Viral Shedding 1 Year Following First-Episode Genital HSV-1 Infection

Abstract

Importance: Herpes simplex virus type 1 (HSV-1) is the leading cause of first-episode genital herpes in many countries.

Objective: To inform counseling messages regarding genital HSV-1 transmission, oral and genital viral shedding patterns among persons with first-episode genital HSV-1 infection were assessed. The trajectory of the development of HSV-specific antibody and T-cell responses was also characterized.

Design, setting, and participants: Prospective cohort followed up for up to 2 years, with 82 participants followed up between 2013 and 2018. Participants were recruited from sexual health and primary care clinics in Seattle, Washington. Persons with laboratory-documented first-episode genital HSV-1 infection, without HIV infection or current pregnancy, were referred for enrollment.

Exposures: First-episode genital HSV-1 infection.

Main outcomes and measures: Genital and oral HSV-1 shedding and lesion rates at 2 months, 11 months, and up to 2 years after initial genital HSV-1 infection. Participants self-collected oral and genital swabs for HSV polymerase chain reaction testing for 30 days at 2 and 11 months and up to 2 years after diagnosis of genital HSV-1. Blood samples were collected at serial time points to assess immune responses to HSV-1. Primary HSV-1 infection was defined as absent HSV antibody at baseline or evolving antibody profile using the University of Washington HSV Western Blot. HSV-specific T-cell responses were detected using interferon γ enzyme-linked immunospot.

Results: Among the 82 participants, the median (range) age was 26 (16-64) years, 54 (65.9%) were women, and 42 (51.2%) had primary HSV-1 infection. At 2 months, HSV-1 was detected from the genital tract in 53 participants (64.6%) and in the mouth in 24 participants (29.3%). Genital HSV-1 shedding was detected on 275 of 2264 days (12.1%) at 2 months and declined significantly to 122 of 1719 days (7.1%) at 11 months (model-predicted rate, 6.2% [95% CI, 4.3%-8.9%] at 2 months vs 3.2% [95% CI, 1.8%-5.7%] at 11 months; relative risk, 0.52 [95% CI, 0.29-0.93]). Genital lesions were rare, reported on 65 of 2497 days (2.6%) at 2 months and 72 of 1872 days (3.8%) at 11 months. Oral HSV-1 shedding was detected on 88 of 2247 days (3.9%) at 2 months. Persons with primary HSV-1 infection had a higher risk of genital shedding compared with those with nonprimary infection (model-predicted rate, 7.9% [95% CI, 5.4%-11.7%] vs 2.9% [95% CI, 1.7%-5.0%]; relative risk, 2.75 [95% CI, 1.40-5.44]). Polyfunctional HSV-specific CD4+ and CD8+ T-cell responses were maintained during the follow-up period.

Conclusions and relevance: Genital HSV-1 shedding was frequent after first-episode genital HSV-1, particularly among those with primary infection, and declined rapidly during the first year after infection.

Figure 1.. Genital and Oral Herpes Simplex Virus Type 1 (HSV-1) Shedding Rates

All participants are included; those who completed only the first session are indicated by a dot for the second session. Twenty-eight participants did not have any genital shedding detected and 49 participants did not have any oral shedding detected. Shedding rates are calculated by dividing the number of days with HSV detected by the total number of days with swabs collected. Study participants are plotted in reverse rank order from least to greatest shedding rate. The order of study participants is not equivalent in panels A and B, and the participant numbers do not relate directly to viral genome isolate numbers in eFigure 3 in the Supplement.

Figure 2.. Bivariable and Multivariable Risk Factors Associated With Genital and Oral Herpes Simplex Virus Type 1 (HSV-1) Shedding

For this analysis, those with unknown acquisition type are grouped with those with nonprimary infection. For the comparison between first and second session, the model does not distinguish primary from nonprimary or unknown acquisition type. For the comparison between nonprimary unknown and primary the model does not distinguish the first from the second session. The multivariable model included an interaction term between session and acquisition type. In multivariable models including both age and sex, neither age nor sex contributed to the model in estimating shedding frequencies, so those measures were removed in backward elimination. Forest plots indicate the point estimate and 95% CI for each comparison. The reference is indicated by a box over the midline without a CI.

Figure 3.. Cellular Immune Responses Measured Over Time for the First 20 Participants With Primary Genital Herpes Simplex Virus Type 1 (HSV-1)

Each line represents the time course for a single participant, and participants are represented by the same line color for both graphs. IFN indicates interferon; PBMC, peripheral blood mononuclear cells.