ENGELBERG, REBECCA BA*; CARRELL, DAVID PhD*; KRANTZ, ELIZABETH MS*; COREY, LAWRENCE MD*†§; WALD, ANNA MD, MPH*†‡
From the Departments of *Laboratory Medicine, †Medicine, and ‡Epidemiology, University of Washington, and §Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington
Supported by a grant from the National Institutes of Health (no. AI-30731).
Reprint requests: Anna Wald, MD, MPH, University of Washington Virology Research Clinic, 600 Broadway, Suite 400, Seattle, WA 98122. E-mail: email@example.com
Received March 27, 2002,
revised June 5, 2002, and accepted June 6, 2002.
Background: Herpes simplex virus type 1 (HSV-1) has been increasingly reported as a cause of genital herpes, yet there have been few studies on the long-term natural history of this infection.
Goal: The goal was to examine the clinical course of genital HSV-1 infection.
Study Design: This was a cohort study of patients presenting with culture-proven primary genital HSV-1 infection.
Results: The median follow-up of the 77 patients was 736 days. The overall rate of recurrences was 1.3/year in the first year of infection, decreasing to 0.7/year in the second year. In the first year of infection, 43% of study patients did not have a recurrence. In the second year of infection, 67% of study patients did not have a recurrence.
Conclusion: Genital HSV-1 recurs infrequently in most patients, and the rate decreases further in the subsequent years of infection. Because the prognoses of genital HSV-1 and HSV-2 infections differ, determination of the viral type is important for patient counseling.
GENITAL HERPES INFECTIONS are among the most prevalent sexually transmitted infections in the United States. 1 Recent data from the United States, Europe, and Asia show a shift from predominantly HSV-2 as a main cause to a large proportion of genital herpes caused by HSV-1 infection. 2–4 Several studies have shown that recurrence rates for genital HSV-1 after acquisition of infection are lower than recurrence rates for genital HSV-2. 5,6 However, these studies involved small numbers of persons followed for a limited time. In this article, we report on a cohort of patients with documented primary genital HSV-1 who were followed for a median of 2 years from acquisition of genital herpes.
Patients and Setting
We reviewed the records of patients with documented primary genital HSV-1 infection seen at the University of Washington Virology Research Clinic (VRC), in Seattle, between November 1975 and July 2000. Patients included in the study had an observed first episode of infection, HSV-1 isolated from the genital region, no serologic or other evidence of HSV-2 infection, and at least 6 months of follow-up. HSV Western blotting was used to document HSV-1 antibody status. 7 Only patients with documented primary genital HSV-1 infection, defined as newly acquired HSV-1 infection in persons without prior antibody to HSV, were included. Viral isolation was performed as previously described, and all isolates were typed with monoclonal antibodies. 8
Data Collection and Statistical Methods
At each clinic visit, information regarding onset and resolution date of recurrence, details of clinical examination during the visit, and treatment were noted on a standardized data form. Data on timing of intercurrent episodes were also collected on each visit. Patient-reported data were used in conjunction with clinician observations to establish episode frequency. Episode duration data are based on clinician-observed episodes only.
We defined an episode of genital HSV-1 as the presence of herpes lesions in the genital region or other sites below the waist. Episode duration was defined as the number of days from the first appearance of lesions to complete reepithelialization. An episode was considered to be culture-positive if virus was isolated from at least one specimen during the episode. If new lesions appeared before complete healing of other lesions, all were considered part of the same episode. Time to first recurrence was defined as the number of days from complete clearing of the primary HSV-1 infection to the first appearance of signs or symptoms of the next episode. 6
Recurrence rates per person-year were calculated for the first, second, and combined third through fifth years following primary infection. The minimum required time of follow-up for inclusion in the year 1 rate calculation was 6 months, and the minimum follow-up required for inclusion in the year 2 rate was 100 days in the second year of infection (i.e., ≥465 days). Recurrence rates were calculated as the sum of all recurrences for all persons meeting the minimum follow-up requirements for a given time period, divided by the sum of all follow-up days for the same group of persons during the same time period, expressed in person-years. For calculations of duration of episodes, the duration was averaged for each person; person means were then used to calculate group statistics. Poisson models were used to calculate relative risks for recurrences by year of follow-up, age, and gender.
Seventy-seven patients presenting with primary HSV-1 met all study inclusion criteria. The participants included 48 women (62%), and 71 (92%) patients were white (Table 1). The median age at onset of primary genital herpes was 23 years (range, 17–46). The median duration of follow-up was 736 days (interquartile range [IQR]: 426–1337). All 77 patients were followed for at least 6 months, and 54 patients were followed for at least the first 100 days in year 2.
The median time to first recurrence was 280 days, with a median of 195 days among women and 567 days among men (Table 2 and Figure 1). Overall, we noted 179 recurrent episodes during follow-up. The rate of recurrences was 1.30 per year in the first year of infection, decreasing to 0.70 per year in the second year (Table 2). However, in both years the rate was higher for women (1.63 and 0.94) than for men (0.76 and 0.33). In the first year of infection, 43% of all patients had no recurrences, 30% had 1 recurrence, and 27% had 2 or more recurrences (Figure 2). In the second year of infection, 67% of patients had no recurrences, 19% had 1 recurrence, and 15% had 2 or more recurrences. A propensity for recurrences appeared to persist in some persons during follow-up. Of the 29 patients who experienced a recurrence in the first year of infection and were followed for at least 100 days into year 2, 15 (52%) also reported a recurrence in the second year. Among the 54 patients followed for at least 2 years, only 6 patients (11%) had 2 or more recurrences in both the first and the second year of infection, and only 1 patient (2%) had 4 or more recurrences in both years. Conversely, among patients followed for 2 years, 22 (88%) of the 25 who were recurrence-free in year 1 were also recurrence-free in year 2. Longer follow-up in a small subset of patients showed that frequent recurrences many years after infection are possible but rare: 11 of 23 patients followed into the 4th year reported a recurrence in that year, with 8 reporting a single recurrence and 1 each reporting 2, 3, and 4 recurrences.
In multivariate analysis, the risk of having a recurrence in year 2 was 0.54 (95% CI, 0.36–0.82), compared with the risk of having a recurrence in year 1, controlling for the effects of gender (Table 3). In both year 1 and year 2, women were at greater risk of having a recurrence than were men, with an adjusted relative risk of 2.29 (95% CI, 1.30–4.04). In an analysis confined to 44 patients who had one or more recurrences in year 1, the adjusted relative risk of recurrence in year 2 was 0.49 (95% CI, 0.32–0.76), and women again were at greater risk of having a recurrence, with an adjusted relative risk of 1.78 (CI, 1.19–2.68). Acyclovir therapy for primary genital herpes was administered to 50 (75%) of the 67 patients for whom treatment data are available; the time to first recurrence did not differ for treated versus untreated patients (data not shown).
Because patients were followed for varying periods of time beyond our 6-month eligibility criterion, we tested for selection bias by comparing the year 1 recurrence rate reported for all patients with the year 1 recurrence rate for patients with at least 100 days of follow-up in year 2. The year 1 recurrence rate for 54 patients followed for ≥100 days in year 2 was similar to the rate for all patients: 1.20 versus 1.30, respectively. The gender distribution between these two groups is also similar (61% versus 62% women, respectively). However, the year 1 recurrence rate for patients followed into the third year is somewhat higher than the rate for all patients (1.51 versus 1.30 recurrences per year, respectively), suggesting that people with more frequent recurrences were more likely to have follow-up beyond 2 years.
Duration of Recurrences
The median duration of the 147 recurrences observed in the clinic, experienced by 44 patients, was 7.0 days (IQR, 5.9–8.9), which is similar to the median recurrence duration of 8.5 days (IQR, 7.0–11.0) observed for 205 persons with genital HSV-2 infection followed in the same manner (unpublished data from Benedetti 6). One or more viral culture specimens were collected during 121 (67.6%) of the 179 recurrent episodes in this cohort. Fifty-six (46.3%) of these episodes were culture-positive, which is comparable to the culture-positivity rate for HSV-2 recurrences.
The 179 recurrent episodes included 174 (97%) with genital lesions and 5 (3%) of buttock or leg/hip lesions. The 5 recurrences involving only nongenital lesions (2 on the buttock and 3 in the leg/hip area) were experienced by 2 people. The two buttock episodes were the first and third of 7 recurrences in 3.7 years of follow-up for a 28-year-old woman. Her primary infection and fourth and fifth episodes also involved buttock lesions, but they were secondary to genital lesions. The three leg/hip episodes were the first, second, and fourth of 4 recurrences in 1.1 years of follow-up for a 29-year-old man whose primary infection also involved secondary leg/hip lesions.
This study, involving the largest cohort of persons with genital HSV-1, indicates the relatively mild natural history of genital HSV-1 infection. Our study showed that genital HSV-1 recurs infrequently and that the rate of recurrences decreases rapidly over time, with a median recurrence rate declining by about 50% from the first to the second year of infection.
Our data support previous findings that patients with genital HSV-1 are less likely to experience recurrences than patients with genital HSV-2. 9–12 With use of the same definitions and study procedures, the recurrence rate for genital HSV-1 during the first year of infection was about 20% of the recurrence rate reported for genital HSV-2 infection in the first year of infection. Furthermore, the rapid decrease in the frequency of recurrences between the first and second year of infection contrasts with the slow decline in HSV-2 recurrence rates, a decline that does not become apparent until 3 to 5 years after primary infection. 6 This site-specific tropism of HSV-1 versus HSV-2 reactivation in the oral and genital area has also been noted in animal models of infection. 13 Despite the lower rate of reactivation of genital HSV-1 infection, reported both for symptomatic recurrences and asymptomatic shedding, the duration of episodes is similar to that for HSV-2. This implies that the mechanism controlling reactivation of HSV in the genital area is particular to the viral type, while the mucosal events that occur after symptomatic reactivation are independent of the viral type.
In both years 1 and 2 following primary genital HSV-1 infection, men were at lower risk of having a recurrence than were women. It is possible that men were less likely to visit a clinic or to report recurrences than were women. However, the proportion of men in the cohort remained constant in subgroups of patients with at least 180, 465, and 730 days of follow-up, suggesting that adherence to clinic visits was not the source of the gender difference.
The varying amounts of follow-up in our cohort may have overestimated the recurrence rates if patients ceased to return to the clinic when they no longer experienced recurrences. Conversely, patients who did not experience a decrease in recurrences may also have stopped attending the clinic. A comparison of recurrence rates for subgroups of patients with at least 1, 2, and 3 years of follow-up suggested that patients with fewer recurrences may have been less likely to continue clinic visits. These effects are unlikely to alter the marked difference in recurrence rates between HSV-1 and HSV-2.
These data indicate that clinical strategies for genital HSV-1 should differ from those for HSV-2. Few if any of our patients with genital HSV-1 meet current criteria for suppressive antiviral therapy. Data reported here indicate episodic antiviral therapy for recurrent episodes may be more appropriate for patients with genital HSV-1. Because the prognoses of genital HSV-1 and HSV-2 infections differ greatly, knowing the viral type is important for prognosis, treatment, and patient counseling. Thus, all patients with genital herpes should know which viral subtype causes their lesions.
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