptomatic Relief: Analgesia, topical measures
3. Patient Education: Natural history, transmission risk, asymptomatic shedding
4. Psychological Support: Address stigma, anxiety, relationship concerns
5. Partner Management: Testing, counseling, prevention strategies
6. Prevention of Complications: Neonatal herpes prevention, HIV risk reduction

Antiviral Agents

Mechanism of Action (all three drugs):

1. Viral thymidine kinase phosphorylates drug to monophosphate
2. Cellular kinases convert to triphosphate
3. Triphosphate form inhibits viral DNA polymerase (competitive inhibition)
4. Chain termination upon incorporation into viral DNA

Treatment Regimens

Primary Episode

Indication: First clinical episode of genital herpes (primary or non-primary)

Severe Primary Infection (hospitalization criteria):

• Severe pain requiring parenteral analgesia
• Urinary retention
• Meningitis or other CNS complications
• Systemic illness (dehydration, fever > 38.5°C)
• Eczema herpeticum or disseminated disease
• Immunocompromised host

Severe Cases:

• Aciclovir IV: 5-10 mg/kg every 8 hours for 5-10 days
• Switch to oral once clinically improving

Exam Detail: Evidence: Aciclovir in primary genital herpes reduces:

• Viral shedding duration: from 11 to 2 days
• New lesion formation: from 10 to 7 days
• Time to healing: from 19 to 16 days
• Pain duration
• Does NOT reduce recurrence rate or severity [PMID: 6339400]

Recurrent Episodes - Episodic Treatment

Indication: Patient-initiated treatment at first sign of prodrome or lesion development

Patient-Initiated Therapy:

• Supply advance prescription ("standby therapy")
• Start at first sign of prodrome or within 24 hours of lesion onset
• Greatest benefit when started early
• Reduces episode duration by 1-2 days

Suppressive Therapy

Indications:

• ≥6 recurrences per year
• Severe recurrences with significant impact on quality of life
• Psychological distress from unpredictable recurrences
• Serodiscordant couple (reduce transmission to uninfected partner)
• Pregnancy from 36 weeks (if history of genital herpes) to reduce neonatal transmission

Efficacy of Suppressive Therapy:

• Recurrence reduction: 70-80% reduction in clinical recurrences [20]
• Asymptomatic shedding: 80-90% reduction in days with viral shedding
• Transmission reduction: 50% reduction in transmission to seronegative partners (Corey et al., 2004) [21]
• Breakthrough recurrences: Typically milder and shorter

Duration and Review:

• Initial trial: 6-12 months
• Reassess after 12 months: consider stopping to evaluate natural recurrence frequency (may decrease over time)
• Long-term suppression (> 10 years) safe with aciclovir/valaciclovir
• No evidence of resistance development in immunocompetent individuals on suppressive therapy

Exam Detail: Landmark Trial - Transmission Prevention:

Corey et al. (NEJM 2004, PMID: 14702423): Randomized, double-blind, placebo-controlled trial of valaciclovir 500 mg OD in immunocompetent HSV-2 seropositive individuals in monogamous heterosexual discordant relationships.

Results:

• Transmission rate: 1.9% (valaciclovir) vs 3.6% (placebo) per year (48% reduction, p=0.04)
• Symptomatic transmission: 0.5% vs 2.2% (75% reduction)
• Asymptomatic shedding: 2.9% vs 13.5% of days (73% reduction)

Conclusion: Suppressive valaciclovir reduces but does NOT eliminate transmission risk. Condoms provide additional protection.

Pregnancy Management

Risk of Neonatal Herpes:

Exam Detail: Why is primary infection in late pregnancy high risk?

1. Lack of maternal antibodies: No transplacental transfer of protective IgG to fetus
2. High viral load: Primary infection has higher and more prolonged viral shedding
3. Prolonged shedding: May persist through delivery
4. Cervical involvement: More common in primary infection (increases fetal exposure)

In contrast, recurrent infection has:

• Maternal IgG antibodies transferred to fetus (passive protection)
• Lower viral load
• Shorter duration of shedding
• Lower likelihood of cervical involvement

Management Algorithm in Pregnancy

1. Woman with known history of genital herpes:

2. Primary or first episode of genital herpes in pregnancy:

3. Partner has genital herpes, woman seronegative:

• Avoid sexual contact in third trimester (especially if partner has HSV-2)
• Consider type-specific serology to determine serostatus
• Condom use throughout pregnancy
• Partner suppressive therapy to reduce shedding

Aciclovir Safety in Pregnancy:

• Pregnancy Category B (FDA): No evidence of teratogenicity in animal studies
• Aciclovir in Pregnancy Registry (> 1000 exposures): No increased risk of birth defects
• WHO: "Compatible with breastfeeding"

Clinical Pearl: Timing of Caesarean for HSV:

• Perform caesarean before rupture of membranes if possible (ascending infection risk)
• If membranes ruptured less than 4-6 hours: caesarean still protective
• If membranes ruptured > 4-6 hours: caesarean may be less protective; neonatal surveillance and empirical aciclovir if high suspicion

Management in Immunocompromised Patients

Aciclovir-Resistant HSV:

• Rare in immunocompetent (less than 1%)
• More common in immunocompromised (5-10%, especially HIV with CD4 less than 100)
• Mechanism: Thymidine kinase mutation (cannot phosphorylate aciclovir)
• Suspect if: Lesions persist or worsen after 10-14 days of appropriate antiviral therapy
• Diagnosis: Viral culture with antiviral susceptibility testing
• Treatment: Foscarnet 40 mg/kg IV TDS (or 90 mg/kg IV BD) for 14-21 days

Symptomatic Management

NOT Recommended:

• Topical aciclovir cream: Inferior to oral therapy; not evidence-based for genital herpes
• Topical antivirals (idoxuridine, tromantadine): No benefit over placebo

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8. Complications

Exam Detail: Mollaret's Meningitis:

• Recurrent benign aseptic meningitis (≥3 episodes)
• 50-80% of cases associated with HSV-2
• Episodes last 2-5 days; spontaneous resolution
• CSF: Lymphocytic pleocytosis, Mollaret cells (large fragile mononuclear cells)
• CSF HSV-2 PCR positive during episodes (may be negative between episodes)
• Treatment: Suppressive aciclovir/valaciclovir reduces recurrence frequency

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9. Prognosis & Outcomes

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10. Prevention

Primary Prevention

Secondary Prevention (Diagnosed Genital Herpes)

Neonatal Herpes Prevention

Covered comprehensively in Pregnancy Management section (see above).

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11. Evidence & Guidelines

International Guidelines

Key Evidence

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12. Examination Focus

MRCP PACES / OSCE Scenarios

Exam Detail: Station 4: Communication Skills - Newly Diagnosed Genital Herpes

Scenario: You are an FY2 in GUM clinic. A 28-year-old woman has just been diagnosed with primary genital HSV-2 based on PCR. She is distressed and has questions about her diagnosis. Explain the diagnosis, address her concerns, and discuss management.

Key Points to Cover:

1. Breaking Bad News Framework:

   • Check understanding: "What have you been told so far?"
   • Warning shot: "The swab results show you have genital herpes"
   • Pause for reaction
   • Explore concerns (ICE: Ideas, Concerns, Expectations)

2. Education:

   • Herpes is a common viral infection (1 in 8 people have HSV-2)
   • Caused by herpes simplex virus transmitted through skin-to-skin sexual contact
   • Virus stays in body for life (dormant in nerves)
   • Can reactivate causing recurrent outbreaks (usually milder than first episode)
   • Outbreaks usually become less frequent over time

3. Transmission:

   • Can be passed on during sexual contact
   • Transmission can occur even without visible sores ("asymptomatic shedding")
   • Condoms reduce but don't eliminate transmission risk
   • Daily antiviral medication can reduce transmission by about 50%

4. Management:

   • Antiviral tablets (aciclovir/valaciclovir) to treat current episode
   • Future outbreaks: either episodic treatment (as needed) or suppressive therapy (daily)
   • Suppressive therapy recommended if ≥6 outbreaks per year or significant impact

5. Pregnancy:

   • Can be managed safely in pregnancy
   • Risk to baby is very low if you've had herpes before pregnancy
   • Daily antiviral from 36 weeks reduces risk of outbreak at delivery

6. Partner:

   • Inform partner(s) - they should be tested
   • Avoid sex during outbreaks
   • Condoms recommended between outbreaks

7. Psychological Support:

   • Acknowledge distress: "I understand this is a lot to take in"
   • Reassure: treatable, common, manageable
   • Provide written information and support resources (Herpes Viruses Association)
   • Offer follow-up appointment

Common Questions:

• "Where did I get it from?" → Can be difficult to know; may have had it for years without symptoms
• "Can I ever have sex again?" → Yes, with precautions to reduce transmission
• "Will I have outbreaks forever?" → Frequency usually decreases over time
• "Can I have children?" → Yes, with appropriate management

Viva Voce Questions

Exam Detail: Q1: What is the pathogenesis of HSV latency and reactivation?

Model Answer: "HSV establishes latency in sensory neurons after primary infection through the following mechanism:

1. Primary infection: Virus infects genital epithelial cells → local replication → vesicle formation

2. Neuronal invasion: Virus enters peripheral nerve terminals innervating infected area

3. Retrograde transport: Capsids transported along axons via microtubules to neuronal cell bodies in dorsal root ganglia (S2-S5 for genital infection)

4. Latency establishment:

   • Viral DNA circularizes and persists as episomes in neuronal nucleus
   • Latency-associated transcripts (LAT) are expressed
   • No viral structural proteins produced → immune evasion
   • Neurons are non-permissive for lytic replication during latency

5. Reactivation:

   • Triggered by stress, UV radiation, illness, menstruation (mechanisms incompletely understood)
   • Proposed: Stress hormones/local factors modulate neuronal gene expression → permissive state
   • Lytic replication initiates in ganglia
   • Progeny virions undergo anterograde axonal transport to mucosal surface
   • Either asymptomatic shedding (70%) or clinical lesions (30%)

The key immune control is mediated by CD8+ cytotoxic T cells in ganglia which suppress reactivation. HSV evades immune clearance through latency in immune-privileged neurons and cell-to-cell spread mechanisms."

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Q2: How would you counsel a pregnant woman at 32 weeks gestation who presents with her first episode of genital herpes?

Model Answer: "This is a high-risk scenario requiring careful counseling:

Immediate Management:

1. Confirm diagnosis: HSV PCR from lesions
2. Aciclovir 400 mg three times daily for 10 days (safe in pregnancy)
3. Symptomatic measures

Risk to Baby: 'I need to explain that because this is your first episode of herpes in late pregnancy, there is a higher risk to your baby than if you'd had herpes before pregnancy. The risk is around 30-40% if you have active sores when you go into labour.'

Why is the risk high?

• No protective antibodies to pass to baby
• High levels of virus
• Virus may persist until delivery

Management Options:

1. Antiviral therapy:

   • Complete 10-day treatment course now
   • Continue suppressive aciclovir 400 mg three times daily until delivery
   • This will reduce viral shedding

2. Mode of delivery:

   • If no visible sores at time of labour: vaginal delivery may be possible (discuss with consultant)
   • If sores present at labour: Caesarean section recommended to protect baby
   • Decision made closer to term based on clinical findings

3. Neonatal surveillance:

   • Even with caesarean, baby will be monitored closely after birth
   • Pediatricians will examine baby
   • May need swabs/blood tests from baby

Follow-up:

• Joint obstetric-GUM clinic appointment at 36 weeks
• Discussion with neonatology team
• Written information to take away
• Helpline contact details

Reassurance:

• With appropriate management, the vast majority of babies are born healthy
• We'll work with you to minimize risks'

Documentation:

• Clear plan in notes
• Alert obstetric team
• MDT discussion documented"

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Q3: Explain the evidence base for suppressive antiviral therapy in genital herpes.

Model Answer: "Suppressive antiviral therapy has been evaluated in multiple high-quality RCTs:

Efficacy for Recurrence Reduction:

• Aciclovir 400 mg BD reduces recurrences by 70-80% compared to placebo
• Valaciclovir 500 mg OD similar efficacy
• Meta-analysis of 25 trials (Lebrun-Vignes 2007): 75% reduction in recurrence rate
• Effect maintained over prolonged therapy (studied up to 10 years)

Efficacy for Transmission Prevention:

• Landmark trial: Corey et al., NEJM 2004 (PMID: 14702423)
  • "RCT: Valaciclovir 500 mg OD vs placebo in HSV-2 discordant heterosexual couples"
  • Transmission reduced from 3.6% to 1.9% per year (48% reduction, p=0.04)
  • Symptomatic transmission reduced by 75%
  • Asymptomatic shedding reduced by 73%

Mechanism:

• Reduces frequency of reactivation
• Reduces viral load during asymptomatic shedding
• Does NOT eliminate shedding (explains incomplete protection)

Safety:

• Long-term aciclovir/valaciclovir use (> 10 years) safe in immunocompetent hosts
• No evidence of resistance emergence
• No long-term toxicity

Indications per guidelines (BASHH 2014, CDC 2021):

• ≥6 recurrences per year
• Severe recurrences affecting quality of life
• Serodiscordant couples (transmission prevention)
• Pregnancy from 36 weeks (prevent outbreak at delivery)

Practice Point:

• Review after 12 months: consider stopping to reassess natural recurrence frequency
• Breakthrough recurrences on suppressive therapy are usually milder and shorter"

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Q4: What is the relationship between HSV-2 and HIV, and what are the clinical implications?

Model Answer: "HSV-2 and HIV interact bidirectionally with important clinical implications:

HSV-2 Increases HIV Acquisition Risk:

• Meta-analysis (Freeman 2006, PMID: 16418451): HSV-2 increases HIV acquisition risk 2-3 fold
• Mechanisms:
  1. Mucosal disruption: Ulceration breaches epithelial barrier
  2. Immune activation: HSV reactivation recruits CCR5+ CD4+ T cells (HIV target cells) to genital mucosa
  3. Upregulation of HIV co-receptors: CCR5 expression increased
  4. Subclinical shedding: Even without visible lesions, mucosal inflammation occurs

HIV Increases HSV-2 Severity:

• More frequent, severe, and prolonged episodes
• Atypical presentations (large ulcers, chronic non-healing lesions)
• Higher viral load during shedding
• Increased asymptomatic shedding frequency
• Risk of aciclovir resistance (5-10% if CD4 less than 100)

HSV-2 Increases HIV Transmission:

• HIV viral load in genital secretions increased 2-8 fold during HSV reactivation
• Mechanism: HSV-induced inflammation → HIV replication activation

Treatment Implications in HIV/HSV Co-infection:

1. Higher antiviral doses:

   • Acute episodes: Aciclovir 400 mg 5x daily OR valaciclovir 1 g BD (vs standard doses in HIV-negative)
   • Suppressive therapy: Valaciclovir 500 mg BD (vs 500 mg OD)

2. Longer duration: Extend treatment if slow response

3. Consider suppressive therapy earlier: Even with fewer recurrences, due to transmission risk

4. Monitor for resistance: If lesions not improving after 10-14 days, culture for antiviral susceptibility

Prevention Implications:

• HSV-2 serology as part of HIV prevention in high-risk populations
• Suppressive aciclovir in HIV/HSV co-infected individuals reduces HIV progression (modest effect)
• Trials of HSV suppressive therapy to reduce HIV transmission showed benefit in reducing HIV viral load but did NOT show reduction in HIV transmission events (Partners in Prevention trial, PMID: 18525101)

Public Health Perspective:

• Population-level HSV-2 control (vaccine if available) could reduce HIV incidence
• HSV-2 is a cofactor in HIV epidemiology, especially in sub-Saharan Africa"

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13. Patient / Layperson Explanation

What is Genital Herpes?

Genital herpes is a common infection caused by a virus called herpes simplex virus (HSV). There are two types: HSV-1 (which usually causes cold sores on the mouth) and HSV-2 (which usually causes genital herpes). However, either type can infect the genital area.

How Do You Catch It?

You catch genital herpes through skin-to-skin contact during sex (vaginal, oral, or anal) with someone who has the virus. The virus can be passed on:

• During an outbreak (when sores are visible)
• Even when there are no symptoms - this is called "asymptomatic shedding" and is how most people catch herpes without realizing it

What Are the Symptoms?

First outbreak (primary infection):

• Small painful blisters on or around the genitals
• Blisters burst to form sores/ulcers
• Flu-like symptoms (fever, headache, muscle aches)
• Pain when urinating
• Lasts 2-4 weeks

Recurrent outbreaks:

• Usually milder than the first outbreak
• Tingling or itching before blisters appear (warning sign)
• Fewer blisters, heal faster (5-10 days)
• Some people get frequent outbreaks (4-5 per year), others rarely

Is There a Cure?

There is no cure for genital herpes - once you have it, the virus stays in your body for life. However:

• Antiviral tablets can treat outbreaks and make them shorter and less painful
• Daily antiviral tablets can prevent most outbreaks
• Outbreaks usually get less frequent over time

Can I Still Have Sex?

Yes, but you need to take precautions:

• Avoid sex during outbreaks (when sores are present)
• Use condoms between outbreaks (reduces but doesn't eliminate risk)
• Daily antiviral tablets reduce the chance of passing it on by about half
• Tell your partner so they can make an informed decision

What About Pregnancy?

If you have genital herpes and become pregnant:

• Tell your midwife or doctor
• The risk to your baby is very low if you had herpes before pregnancy (less than 1 in 1000)
• You'll be offered daily antiviral tablets from 36 weeks to prevent an outbreak during delivery
• If you have sores when you go into labour, a caesarean section will be recommended
• If you catch herpes for the first time late in pregnancy, there's a higher risk to the baby

How Will This Affect My Life?

Many people find the emotional impact harder than the physical symptoms:

• Feelings of shame, worry, or isolation are common but remember:
  • Genital herpes is very common (1 in 8 people have it)
  • It doesn't affect your general health or life expectancy
  • It's manageable with treatment
  • Most people have fewer outbreaks over time

Where Can I Get Support?

• Your doctor or sexual health clinic
• Herpes Viruses Association (UK): www.herpes.org.uk
• American Sexual Health Association (US): www.ashasexualhealth.org

Key Messages

✅ Genital herpes is common and treatable (even though not curable) ✅ You can still have relationships and children ✅ Outbreaks usually get better over time ✅ Daily tablets can prevent most outbreaks and reduce transmission ✅ Be open with partners about your diagnosis

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14. References

1. Looker KJ, Magaret AS, May MT, et al. Global and regional estimates of prevalent and incident herpes simplex virus type 1 infections in 2012. PLoS One. 2015;10(10):e0140765. doi:10.1371/journal.pone.0140765

2. James C, Harfouche M, Welton NJ, et al. Herpes simplex virus: global infection prevalence and incidence estimates, 2016. Bull World Health Organ. 2020;98(5):315-329. doi:10.2471/BLT.19.237149

3. Gupta R, Warren T, Wald A. Genital herpes. Lancet. 2007;370(9605):2127-2137. doi:10.1016/S0140-6736(07)61908-4

4. Bernstein DI, Bellamy AR, Hook EW 3rd, et al. Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis. 2013;56(3):344-351. doi:10.1093/cid/cis891

5. Roberts CM, Pfister JR, Spear SJ. Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis. 2003;30(10):797-800. doi:10.1097/01.OLQ.0000092387.58746.C7

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28. World Health Organization. WHO guidelines for the treatment of genital herpes simplex virus. Geneva: WHO; 2016. Available at: https://www.who.int/publications/i/item/9789241549950

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Last Updated: 2026-01-06 Evidence Level: High Citation Count: 28 Target Examinations: MRCP, MRCOG, Sexual Health Diploma