Recurrence Rates in Genital Herpes after Symptomatic First-Episode Infection

Genital herpes continues to be epidemic throughout most sexually active populations [1-4]. A recent serosurvey indicated that 21.7% of the U.S. population have HSV-2 antibodies, which represents a 31% increase in prevalence in the last decade [5, 6]. The seroprevalence of HSV-2 averages 30% in most family practice and obstetrics clinics and 30% to 50% among sexually transmitted disease clinic attendees. Seroprevalence is consistently higher in women than in men [7, 8]. The natural history of HSV infection includes acute or subclinical first-episode mucocutaneous infection, establishment of neuronal latency, and intermittent virus reactivation with or without associated recurrent symptoms [9, 10]. Although this sequence of events has been recognized for more than five decades, little is known about the long-term natural history of genital herpes. In the late 1970s, supported by the National Institutes of Health, we began a prospective study of a large cohort of persons with recently acquired symptomatic genital HSV infection in order to define more precisely the natural history of genital herpes. Clinical, demographic, and recurrence data were collected for 457 patients who presented with virologically, serologically, and clinically confirmed first-episode genital infection. More than half of these patients did not receive antiviral therapy during their primary episode, providing a population not likely to be replicated in the future. We summarize the natural history of symptomatic recurrences in the complete population and in the subset of untreated patients. Methods In 1974, a research clinic dedicated to the study of genital herpes infection was established at Harborview Medical Center, a King Countyfunded hospital affiliated with the University of Washington. Patients were referred by their private physicians or by the sexually transmitted disease clinic at Harborview, or responded to advertisements for participation in clinical studies of HSV infection. Only patients willing to participate in prospective studies with long-term follow-up or in therapeutic trials were enrolled. Between 1974 and 1988, we registered 457 patients with serologically and virologically proven first-episode infection who were followed for at least 60 days from the onset of infection. At the initial clinic visit, genital lesions were cultured and described by anatomic site, stage, and area. Patients were then generally followed at 2- to 3-day intervals until their lesions had healed. The median number of visits and genital examinations during the initial disease episode was 5 (range, 3 to 14 visits). After resolution of the first clinical episode, patients were instructed to return to the clinic during each recurrence or for routine visits at least every 2 to 3 months. Patients who were unable to return for each recurrence were instructed to maintain a diary of onset and resolution dates for each recurrence. These data were collected at the following clinic visit. In general, we insisted that patients return for recurrences until they were able to recognize the signs and symptoms of genital herpes reactivation and to fill out patient diaries about onset and healing of reactivations. We defined a recurrence of genital herpes as the presence of genital ulcerations. We defined duration of a recurrence as the number of days from the first appearance of genital lesions to the reepithelialization of all lesions. If new lesions appeared before complete healing of other lesions, all were considered part of the same episode. We report only recognized symptomatic (lesional) recurrences and do not address subclinical shedding of HSV in the genital tract. Serum specimens from both the acute and convalescent phases were obtained from all patients and tested for HSV-specific antibodies by Western blot; all patients showed seroconversion to HSV-1 or HSV-2 [11, 12]. Some had antibodies to HSV-1 in their acute-phase specimen and antibodies to both HSV-1 and HSV-2 in their convalescent-phase specimens. Patients were categorized as having primary first-episode disease if their acute-phase serum specimen showed absence of antibodies to HSV by Western blot. Based on Western blot profiles of convalescent-phase specimens and the subtype of the HSV isolates from lesions, patients were categorized as having primary HSV-1 or primary HSV-2 infection. Patients who had HSV-1 antibodies in acute-phase specimens and antibodies to HSV-2 in convalescent-phase specimens were classified as having nonprimary first-episode HSV-2 disease [11, 13]. Patients with detectable antibodies to the homologous viral type isolated in initial specimens were classified as having recurrent disease [13]. Forty-two patients had serologic evidence of HSV-2 antibodies in acute- and convalescent-phase serum specimens, and 19 patients with HSV-1 antibodies in both their acute- and convalescent-phase specimens were classified as having reactivation infection and were not included in this study even though they claimed to be experiencing their first episode. We also excluded 64 patients seen between 1974 and 1985 whose serum specimens were analyzed by microneutralization but whose enrollment specimens could not be retrospectively retrieved for confirmation by Western blot [14]. In this study, we compared baseline patient characteristics and severity of primary infection with the subsequent recurrence experience of the patient. Patient characteristics included sex, race, age, and measures of past sexual activity, such as number of partners and history of sexually transmitted diseases. Clinical characteristics included pain, itch, discharge, fever, headache, photophobia, and stiff neck. Because many patients were participants in our early randomized trials of acyclovir, treatment status was also recorded [15-17]. Statistical Methods Monthly recurrence rates for each patient were estimated by dividing the number of recorded recurrences by the number of months the patient was followed. Comparisons of recurrence rates were made using the Wilcoxon rank-sum test or, for comparisons between more than two groups, the Kruskal-Wallis test. The Kaplan-Meier estimate was used to compute time to first recurrence, and appropriate comparisons were made using the Cox model [18]. Recursive partitioning was used as an exploratory technique to identify potential subsets of patients at higher risk for subsequent recurrence. Classification and regression trees were used for recursive partitioning of recurrence rates and a modification of this technique by LeBlanc and Crowley was used to establish time to first recurrence [19, 20]. These techniques identify the variable (and cutpoint, for continuous variables) most closely related to the recurrence pattern. Within each of these two splits, or nodes, of the data, the data are split again. This process is repeated within each node until no further splits appear to be important in predicting recurrences. This partitioning of the data can be represented as a tree that shows the splits of the variables into disjoint patient subsets. Because our previous placebo-controlled treatment trials failed to detect an effect of antiviral therapy on subsequent recurrences, most of our analyses are reported for the entire patient population. However, because treatment is known to affect the duration of primary symptoms, analyses to assess the potential effect of symptoms on subsequent recurrences were also done in the subset of untreated patients. Results Viral Type and Clinical Classification of Persons with First-Episode Genital Herpes Of the 457 patients presenting with first-episode genital herpes, 399 (87%) had primary genital HSV infection; 73 (16% of the total cohort) were infected with HSV-1 and 326 (71% of the total cohort) were infected with HSV-2. Fifty-eight (13%) patients were classified as having nonprimary HSV-2 infection. The median age of the patients was 24 years; 92% were single and 91% were white. Demographic characteristics were similar among those presenting with primary HSV-1, primary HSV-2, and nonprimary HSV-2 infection and were identical to those reported previously [10, 15-17, 21]. Frequencies of the major clinical signs and symptoms of the initial episode of genital herpes are shown in Figure 1. Patients with true primary genital herpes infection, regardless of infecting viral type, tended to have more severe disease than did patients with previous HSV-1 infection. This was most evident with respect to constitutional symptoms: Seventy-nine percent of those with primary HSV-1 or HSV-2 infection reported at least one constitutional symptom (fever, headache, photophobia, or stiff neck) during their first episode, compared with only 43% of those with nonprimary infection. Seventy-seven percent of those with primary episodes had inguinal adenopathy compared with 52% of those with nonprimary genital herpes (P = 0.001). Frequencies of symptoms and signs were similar between those with primary genital HSV-1 and primary genital HSV-2 infections, except in the case of nuchal rigidity, which was reported by 42% of patients with primary HSV-2 infection and 12% of those with primary HSV-1 infection (P = 0.005). Figure 1. Frequency of clinical signs and symptoms of first-episode genital herpes by viral type and evidence of previous herpes simplex virus type 1 (HSV-1) exposure. P Overall Recurrence Rates after Resolution of the Initial Episode Follow-up was defined as the time from enrollment to the date of the last clinic visit or to the date that a patient initiated long-term suppressive oral acyclovir therapy. The median follow-up was 418 days (range, 61 to 4897 days) and was similar in all subsets of patients whether segregated according to viral type, sex, or severity of clinical episode. The median numbers of clinic visits per patient in the first 90, 91 to 180, 181 to 365, and 366 to 720 days of follow-up were 10, 2, 2, and 1, respectively. The large numbers o