What are the recommended tests and treatments for Herpes Simplex Virus (HSV) infection?

HSV Testing: Diagnostic Approach

For active genital or oral lesions, nucleic acid amplification testing (NAAT/PCR) that differentiates HSV-1 from HSV-2 is the first-line diagnostic test, with >90% sensitivity and specificity, far superior to viral culture. 1

Testing Strategy for Active Lesions

Primary Diagnostic Method

• Obtain NAAT/PCR directly from vesicular or ulcerative lesions as the preferred diagnostic approach, providing results within approximately 2 hours with the highest sensitivity (11-71% superior to viral culture). 1, 2, 3
• The test must differentiate between HSV-1 and HSV-2, as this distinction provides critical prognostic information—HSV-1 genital infections recur far less frequently than HSV-2. 1
• Sample early in the disease course by piercing vesicles to collect fluid or swabbing the base of ulcers with cotton-wool or Dacron swabs, as viral DNA detection decreases dramatically as lesions heal. 1, 2

When NAAT/PCR is Unavailable

• Viral culture is acceptable but significantly less sensitive, requiring 24-72 hours for results and strict refrigeration during transport. 1
• If culture is negative but HSV is still suspected clinically, proceed to type-specific serologic testing to rule out HSV-2 infection. 1

Tests to Avoid

• Do not use Tzanck smear or direct immunofluorescence assay—both lack adequate sensitivity and are not recommended for diagnosis of HSV genital or oral ulcer disease. 1

Serologic Testing Strategy

When to Use Serology

• Order type-specific HSV-2 IgG serology when lesions have healed and direct testing was not performed, when recurrent episodes occur but direct testing has been negative, or to detect asymptomatic infections in high-risk populations. 1, 4
• Consider serologic testing for pregnant women at risk of acquiring HSV near delivery, men who have sex with men, and people living with HIV. 4

Critical Interpretation Algorithm

• Index value <0.9: Negative result. 1, 4
• Index value 0.9-1.1: Indeterminate—repeat testing or use alternative assay. 1, 4
• Index value 1.1-2.9: Low positive with only 39.8% specificity—must confirm with a second assay using different glycoprotein G antigen, which improves specificity from 93.2% to 98.7%. 1, 4
• Index value ≥3.0: Positive with 78.6% specificity—more reliable but still consider confirmation in low-prevalence populations. 1, 4

Common Serologic Pitfalls

• HSV-1 serology has only 70.2% sensitivity, resulting in frequent false-negative results—do not rely on it for diagnosis. 1, 4
• Patients with HSV-1 infection are significantly more likely to have false-positive HSV-2 results, especially at low index values (1.1-2.9). 1, 4
• Never report low-positive results (1.1-2.9) without confirmatory testing—this leads to false-positive diagnoses with severe psychological and relationship consequences. 4
• Testing within 12 weeks of exposure will miss infections due to the antibody window period. 1, 4
• Do not order serology when active lesions are present—this misses the opportunity for definitive NAAT/PCR diagnosis. 1, 4

Special Clinical Scenarios

HSV Encephalitis

• Detection of HSV DNA by PCR in cerebrospinal fluid is the diagnostic test of choice. 1

Immunocompromised Patients

• More aggressive diagnostic evaluation is warranted, including early biopsy for atypical presentations or non-healing ulcerations. 1, 5
• Extensive, deep, non-healing ulcerations most commonly occur with CD4+ counts <100 cells/µL and may harbor acyclovir-resistant virus. 1

Asymptomatic Screening

• Widespread screening for HSV antibodies in asymptomatic general populations is not recommended. 4

Treatment Considerations

Standard Antiviral Therapy

• Oral acyclovir, valacyclovir, or famciclovir are first-line for mild to moderate infections. 6, 7, 8, 5
• Intravenous acyclovir 5-10 mg/kg every 8 hours is the drug of choice for severe, disseminated, or CNS infections. 6, 5
• For HSV encephalitis, IV acyclovir 10 mg/kg every 8 hours for 10 days reduced mortality from 59% to 25% compared to vidarabine. 6

Acyclovir-Resistant HSV

• Foscarnet is the treatment when acyclovir resistance is confirmed or suspected, particularly in immunocompromised patients with non-healing ulcerations. 7, 8, 5
• Resistance results from mutations in viral thymidine kinase or DNA polymerase genes, most commonly in patients with advanced HIV infection. 7, 8