Risk of recurrence after treatment of first-episode genital herpes with intravenous acyclovir

To determine whether intravenous acyclovir treatment for a first episode of genital herpes could prevent or reduce subsequent recurrences, we combined and analyzed the results of two independently conducted, randomized, double-blind, placebo-controlled studies. Sixty-one patients were enrolled in the two trials; 30 received the drug, and 31 received placebo. At entry the demographic, epidemiologic, and clinical features of acyclovir- and placebo-treated patients from the two centers showed no significant differences. The median time to the first recurrence and the frequency of recurrences showed no significant differences when acyclovir and placebo recipients infected with either herpes simplex virus type 1 (HSV-1) or herpes simplex virus type 2 (HSV-2) were compared. However, irrespective of treatment, the median time to the first recurrence was significantly longer (293 days vs. 69 days; P less than .02) and the frequency of recurrence significantly less (0.11 recurrences per month vs. 0.43 recurrences per month; P less than .01) among patients with HSV-1 infection as compared with those who had HSV-2. It is concluded that in patients with first-attack genital herpes, the type of HSV is the most important determinant of subsequent recurrences and that intravenous acyclovir has little effect on subsequent recurrences.     

Herpes simplex virus type 1 remains the principal cause of initial anogenital herpes in Edinburgh, Scotland

GOAL: The goal of this study was to investigate the trends in the prevalence of anogenital herpes caused by herpes simplex virus (HSV) type-1 and HSV-2 among patients attending a sexually transmitted infections clinic. METHODS: We conducted a retrospective study of virologically proven first-episode genital herpes diagnosed in the Department of Genitourinary Medicine in Edinburgh between 1989 and 2002. RESULTS: First-episode anogenital herpes was associated with HSV-1 in 659 (62%) women and 294 (42%) men (P <0.0002). HSV-1 was recovered more often from women younger than 25 years than from older women (P <0.0005). For both HSV-1 and HSV-2 infections, the median ages of heterosexual men (26.0 and 28.0 years, respectively) were significantly higher than those of women (23.0 and 25.0 years, respectively)(P <0.05). The median age of men who have sex with men with HSV-1 (29.0 years) was significantly higher than that of heterosexual men (26.0 years)(P <0.01). CONCLUSION: HSV-1 remains the most common cause of symptomatic first-episode anogenital herpes, especially among young women in our clinic population.     

Predictors of herpes simplex virus type 2 antibody positivity among persons with no history of genital herpes

BACKGROUND: The demographic, historical, and behavioral factors that predict a positive herpes simplex virus type 2 (HSV-2) antibody test in persons without a history of genital herpes have not been well-defined. METHODS: Individuals (age 14-30 years) without a history of genital herpes completed a questionnaire and were offered free HSV-2 antibody testing. Factors from the questionnaire were correlated with the HSV-2 antibody result. RESULTS: Univariate analysis showed that female gender was significantly associated with positive test results. In gender-specific, multiple logistic regression models, a positive HSV-2 antibody test among men was associated with older age, non-white race, and a history of sexually transmitted disease (STD). Gender-specific symptom scores from the questionnaire were not predictive in either gender, but the gender-common symptom score was marginally predictive of a positive HSV-2 antibody test in women. Among women, older age, non-white race, and STD history predicted a positive test. CONCLUSIONS: Among young persons with no history of genital herpes who agreed to HSV-2 antibody testing, increasing age, non-white race, and a history of an STD were predictors of a positive test. A history of frequent pain, itching, burning, and rashes in the anogenital region was marginally associated with positive HSV-2 tests in women. These results might help guide selective use of HSV-2 antibody screening.     

Lack of evidence for intertypic recombinants in the pathogenesis of recurrent genital infections with herpes simplex virus type 1

Clinical observations indicate that herpes simplex virus type 1 (HSV-1) is significantly less likely than herpes simplex virus type 2 (HSV-2) to establish latency in (or reactivate from) sacral ganglionic tissue. In an effort to identify viral functions associated with latency, we analyzed HSV-1 isolates from three patients with established recurrent genital herpes and sought evidence of DNA sequences and proteins similar to those found in HSV-2. By restriction endonuclease cleavage patterns and by DNA hybridization analysis using either whole HSV-2 DNA or several cloned segments of HSV-2 DNA as probes, we found that the three HSV-1 isolates from patients with recurrent genital herpes showed no unusual homology to HSV-2 as compared with other HSV-1 isolates. Similarly, the proteins of these isolates could not be distinguished from those of other HSV-1 isolates and were distinct from those of HSV-2. At this level of resolution, there was no evidence to suggest that these recurrent genital HSV-1 isolates were intertypic recombinants, nor did they show any other unusual similarity to HSV-2.     

Confirmation of herpes simplex virus type 2 infections in herpes-like genital lesions by a simple complement-fixation test.

The presence of complement-fixing antibody to an early herpes simplex virus type 2 (HSV-2) antigen (the AG-4 antigen) was correlated with HSV-2 infection in the sera of patients with genital herpes. Eighty-eight per cent of sera taken two weeks after clinical diagnosis of a primary or recurrent herpes infection in patients, confirmed to have HSV-2 by virus isolation and typing, contained the anti-AG-4 complement-fixing antibody. None of the patients with genital HSV-1 had the antibody, and only 9% of controls or patients with facial HSV-1 infection had positive results for the antibody. This correlation was used to identify genital HSV-2 infections when either no virus sample had been taken or when virus isolations had been unsuccessful. Thus, a simple complement-fixation test can confirm an HSV-2 virus infection without isolation of the virus from the herpetic lesion.     

Confirmation of herpes simplex virus type 2 infections in herpes-like genital lesions by a simple complement-fixation test

The presence of complement-fixing antibody to an early herpes simplex virus type 2 (HSV-2) antigen (the AG-4 antigen) was correlated with HSV-2 infection in the sera of patients with genital herpes. Eighty-eight per cent of sera taken two weeks after clinical diagnosis of a primary or recurrent herpes infection in patients, confirmed to have HSV-2 by virus isolation and typing, contained the anti-AG-4 complement-fixing antibody. None of the patients with genital HSV-1 had the antibody, and only 9% of controls or patients with facial HSV-1 infection had positive results for the antibody. This correlation was used to identify genital HSV-2 infections when either no virus sample had been taken or when virus isolations had been unsuccessful. Thus, a simple complement-fixation test can confirm an HSV-2 virus infection without isolation of the virus from the herpetic lesion.     

Sequential genital infections by herpes simplex viruses types 1 and 2: restriction nuclease analyses of viruses from recurrent infections

Virus isolated from a woman presenting with the first symptomatic episode of genital herpes was identified as herpes simplex virus type 1 (HSV-1) by restriction nuclease fingerprinting. Testing for IgM antibody to HSV indicated that the patient had recently contracted a new HSV infection. Virus microneutralization and the micro-solid phase radioimmunometric test for IgG, however, showed that the patient had had prior infection with herpes simplex virus type 2 (HSV-2); thus the HSV-1 infection was acquired despite the presence of antibody to HSV-2. Genital herpes recurred about four, seven, and nine months after the HSV-1 infection. Isolates from the latter three episodes all were of an identical strain of HSV-2 and were not recombinants or a mixture of the viruses. The data show that two distinctly different herpes simplex viruses can initiate genital infections in one individual and suggest that HSV-2 is more likely to recur than HSV-1.     

Clinician and patient recognition of anogenital herpes disease in HIV positive men who have sex with men

Anogenital ulcers caused by herpes simplex virus type 2 (HSV-2) are associated with an increased risk of human immunodeficiency virus (HIV) transmission. When compared with clinician examination, HIV/HSV-2 coinfected men who have sex with men are frequently unaware of anogenital ulcers. These data highlight the importance of condom use and the need for new HSV-2 prevention strategies.     

Epidemiology of genital herpes simplex virus infections in a community-based sample in France: results of the HERPIMAX study

OBJECTIVE: The objective of this study was to provide information on the prevalence of herpes simplex infections in the general population in Europe. GOALS: The goals of this study were to determine the prevalence of clinically probable genital herpes and the relationship between serotype and clinical expression in a French community-based sample. STUDY: A total of 4410 subjects chosen at random were serotyped for herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). Data on symptoms were obtained by questionnaire allowing retrospective diagnosis of clinically probable genital herpes. RESULTS: Questionnaire data and serotype were available for 3192 subjects. Seroprevalences of HSV-1 and HSV-2 were 65.6% and 15.5%, respectively. Prevalence of clinically probable genital herpes was 11.8%, identified in 11.1% of HSV-1-positive subjects and 26.8% of HSV-2-positive subjects, with a lower prevalence in those coinfected with both virus types. CONCLUSIONS: Clinically probable genital herpes was observed in one fourth of subjects with HSV-2 infections and in some subjects with HSV-1 infection. Coinfection with HSV-1 appeared to protect against symptom expression in subjects infected with HSV-2.     

Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students

A retrospective review of genital herpes simplex virus (HSV) isolates collected in a university student health service over a 9-year period showed that an increasing proportion of isolates were HSV-1 rather than HSV-2. HSV-1 accounted for 78% of all genital isolates in this population by 2001, compared with 31% of isolates in 1993. BACKGROUND: Herpes simplex virus (HSV) type 1 is usually thought to cause less than 30% of genital herpes infections in the United States, but the proportion of infections resulting from HSV-1 is increasing in some populations. GOAL: The goal was to review the relative proportion of HSV-1 and HSV-2 as the cause of newly diagnosed genital herpes infections in a population of U.S. college students and to assess trends in the change of this proportion over time. STUDY DESIGN: Genital HSV isolates collected at a university student health service from 1993 to 2001 (n = 499) were reviewed retrospectively. Analyses included comparisons of isolates by HSV type, age group, and sex. RESULTS: The proportion of newly diagnosed genital herpes infections resulting from HSV-1 increased from 31% in 1993 to 78% in 2001 (P <0.001, linear trend P <0.001). HSV-1 was more common in females than males, but increases were noted for both sexes. HSV-1 was more common in persons aged 16 to 21 than in persons aged 22 or older. CONCLUSIONS: HSV-1 has become the most common cause of newly diagnosed genital herpes infections in this population of college students and reflects a reversal of the usual HSV-1/HSV-2 ratio.     

Premarket evaluation of the POCkit HSV-2 type-specific serologic test in culture-documented cases of genital herpes simplex virus type 2 [see comment

BACKGROUND AND OBJECTIVES: The genital herpes epidemic continues, in part, because patients with subclinical or atypical presentations cannot be identified by most herpes simplex virus (HSV) antibody tests. A new product, POCkit HSV-2, has been developed to rapidly and accurately detect antibodies to HSV type 2 (HSV-2) in capillary blood or serum. GOAL: Sera from patients with culture-documented genital or oral herpes were tested to determine the sensitivity and specificity of the POCkit HSV-2 rapid point-of-care antibody test (Diagnology, Belfast, Northern Ireland). STUDY DESIGN: Sera from 50 patients with culture-documented HSV type 1 (9 oral, 41 genital) and from 253 patients with genital HSV-2 were tested by POCkit HSV-2 for HSV-2 antibodies. Each subject had a positive culture for HSV within 6 months of serum collection. Sera were preselected to include only those that were seropositive to the respective virus subtype by University of Washington Western blot. RESULTS: Compared with viral culture and Western blot analysis, sensitivity of the POCkit HSV-2 test for HSV-2 antibody was 96%; specificity was 98%. CONCLUSION: This test provides rapid, accurate identification of HSV-2 antibody in subjects with established HSV infections.     

Increase in rates of herpes simplex virus type 1 as a cause of anogenital herpes in western Sydney, Australia, between 1979 and 2003

BACKGROUND/ OBJECTIVE: Recent studies suggest that herpes simplex virus type 1 (HSV-1) is becoming more common as a cause for genital herpes, relative to HSV-2. We aimed to calculate trends in HSV type from isolates and serology samples sent to a reference virology laboratory in New South Wales (NSW), Australia. METHODS: We compared the proportions of HSV-1 and HSV-2 positive samples, adjusting for age and sex of source patient, in three datasets: anogenital isolates from 1979 to 1988; anogenital isolates from 1989 to 2003; and HSV type specific IgM seropositivity from 1994 to 2003. RESULTS: The number of specimens in each analysis was 17 512, 4359, and 497, respectively. There was a progressive rise in the proportions of typed specimens being HSV-1 in all analyses. The proportion of isolates that were HSV-1 ranged from 3% in 1980 to 41% in 2001. Female sex and age under 25 were associated with a greater proportion of HSV-1 isolates in both time periods. In the period 1979-88, comparing the proportions of HSV-1 and HSV-2 gave an odds ratio (OR) per additional year of 1.24 (95% confidence interval (CI) 1.20 to 1.27; p<0.005) after adjustment for age and sex. In the period 1989-2003 there was a steeper rise in the proportion of isolates that were HSV-1 in samples from younger individuals (OR per year 1.17, 1.12 to 1.22) compared to those over 25 (OR per year 1.06, 1.03 to 1.08). The rise in the proportion of IgM seropositive results reactive for HSV-1 compared to HSV-2 gave an OR of 1.36 per year (1.26 to 1.47; p<0.005). CONCLUSIONS: These data suggest that HSV-1 has become more common as a cause of anogenital herpes in NSW.     

Recurrent genital herpes in a population attending a clinic for sexually transmitted diseases.

Patients with recurrent genital herpes attending a sexually transmitted disease clinic were studied and transmission of the infection was elucidated by evaluating serostatus in their partners. Of 84 patients attending for recurrent genital herpes, 94% had a herpes simplex virus type 2 (HSV-2) infection and only 6% (5 patients) a type 1 infection. The mean age of the patients was 36 years and the duration of their infection was up to 37 years (median 4 years). In most patients the number of recurrences had not decreased between the first year and the last year. About half had experienced a more severe first episode infection. Of the patients, 64% were not aware of asymptomatic shedding and the risk of sexual transmission without clinical symptoms. Of 67 steady partners of patients with genital HSV-2, 15% had a history of genital herpes. By HSV serology, HSV-2 antibodies (indicating subclinical genital herpes) were demonstrated in more than half of the partners. The duration of the relationship or condom use did not seem to influence the frequency of transmission to the partner, which may indicate an individual susceptibility for acquiring a genital HSV-2 infection. Eleven per cent of the patients were on suppressive antiviral therapy, while 39% had no experience of antiviral therapy. Type-specific HSV serology was found to be of value in counselling partners of patients with genital herpes.     

Advances in antiviral therapy

Infections with five of the herpesviruses (herpes simplex virus 1 [HSV-1], HSV-2, varicella zoster virus, Epstein-Barr virus, and cytomegalovirus) are treated with topical or systemic antiviral therapies. There are more than 100 genotypes of human papillomaviruses (HPVs), which may manifest as warts, skin cancers, cervical cancer, anogenital cancers, and upper digestive tract cancers. Molluscum contagiosum (MC) is a common, benign viral infection of the skin. Immunomodulating agents, such as imiquimod, act on HPV and MC indirectly by inducing host immune responses, such as cytokines and cell-mediated immunity, and thereby reduce recurrences. There are multiple vaccines available for certain viral diseases and others in development for HSV-2 and HPV.     

Changing epidemiology of genital herpes simplex virus infection in Melbourne, Australia, between 1980 and 2003

OBJECTIVE: To investigate changes in the proportions of patients infected with genital herpes simplex virus (HSV) types 1 and 2 from 1980 to 2003 in Melbourne, Australia. METHODS: A total of 25 372 patients were studied retrospectively. The proportions of HSV-1 and HSV-2 detected in these individuals were analysed by age, sex, and genital site. RESULTS: In 1980 only 15.8% of HSV positive genital specimens were HSV-1 compared to 34.9% in 2003. In 2003 HSV-1 was detected in 77% of patients aged less than 20 years. Females were more likely to be infected with HSV-1, although the rate of increased detection was more pronounced in males. Except for females over the age of 40, the trend for the increase in HSV-1 was detected in all age groups. No specific genital site in either sex was associated with the increase. CONCLUSIONS: The proportion of genital HSV-1 has increased in Australian patients, although HSV-2 is still the most common cause of genital infection. Confirmation of HSV type is necessary for optimal patient management.     

Proportion of herpes simplex virus (HSV) type 1 and type 2 among genital and extragenital HSV isolates

Herpes simplex virus type 1 (HSV-1) has been associated with orofacial infections and HSV type 2 (HSV-2) with genital infections. This tropism of the virus seems to have changed and in clinical reports an increasing number of genital herpes infections caused by HSV-1 have been recognized. The aim of this study was to estimate the proportion of HSV-1 and HSV-2, respectively, among isolates from different anatomical sites typed in our laboratory during the years 1994-1998. Out of a total of 3,085 anogenital isolates, 29% were typed as HSV-1 and 71% as HSV-2. The highest prevalence of HSV-1 was registered among isolates from young women. Of 631 orofacial isolates, 4% were typed as HSV-2 and 96% as HSV-1. Of 69 finger/hand isolates, 54% were typed as HSV-1 and 46% as HSV-2, and of 95 isolates from other regions (abdomen, foot, etc.), 60% were typed as HSV-1 and 40% as HSV-2. It was found that HSV-2 was as common as HSV-1 in the extra-genital regions with the exception of the orofacial area, in which HSV-2 was seldom detected. Furthermore, the study showed an increasing proportion of HSV-1 among anogenital isolates during the study period. Taken together, these results suggest that a clear HSV type-related tropism might be limited to the permissiveness of the orofacial region for HSV-1, and that both serotypes may readily establish infections below the neck.     

生殖器疱疹患者530例HSV抗体型别检测分析

目的了解生殖器疱疹患者HSV-1和HSV-2的感染情况,并分析生殖器疱疹的流行特点。方法采用酶联免疫吸附试验(ELISA)法对性病门诊530例临床诊断为生殖器疱疹的患者进行了HSV血清抗体检测。结果 530例中男311例(58.68%),女219例(41.32%)。HSV-1IgM抗体阳性60例(11.32%),HSV-1IgG抗体阳性471例(88.87%),HSV-2IgM抗体阳性213例(40.19%),HSV-2IgG抗体阳性349例(65.85%)。年龄以31～40岁最多,为210例,其次为21～30岁194例。职业中最多的是自由职业和民工。初发者304例(57.36%),复发者226例(42.64%),其中频繁发作(≥6次/年)85例(16.04%)。结论长春地区生殖器疱疹患者以HSV-2感染为主。女性近期感染多于男性。以21～40岁性活跃人群为高发年龄组。     

First episodes of genital herpes in a Swedish STD population: a study of epidemiology and transmission by the use of herpes simplex virus (HSV) typing and specific serology

OBJECTIVES: To determine the proportion of herpes simplex virus type 1 (HSV-1) and HSV type 2 (HSV-2) in first episodes of genital herpes. To evaluate the use of HSV specific serology for classifying first episodes of genital herpes and for defining HSV serostatus in the patients' sexual partners. METHODS: 108 consecutive patients with first episodes of genital herpes seen at three STD clinics in Sweden from 1995 to 1999 were included in the study. HSV culture and typing were performed and serum was tested for antibodies against a type common HSV antigen and a type specific HSV-2 antigen, glycoprotein G2 (gG2). A structured interview including questions about sexual behaviour and sexual partners was taken. "Steady" partners were offered a blood test for HSV serology and counselling. RESULTS: Of 108 patients, 11 had a negative HSV culture. Of the 97 who were HSV culture positive, 44% (43/97) were typed as HSV-1 and 56% (54/97) as HSV-2. For 86 of these 97 patients, HSV serology from the initial visit was available. Of 52 primary infections, thus initially seronegative, 64% were HSV-1 infections and of 19 female primary infections 16 (84%) were HSV-1. In 17% the first episode of genital herpes corresponded to the first clinical recurrence of an infection acquired earlier in life. There was a significant correlation between having orogenital sex and being infected with HSV-1 and also a history of labial herpes in the partner. Only 20% of partners of patients with an HSV-2 infection had a history of genital herpes. CONCLUSIONS: Almost half of first episodes of genital herpes are caused by HSV-1. In young women with a primary genital infection, HSV-1 is much more frequent than HSV-2. Besides HSV typing, we found specific HSV serology of value for classifying first episodes and for diagnosing a subclinical HSV-2 infection in partners. Anamnestic data supported the suggestion that the orogenital route of transmission was common in genital HSV-1 infections.     

Serological evaluation of herpes simplex virus type 1 and type 2 infections in pregnancy

OBJECTIVE: Serological evaluation of herpes simplex virus infections during pregnancy. METHODS: 2991 serum samples were obtained during 1st, 2nd, and 3rd trimester from 997 pregnant women. Baculovirus expressed glycoproteins gG1 (HSV-1) and gG2 (HSV-2) were used as antigens in ELISA for HSV-1 and HSV-2 IgG and IgA antibodies. RESULTS: The prevalence of HSV-1 gG1 antibodies was 70% and that of HSV-2 gG2 antibodies 16%. Among susceptible women we found five (0.6%) cases with serological evidence of primary HSV-2 infection during pregnancy. Evidence of active HSV-1 infection was found in nine (0.9%) cases. Decline of HSV-2 gG2 IgG antibody levels during pregnancy was pronounced compared with HSV-1 gG1 IgG antibody levels (p < 0.01); also the proportion of seroreversions was considerably higher among HSV-2 seropositives (25%) than among HSV-1 seropositives (3%) (p < 0.001). CONCLUSIONS: HSV-2 gG2 IgG antibodies were readily distinguished from HSV-1 gG1 IgG antibodies by the glycoprotein gG ELISAs. Serological assays for gG2 antibodies should guard against the decline of specific antibodies during pregnancy.     

An international, randomized, double-blind, placebo-controlled, study of valacyclovir for the suppression of herpes simplex virus type 2 genital herpes in newly diagnosed patients.

BACKGROUND: Antiviral suppressive therapy of genital herpes is often initiated based on the established pattern of recurrences in an individual. Because most persons with first episode herpes simplex virus type 2 (HSV-2) infection experience recurrences and because viral shedding occurs frequently in the first year after infection, we examined the strategy of initiating suppressive therapy shortly after diagnosis of genital HSV-2 infection. SUBJECTS AND METHODS: From June 16, 2004 to July 26, 2006, 384 subjects from 74 sites in the United States, Canada, Argentina, Brazil, and Chile who were newly diagnosed with a first recognized episode of genital herpes at the time of the screening visit or within 3 months before the screening visit were randomized (2:1) to receive valacyclovir 1 g once daily or placebo for 24 weeks. Subjects were instructed to return to clinic during suspected genital herpes outbreaks for clinician confirmation of recurrences. RESULTS: Valacyclovir significantly prolonged the time to first recurrence of HSV-2 genital herpes in newly diagnosed subjects compared with placebo, with approximately 43% of subjects on placebo and 71% of subjects on valacyclovir recurrence-free at 24 weeks (P <0.001). Valacyclovir significantly reduced the mean number of genital HSV-2 recurrences per month occurring during the 24-week study period (0.11 for valacyclovir, 0.48 for placebo, P <0.001). Adverse events were comparable in the valacyclovir and placebo arms. CONCLUSION: Valacyclovir 1 g once daily administered for 24 weeks was well-tolerated and effective in suppressing genital herpes recurrences in immunocompetent newly diagnosed persons without an established recurrence pattern.