Clinical Reactivation of Genital Herpes Simplex Virus Infection Decreases in Frequency over Time

Genital herpes continues to be epidemic throughout the world (1-7). A recent population-based survey in the United States showed a 31% increase in herpes simplex virus (HSV) type 2 seropositivity during the past decade (6). The seroprevalence of HSV-2 infection ranges from 30% to 50% in most sexually transmitted disease clinics and from 20% to 30% in most family practice, obstetric, and general medicine clinics (5, 7-9). The seroprevalence of genital HSV-1 infection is also being reported with increasing frequency (10). Previous studies of persons with initial episodes of genital herpes have shown that more than 90% of persons infected with HSV-2 have a recurrence during the first year of follow-up (11, 12). However, little is known about the subsequent course of infection. Anecdotal reports have suggested that recurrences of HSV decrease over time (13, 14). However, in a study of the frequency of genital herpes recurrences among 22 women followed for two consecutive pregnancies, Harger and colleagues (15) were unable to detect any appreciable difference in recurrence rates between the first and second pregnancies. Fife and coworkers (16) investigated a group of patients enrolled in a long-term study of continuous daily acyclovir therapy. On discontinuation of therapy, most patients subsequently had a recurrence, although the rate was lower than that reported before treatment. The authors could not determine whether the lower rates were related to antiviral therapy or reflected the long-term natural history of the infection. Studies of objectively defined observations on the long-term clinical course of recurrent genital herpes are not available. Because decisions to use long-term suppressive therapy or episodic therapy are based on frequency of reactivation, knowledge of the infection's natural history directly benefits clinical management (17). We report on the long-term history of recurrence rates among persons enrolled at a research clinic that studied the clinical course and pathogenesis of genital HSV infection. Methods Patients In 1974, a research clinic dedicated to the study of symptomatic genital herpes infection was established at the Harborview Medical Center in Seattle, Washington (18-21). From 1974 to 1991, we recruited 664 patients with HSV infection documented by serologic studies or culture. These patients were enrolled in a prospective observational study of the frequency of genital HSV reactivation and were followed for at least 14 months. Testing for HIV infection was not part of the study protocol; however, none of these patients demonstrated clinical immunosuppression at study entry or during follow-up. All patients gave informed consent, and institutional review board approval was obtained throughout observation. Using history, serologic studies, and viral isolation, we classified patients who presented to the clinic as having new or previous acquisition of genital herpes (12, 18-21). Patients with newly acquired HSV infection lack serum antibodies to the acquired HSV type, whereas patients with recurrent infection have these antibodies. From 1983 to 1991, the serologic status of all patients was determined by using Western blot assay, which accurately distinguishes antibodies to HSV-1 from antibodies to HSV-2 (22, 23). Between 1974 and 1983, all serum samples obtained at entry were screened by microneutralization assay (18). All serum samples that demonstrated neutralizing activity were retrospectively analyzed by Western blot assay. Patients who had only antibodies to HSV-1 and whose HSV-2 infection was documented by culture or subsequent seroconversion to HSV-2 were included in this report as having nonprimary initial HSV-2 infection. Patients who had antibodies to HSV-2 at enrollment were included as having recurrent HSV-2 infection. Because neutralization and Western blot assays have equal sensitivity for detecting antibodies to HSV, all patients with entry serum samples that lacked neutralization were classified as having primary HSV infection (23). A viral isolate for genital herpes was used to classify these patients as having primary HSV-1 or primary HSV-2 infection. Data Collection Patients presenting at the clinic with a symptomatic recurrence were followed every 2 to 3 days until their lesions healed. Patients were instructed to return to the clinic during each subsequent recurrence and for routine visits every 2 to 3 months; they were also asked to return to the clinic for assessment of all genital symptoms until they were able to accurately recognize signs and symptoms of genital herpes recurrence (11, 12). At this time, routine clinic visits were changed from 2-month intervals to 4- to 6-month intervals to enhance long-term compliance with the protocol. Patients were asked to keep a record of onset and resolution dates for all recurrences so that we could document the time of onset of recurrences not observed by clinic personnel. Diary cards were collected and reviewed with clinic staff at each clinic visit. Data were coded on a standardized coding sheet and entered into a centralized database. Anatomic site of recurrence, date of onset, duration, and therapy were recorded for all genital lesions. A recurrence was defined as the presence of vesicles, ulcers, or crusts. Anatomic sites categorized as genital recurrences were the mons, vulva, or perineum in women; the periurethral area, penis, and scrotum in men; and the perianal area and buttocks in both sexes. If new lesions appeared before other lesions completely healed, all lesions were considered part of the same recurrence. Statistical Analysis Annual recurrence rates for each patient were estimated by dividing the number of recorded recurrences in a specified period by the number of years in that period (12, 20). For example, the second-year recurrence rate for a patient followed the entire year is the number of recurrences in the second year. For a patient followed for only the first 2 months of the second year, the denominator is 2 divided by 12 (0.167). Comparisons of patient groups with respect to recurrence rates were made by using the Wilcoxon rank-sum test. Recurrence rates between years 1 and 2 were compared by using the Wilcoxon signed-rank test. Exploratory data analyses (24) were used to investigate patterns over time in patients followed for more than 2 years. Two-way tables of recurrence rates with a row for each patient and a column for each year of data were created for subsets of patients with varying lengths of follow-up. Two methods were used to estimate an overall effect and patient and year effects: the least-squares fit (the method used in a two-way analysis of variance when no values are missing) and the median polish fit (a method that is resistant to outliers). Outliers in estimated recurrence rates occurred when persons were followed for a short period; that coincided with an unusually high number of recurrences. Examination of year effects suggested that it was reasonable to hypothesize a linear time trend in recurrence rates. We therefore used a random-effects model (25) to assess the changes in recurrence rates over time. The slope coefficient in this model represents the average annual change in the recurrence rate (a positive slope if the recurrence rate increased and a negative slope if the recurrence rate decreased); the intercept represents the average rate in the first year of follow-up. A plot of mean annual recurrence rates by year provided a visual description of the fitted models. We used a model that allowed the slope and intercept to vary from patient to patient. A consequence of this variability is correlation among the observations from a given patient. This is taken into account in the estimation procedure. We computed approximate 95% CIs, assuming that the estimated slopes and intercepts were normally distributed. Whether such a normal distribution existed for all data on recurrence rates for all subsets of patients is unclear. Therefore, the reported CIs should be interpreted descriptively. When computing recurrence rates for individual patients, we excluded data from any time at which suppressive antiviral therapy was used. Some analyses were restricted to patients who never received suppressive therapy. Because antiviral treatment of symptomatic episodes has not been shown to affect recurrence rates (26-28), such treatment was not considered in these analyses. All analyses were done by using S-Plus, version 3.1 (Statistical Sciences, Inc., Seattle, Washington). The function twoway was used for two-way table analyses, and the function varcomp was used for fitting random-effects models. Role of the Funding Source The agency had no role in the collection, analysis, or interpretation of the data or in the decision to submit this paper for publication. Results Of the 664 patients, 306 had newly acquired (first-episode) genital herpes. Sixty had primary HSV-1 infection, 205 had primary HSV-2 infection, and 41 had nonprimary initial HSV-2 infection (that is, HSV-2 infection after previous HSV-1 infection). Previously acquired (recurrent) HSV-2 infection was present at enrollment in the other 358 patients (Table 1). Our study included 277 men and 387 women. Demographic, socioeconomic, and sexual histories of our patients were similar to those of patients in previous reports (12, 18-21). Of the 664 patients, 412 were followed for more than 2 years, 277 were followed for more than 3 years, 117 were followed for more than 6 years, and 52 were followed for more than 9 years. Table 1. Characteristics of Study Sample One hundred ninety-four patients received suppressive therapy at some time during follow-up, including 38 of the patients who presented with first-episode infection. Among these patients, the median duration of suppressive therapy was 10 months; the median follow-up time while patients were not receiving therapy was 35 months. During follow-up, patients had 11 967 genital