Herpes simplex virus type 2: epidemiology and management options in developing countries

Genital herpes simplex virus type 2 (HSV2) is highly prevalent worldwide and an increasingly important cause of genital ulcer disease (GUD). Continued HSV2 transmission is facilitated by the large number of undiagnosed cases, the frequency of atypical disease and the occurrence of asymptomatic shedding. The lack of easy, affordable diagnostic methods and specific antiviral treatment in countries with low and middle income is of great concern, given the ability of GUD to enhance HIV transmission and acquisition. With rising HSV2 prevalence contributing to an increase in the proportion of GUD attributed to genital herpes in high-HIV prevalence settings, a safe and effective HSV vaccine is urgently needed. Meanwhile, multifaceted interventions are required to improve recognition of genital herpes, to prevent its spread and also to prevent its potential to promote HIV transmission in developing countries.     

Update on antiviral therapy for herpes simplex virus infection

ABSTRACT: The prevalence of infection with herpes simplex virus (HSV) continues to increase largely due to the inability of current antiviral agents to eradicate latent infection. This article reviews strategies to slow the transmission of HSV infection, most importantly through the development of vaccines, as well as established and emerging choices for treatment of primary and recurrent genital herpes, herpes labialis, infections in immunocompromised hosts, and acyclovir-resistant infections. The role of chronic suppressive therapy in the management of genital herpes as well as its potential impact on transmission rates will also be discussed.
Herpes simplex virus (HSV) is a widespread pathogen in the United States, with more than 100 million U.S. citizens having serologic evidence of HSV-1 infection and 40–60 million, nearly one-fifth of the adolescent and adult population, infected with HSV-2 (1,2) . The prevalence of HSV-2, the major cause of genital herpes, has increased 30% since the late 1970s (2) . The fact that most of those infected with HSV are asymptomatic and yet may still be subclinically shedding virus further complicates efforts to slow the spread of transmission (3) . Therefore proper management of herpetic infections requires that the clinician be able to effectively diagnose those with HSV infection, to educate them regarding means of spread and symptoms indicative of infection, and to adequately treat infections which are identified in order to alleviate patient symptoms and slow the transmission of the virus. We review options for preventing infection, treating primary infections, and treating recurrent infections in order to accomplish these goals.     

Famciclovir reduces viral mucosal shedding in HSV-seropositive persons

OBJECTIVE: Many cases of herpes simplex virus (HSV) infection occur through asymptomatic shedding from persons without evidence of clinical disease. This study explores whether famciclovir reduces HSV shedding in HSV-2 seropositive persons with or without a history of symptomatic genital herpes. STUDY DESIGN: One hundred twenty-seven HSV-2 seropositive participants were randomly assigned to 42 days of famciclovir, followed by 14 days of washout and 42 days of placebo, or vice versa. All subjects swabbed the genital/perianal area; those with HSV-1 infection also swabbed the oral area daily for HSV DNA PCR. RESULTS: Famciclovir reduced genital and oral HSV shedding from 11.4% of days during the placebo period to 4.7% of days during famciclovir therapy. The reduction was greater in participants with a history of genital herpes (74%) than in those without such a history (30%). In multivariate analyses, famciclovir protected against total (clinical and subclinical) genital shedding among persons with a clinical history of genital herpes (RR, 0.23; 95% CI, 0.15-0.35; P < 0.001). Among HSV-2 seropositive participants without a history of genital herpes, 60% had HSV detected in the genital area at least once during the study. Famciclovir therapy did not result in a statistically significant reduction in total HSV shedding in participants without a history of genital herpes. CONCLUSION: Famciclovir therapy decreases genital HSV shedding in HSV-seropositive persons, especially those with a history of genital herpes. Overall, antiviral drugs may have varying effects on symptomatic and asymptomatic viral shedding, depending on the clinical history of the disease.     

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.     

Herpes simplex virus seroprevalence and risk factors in 2 Canadian sexually transmitted disease clinics

OBJECTIVES: The objectives of this study were to determine the seroprevalence and risk factors for herpes simplex virus (HSV) types 1 and 2 in patients attending 2 Canadian sexually transmitted disease (STD) clinics. STUDY: Stored sera were tested for the presence of IgG class antibodies to HSV-1 and HSV-2 and results linked to that obtained from a risk behavior questionnaire. RESULTS: Overall prevalences for HSV-1 and -2 were 56% and 19%, respectively. HSV-1 and -2 seropositivity was associated with increasing age, female gender, nonwhite ethnicity, and a history of STD. HSV-2 seropositivity was also associated with a history of genital herpes, presence of genital sores, and coinfection with either human immunodeficiency virus (HIV) or hepatitis C (HCV). CONCLUSIONS: Herpes simplex infection is common in this high-risk Canadian population. Our finding that HCV seropositivity was a significant predictor for HSV-2 seropositivity emphasizes the overlap between pathogens that are primarily thought to be bloodborne pathogens and sexually transmitted infections and the need to target prevention in these areas concurrently.     

The frequency of unrecognized type 2 herpes simplex virus infection among women. Implications for the control of genital herpes

To evaluate the prevalence of symptomatic versus asymptomatic or unrecognized type 2 herpes simplex virus (HSV-2) infection, the authors performed physical examination, viral cultures, and type-specific serologic assays in 776 randomly selected women attending an STD clinic and 636 female university students. Forty-six percent of women attending the STD clinic compared with 8.8% of the university students had serologic evidence of HSV-2 infection. Clinical or historical evidence of genital herpes was present in only 34% of the HSV-2 seropositive women attending the STD clinic and in 29% of the HSV-2 seropositive women attending the university clinic. Among women attending the STD clinic, the prevalence of recognized genital infection was more common among those with HSV-2 antibodies only versus those with HSV-1 and -2 antibodies (odds ratio = 2.39; 95% confidence interval = 1.30-4.37), suggesting that HSV-1 infection reduces the likelihood of recognizing HSV-2 infection. In view of the high proportion of seropositive individuals with unrecognized HSV-2 infection in both high and low prevalence HSV-2 seropositive populations, newly developed HSV type-specific serologic methods should be evaluated for detecting carriers of HSV-2 infection and counseling these individuals about strategies for avoiding sexual and perinatal transmission of HSV-2.     

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.     

Herpes simplex virus 2 infection in women attending an antenatal clinic in Fuzhou, China

Genital herpes caused by herpes simplex virus (HSV) infection is one of the most prevalent sexually transmitted infections (STIs) and the most common cause of genital ulcer disease (GUD) in developed and developing countries. The monitoring of HSV-2 seroprevalence in pregnant women can identify women at a higher risk of HIV and of neonatal HSV transmission. Very few data are available on type specific seroprevalence of HSV-2 in China, with only one previous study from southern China. Consequently, we conducted a survey to determine type specific seroprevalence of HSV-2 and associated risk factors in Fuzhou City, eastern China.     

Asymptomatic shedding and subsequent transmission of genital herpes simplex virus.

We report the transmission of genital herpes simplex virus (HSV) infection from an asymptomatic woman shedding virus from the cervix to two male sexual partners and further transmission from these two men while their infection was in the prodromal phase. The value of the restriction enzyme analysis of viral deoxyribonucleic acid (DNA) is presented. Guidelines regarding the management of patients who are found to be asymptomatic shedders of HSV are discussed.     

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.     

Epidemiology of recurrent genital herpes simplex virus types 1 and 2

OBJECTIVES: To describe the epidemiology of type specific recurrent genital herpes, and to compare the duration of recurrent genital lesions caused by herpes simplex virus (HSV) types 1 and 2. METHODS: Participants were enrolled at clinics across the United States. Adults suspected of having active genital herpes were eligible. Lesions were cultured for HSV and typed. Data from 940 participants with recurrent culture positive HSV lesions were analysed. Pearson's chi(2) and Fisher's exact tests, multivariate logistic regression models, and a stratified Cox proportional hazards model were used to compare epidemiological characteristics and lesion duration of HSV-1 and HSV-2. RESULTS: HSV-1 was present in 4.2% of the recurrent HSV culture positive lesions. HSV-1 was most prevalent among whites (6.5%) and individuals with 0-2 recurrences in the previous year (9.1%) and, among men, in those with rectal/perirectal lesions (13.2%). Longer lesion duration was not significantly associated with virus type (hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.65 to 1.38, p = 0.79), but was associated with male sex (HR 0.85, 95% CI 0.74 to 0.99, p = 0.04), and HIV seropositivity (HR 0.62, 95% CI 0.48 to 0.81, p<0.01). CONCLUSIONS: The authors found that, in the United States, recurrent genital HSV-1 is relatively rare in the STD and HIV clinic setting, especially among black people. Among men, rectal/perirectal recurrent lesions are more likely to be caused by HSV-1 than are penile lesions. In addition, lesion duration depends on sex and HIV status but not virus type. These findings shed new light on the type specific epidemiology of recurrent genital HSV, and suggest that type specific testing can inform the prognosis and management of genital herpes.     

Prevalence of herpes simplex virus type 2 antibody in Cameroon

BACKGROUND: Genital herpes is one of the most common sexually transmitted diseases. As a leading cause of genital ulceration, herpes genitalis plays a role in facilitating the transmission of HIV. Although HIV infection is most prevalent in Cameroon, information is lacking about prevalence of herpes simplex virus (HSV) type 2 infection in this country. GOAL: The goal was to determine the prevalence of HSV-2-specific antibody in blood specimens from individuals in Cameroon. STUDY DESIGN: Blood specimens were randomly collected from 410 clinic attendees (215 males, 195 females) in Douala, the most populous city in Cameroon. One hundred fifteen of the individuals (28.0%) were HIV-infected. Samples were tested by a type-common HSV IgG enzyme immunoassay not discriminating between HSV-1 and HSV-2 antibodies and by two glycoprotein G-2-based enzyme immunoassays for detection of HSV-2-specific antibody. RESULTS: All but three blood samples were positive for type-common HSV IgG antibodies. Sixty-seven specimens (16.3%) were concordantly negative for HSV-2 antibody by both assays, and 287 (70.0%) specimens were concordantly positive. Fifty-six specimens (13.7%) yielded discrepant results between the two assays. CONCLUSION: On the basis of specimens with concordantly positive results, the overall HSV-2 seroprevalence was 70.0%. HSV-2 seroprevalence was significantly higher among HIV-infected individuals than among HIV-negative ones. Because of the serious morbidity and mortality caused by HSV-2, effective programs are needed to halt the spread of HSV-2 infection in Cameroon.     

Evaluation eines dominant-negativen rekombinanten Herpes-simplex-Virus (HSV) Typ 1 als Impfstoff gegen Herpes genitalis bei Mäusen und Meerschweinchen

Genital herpes caused by herpes simplex virus (HSV) is one of the most common sexually transmitted diseases worldwide. Currently, no safe and effective vaccine against HSV is available. CJ9-gD is a completely replication-defective HSV-1 recombinant which inhibits replication of wild-type HSV-1/-2 in co-infected cells (dominant-negative effect). Moreover, it expresses high levels of HSV-1 major antigen glycoprotein D (gD). Immunization with CJ9-gD induces strong and long-lasting humoral and Th1-like cellular immune responses against both HSV-1 and HSV-2 in mice protecting immunized animals significantly against genital challenge with HSV-1 or HSV-2. Guinea pigs immunized with CJ9-gD were significantly protected against primary and recurrent HSV-2 genital disease and latent infection.     

Control of STDs--the role of prophylactic vaccines against herpes simplex virus

OBJECTIVES: To summarise the current status of genital herpes simplex virus (HSV) vaccine development and provide a discussion of the potential benefits and limitations of genital herpes vaccines. METHODS: Literature review. RESULTS: Genital herpes simplex virus infection has a complex pathogenesis that has contributed to it becoming a serious worldwide problem. In an attempt to control the problem five different types of genital herpes vaccines have been developed. These include inactivated virion derived vaccines, adjuvanted subunit vaccines, vectored vaccines, replication limited live viral vaccines, genetically attenuated live viral vaccines, and nucleic acid vaccines. While available commercially in some parts of the world, inactivated virion derived vaccines have not been proved effective. Of the others, adjuvanted subunit vaccines, replication limited live viral vaccines, and nucleic acid vaccines are currently in clinical trials and vectored vaccines and genetically attenuated live viral vaccines are in preclinical development. CONCLUSION: With regard to HSV vaccines in general, it is reasonable to expect that the newer vaccines may protect the individual from developing symptomatic genital herpes but may not protect against asymptomatic viral infection. With widespread use HSV vaccines might help to prevent the spread of genital herpes.     

Detection of varicella zoster virus in genital specimens using a multiplex polymerase chain reaction

OBJECTIVE: To compare the relative proportions of varicella zoster virus (VZV) and herpes simplex viruses in specimens obtained from the genital lesions of adults presenting with presumed genital herpes infection. METHODS: Swabs of genital lesions from 6210 patients attending general practices, infectious diseases clinics within hospitals, or sexual health centres for treatment of their genital lesions were tested using polymerase chain reaction (PCR) technology. The multiplexed PCR was capable of detecting herpes simplex virus types 1 and 2 (HSV-1, HSV-2), VZV, and cytomegalovirus in a single sample. RESULTS: A total of 2225 patients had viruses detected by PCR. HSV-1 was detected in 36%, HSV-2 in 61%, and VZV in 2.9% of PCR positive samples. Of the 65 patients with VZV genital infection, many were thought to have HSV infection before laboratory testing. CONCLUSIONS: The finding of VZV in nearly 3% of virus positive genital specimens demonstrates that this virus needs to be considered as a differential diagnosis for genital herpetic lesions. Advice provided to patients with VZV genital infection regarding the source of infection, likelihood of recurrence, and potential for transmission of the virus will be different from that given to patients with HSV infection.     

The epidemiology of herpes simplex types 1 and 2 infection of the genital tract in Edinburgh 1978-1991.

INTRODUCTION--The changing epidemiology of genital herpes in Edinburgh is described in relation to herpes simplex virus (HSV) Type 1 and herpes simplex virus Type 2 infection over a period of 14 years. METHODS--2018 episodes of genital herpes in 1794 patients over a 14 year period were assessed. Data on age, sex, sexual orientation, geographical origin and herpes antibodies were also analysed. RESULTS--The proportion of cases that were HSV Type 1 increased over the period from approximately 20% to over 40%. Type 1 infection is more common in the young, in women and as a primary infection. CONCLUSIONS--HSV Type 1 is of increasing importance as a cause of genital herpes in our population. This may reflect changes in sexual attitudes and practises over the past decade.     

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.     

Using the evidence base on genital herpes: optimising the use of diagnostic tests and information provision

There have been several important advances in the range of available diagnostic tests for genital herpes simplex virus (HSV) infection in recent years; polymerase chain reaction (PCR) is emerging in routine clinical use and the potential role of type specific serological tests is currently under debate. Several large trials of prophylactic vaccines, subsequently proved to be ineffective, have expanded knowledge of the transmission and epidemiology of HSV infection. This article discusses optimal application of recent research evidence to clinical care, structured around the key issues for patients and their partners. These include acquisition and transmission of genital HSV-1 and HSV-2 infection, the natural history of genital herpes, and the role of partner notification.     

Seroprevalence and correlates of herpes simplex virus type 2 among urban Tanzanian women

BACKGROUND: Data on herpes simplex virus type 2 (HSV-2) among women in the general population of developing countries are limited. GOALS: The goal of the study was to determine the seroprevalence of HSV-2 and to identify clinical, demographic, and behavioral correlates among women attending primary health care clinics. STUDY DESIGN: This was a cross-sectional survey of 382 randomly chosen women aged 15 to 49 years. RESULTS: The seroprevalence of HSV-2 was 39%. Only 2% had a history of genital herpes. HSV-2 was associated with antibody to HIV-1 (OR=2.3 [CI, 1.1-4.7]), syphilis (OR=4.7 [CI, 1.4-4.7]), and genital ulcers (OR=9.7 [CI 2.5-36.9]). Age, sexual debut, number of sex partners, and history of spontaneous abortion were found to be significantly associated with HSV-2. Eighty-two percent of the women with genital ulcers were HSV-2-seropositive, while syphilis accounted for 6% of cases. HSV-2 may thus be the most common cause of genital ulcers in this population. CONCLUSION: In view of the high HSV-2 seroprevalence and its association with HIV-1 and genital ulcers, integration of HSV-2 therapeutic management in STD syndromic algorithms is recommended. Counseling on symptom recognition, asymptomatic shedding, and preventive measures is needed.     

Relation between herpes simplex viruses and human immunodeficiency virus infections

The rates of herpes simplex virus (HSV) infection are rising, the highest prevalence being in the group infected with the human immunodeficiency virus (HIV). We review the relation between these 2 infections. The presence of genital ulcers increases the transmission of HIV, and the presence of HIV adversely affects the natural history of HSV infection. The detection and treatment of sexually transmitted diseases such as genital herpes actually decrease the rates of HIV infection in groups studied. The treatment of HSV in persons with HIV is challenging because the incidence of immunosuppression increases. Acyclovir resistance is more common in this group, but acyclovir use may prolong survival in some HIV-seropositive patients. Further studies are needed to determine whether persons with HIV disease should routinely be given HSV-specific therapy.