What are the diagnostic tests and treatment options for Herpes Simplex Virus (HSV) infection?

Diagnostic Testing for Herpes Simplex Virus Infection

For patients with active genital lesions, nucleic acid amplification testing (NAAT/PCR) from the lesion is the first-line diagnostic test, with sensitivity and specificity exceeding 90% for most FDA-approved assays. 1, 2

Diagnostic Approach Based on Clinical Presentation

Active Lesions Present

• NAAT/PCR is the preferred test for detecting HSV from genital ulcers or lesions, offering 11-71% superior sensitivity compared to viral culture 2, 3
• Sample collection technique matters: obtain fluid from intact vesicles or swab the base of ulcers for optimal yield 2
• For male patients, use urethral swabs; for female patients, use cervical/urethral swabs 2
• Type-specific testing is essential to differentiate HSV-1 from HSV-2, as this affects prognosis and counseling 1, 2
• If NAAT is unavailable, viral culture is acceptable as a second choice, though it has significantly lower sensitivity 1, 3
• Avoid direct immunofluorescence assay and Tzanck smear due to poor sensitivity 1, 2

Critical pitfall: Do not obtain HSV molecular assays in the absence of genital ulcers—intermittent viral shedding makes this approach insensitive 1, 2

No Active Lesions (Serologic Testing)

• Type-specific HSV serologic assays using glycoprotein G-based EIA or CLIA differentiate HSV-1 from HSV-2 1
• Western blot is the gold standard for serologic testing, but commercial assays have significant limitations 1

Understanding Serologic Test Limitations

HSV-2 serology has poor specificity, particularly at low index values:

• Index values 1.1-2.9: only 39.8% specificity 1
• Index values ≥3.0: improved to 78.6% specificity 1
• For index values <3.0, confirm with a second assay using a different glycoprotein G antigen before giving results to patients 1, 3, 4
• Combining HerpeSelect with Biokit HSV-2 rapid assay improves specificity from 93.2% to 98.7% and positive predictive value from 80.5% to 95.6% 1
• If Biokit unavailable, consider Western blot confirmation, though access may be limited 1
• False positives occur even at index values >3.5 1

HSV-1 serology has poor sensitivity:

• Sensitivity only 70.2%, leading to false-negative diagnoses 1

Window period considerations:

• Antibodies may take up to 12 weeks to develop after infection 1, 3, 4
• Do not repeat serologic testing until 12 weeks after exposure if initial test is negative 1, 3, 4
• Sensitivity of HSV-2 serology is 92% after the window period 1

Who Should Be Tested

Serologic Testing Recommended For:

• Patients with genital symptoms consistent with herpes (classic or atypical) 1
• Patients told they have genital herpes without virologic confirmation 1
• Sexual partners of individuals with known genital HSV-2 infection 1, 4
• Pregnant women at risk of acquiring HSV close to delivery 2, 3, 4
• Men who have sex with men 3, 4
• HIV-positive individuals 3, 4

Screening NOT Recommended For:

• Asymptomatic adolescents and adults in the general population 1, 2, 3, 4
• Asymptomatic people with low pretest probability (few lifetime partners, no known HSV-2 positive partners, no genital symptoms) 1
• Pregnant women as routine screening 1

Treatment Options

FDA-Approved Antiviral Medications

Three medications are available: acyclovir, famciclovir, and valacyclovir 1

Mechanism of action: These are nucleoside analogues that inhibit viral DNA polymerase through competitive inhibition, incorporation into viral DNA causing chain termination, and inactivation of viral DNA polymerase 5, 6

Treatment Strategies

Two management goals: (1) prevention of symptoms/recurrences and improvement in quality of life, and (2) prevention of transmission to sexual partners 1

For Symptomatic HSV-2 Infection:

• Offer suppressive therapy (daily medication) to all patients—this reduces recurrences and prevents transmission to sexual partners 1
• Alternative: episodic therapy (short-term treatment for symptomatic recurrences) 1
• Suppressive therapy prevents transmission through suppression of viral shedding 1
• Same medication dosages recommended for both HSV-1 and HSV-2 genital infections 1, 2

Practical consideration: Prioritize dosing regimens that are most feasible for patient adherence 1

Resistance Considerations

• Viral resistance can result from mutations in viral thymidine kinase (TK) or DNA polymerase genes 5, 6
• Consider resistance in patients with poor clinical response or recurrent viral shedding during therapy 5, 6
• Most resistant mutants are TK-deficient, particularly in immunocompromised patients with advanced HIV 1
• Cross-resistance occurs among HSV isolates with frameshift mutations, conferring reduced susceptibility to penciclovir, famciclovir, and foscarnet 6

Key Clinical Pitfalls to Avoid

• Never rely on clinical diagnosis alone—laboratory confirmation is essential 2
• Never test asymptomatic patients with NAAT/PCR—only use for active lesions 1, 2
• Never give HSV-2 serologic results with index values <3.0 without confirmatory testing—false positives are common 1, 3, 4
• Never repeat serologic testing before 12 weeks if evaluating for recent acquisition 1, 3, 4
• Patients with HSV-1 infection are more likely to have false-positive HSV-2 tests at low index values 1
• Up to 50% of first-episode genital herpes cases are caused by HSV-1, which has less frequent recurrences and subclinical shedding than HSV-2 2