An Assessment of Risk Factors for Herpes Simplex Virus Type 2 Infection in Malawian Women Using 2 Classifications for the HerpeSelect 2 Test.

BACKGROUND: The HerpeSelect 2 ELISA IgG test for herpes simplex virus type 2 (HSV-2) infection is widely used, convenient, and inexpensive. However, it has been shown to have lower specificity among populations in Sub-Saharan Africa compared with HSV-2 tests regarded as criterion standards. METHODS: In 2016, we collected blood and survey data from 248 women participating in a community-based cohort study in rural Malawi (the Umoyo wa Thanzi project). Using multinomial logistic regression accounting for village-level clustering, we examined unadjusted associations between select demographic and sexual risk factors and HSV-2 serostatus. Because increasing the index value cutpoint for a positive result improves specificity, we coded HSV-2 serostatus in 2 ways: the manufacturer's recommended cutpoints (<0.9, negative; 0.9-1.1, indeterminate; >1.1, positive) and modified cutpoints with improved specificity (<0.9, negative; 0.9-3.5, indeterminate; >3.5, positive). We aimed to investigate whether associations between select risk factors and HSV-2 serostatus varied under the 2 approaches. RESULTS: The prevalence of HSV-2 in this sample was 67% under the manufacturer's cutpoint and 22% under the modified cutpoint. Under both cutpoints, age, household size, number of marriages, and number of pregnancies were associated with HSV-2-positive serostatus. Using modified cutpoints, current bacterial vaginosis (odds ratio [OR], 3.17; 95% confidence interval [CI], 1.35-7.47), partner concurrency (OR, 4.88; 95% CI, 2.54-9.37) and unsure about partner concurrency (OR, 1.91; 95% CI, 1.08-3.38) were associated with HSV-2 seropositivity. Household size, education, and marital status were the only variables significantly associated with indeterminate HSV-2 serostatus using the modified cutpoints. CONCLUSION: HSV-2-focused interventions informed by identifying individuals likely to have or acquire HSV-2 must be aware that different target populations may emerge depending on which cutpoints are adopted.

Precision of the Kalon Herpes Simplex Virus Type 2 IgG ELISA: an international inter-laboratory assessment.

BACKGROUND: The commercial Kalon HSV-2 IgG ELISA is currently recommended for research use in sub-Saharan Africa because of its superior accuracy compared to other serologic assays. However, there are no data on key precision parameters of Kalon such as inter-operator variation, repeatability, and reproducibility, thus contributing to a barrier for its acceptance and use in clinical trials in sub-Saharan Africa. We evaluated the analytical and field precision of the Kalon HSV-2 IgG ELISA. METHODS: A total of 600 HIV-infected and uninfected serum samples from South Africa and Zambia, previously tested by the gold standard University of Washington HSV western blot (UW-WB), were tested using Kalon by two technologists in an United States reference laboratory. Aliquots of 183 samples were retested using Kalon by an on-site technologist in a South African laboratory and a Zambian laboratory. RESULTS: Intra-assay variation was below 10 %. Intra-assay, intra-laboratory, and inter-laboratory correlation and agreement were significantly high (p < 0.01). In comparison to the UW-WB, accurate performance of Kalon was reproducible by each operator and laboratory. Receiver operating characteristic curve analysis indicated high selectivity of Kalon in the overall study population (area under the curve = 0.95, 95%CI = 0.92-0.97). DISCUSSION: Kalon is a robust assay with high precision and reproducibility. Accordingly, operator errorlikely does not contribute to the variability observed in Kalon's specificity throughout sera from sub-Saharan Africa. CONCLUSIONS: In populations with optimal diagnostic accuracy, Kalon is a reliable stand-alone method for on-site HSV-2 IgG antibody detection.

Epidemiology of herpes simplex virus types 2 and 1 amongst men who have sex with men attending sexual health clinics in England and Wales: implications for HIV prevention and management.

The objective was to investigate herpes simplex virus (HSV) epidemiology amongst HIV-positive and HIV-negative men who have sex with men (MSM) in England and Wales. Unlinked anonymous sera from 3,968 MSM attending 12 sexual health clinics in 2003 were tested for HIV, HSV-2 and HSV-1 antibodies. Fifty-five percent of HIV-positive MSM were HSV-2-seropositive, compared to 17% of HIV-negative MSM (Adj RR: 2.14 [CI: 1.92-2.37]). Amongst HIV-positive individuals, there was no significant difference in HSV-2 seroprevalence by knowledge of HIV status or whether the HIV infection was recently acquired (determined through STARHS). HIV infection was also independently associated with HSV-1 serostatus (Adj RR 1.19 [CI: 1.14-1.24)]). Four of the twelve attendees who received a diagnosis of recurrent anogenital herpes at the clinic visit were HSV-1-seropositive but not HSV-2-seropositive at the time, although no cultures or PCR results were available to type the cause of the ano-genital presenting disease. It is of concern that one in two HIV-positive MSM and one in six HIV-negative MSM may be infected with HSV-2, given increasing evidence of its impact on HIV progression, onward transmission and acquisition. To date results have been disappointing from trials aimed at reducing HIV onward transmission and HIV acquisition using HSV antiviral medication. However, recent research in an African context demonstrates the efficacy of HSV antivirals in delaying HIV progression. The high prevalence of HSV-2 amongst HIV-positive MSM suggests that an increased focus on HSV control in the management of HIV amongst MSM in the United Kingdom may be warranted. Given this and existing research on the high prevalence of genitally acquired HSV-1 amongst MSM in the UK, further research is also warranted into the role of HSV-1 in the HIV epidemic in this context.

Upstairs and downstairs: socio-economic and gender interactions in herpes simplex virus type 2 seroprevalence in australia.

BACKGROUND: This study investigates socio-economic differentials in herpes simplex virus type 2 (HSV-2) seroprevalence in Australian men and women using individual and geographic measures of socio-economic status. METHODS: HSV-2 seropositivity among men and women aged over 25 years was investigated by levels of individual and area-based measures of socio-economic status (SES) in a series of Poisson regression models, variously adjusting for age, country of birth, marital status, indigenous status, and urban/rural residence as potential confounders. Serum and socio-demographics were collected during 1999 and 2000 in a population-based Australia-wide prevalence survey. RESULTS: HSV-2 seroprevalence was significantly lower in areas of low SES than in high SES areas among both men (P for trend <0.001) and women (P for trend = 0.004) for all ages. A similar pattern was evident for individual education level for men with lower rates of HSV-2 in respondents with lower educational achievement (relative risk = 0.77, 95% CI 0.61-0.97, P = 0.024). In contrast, HSV-2 prevalence was higher for women with lower individual levels of education for all ages (relative risk = 1.22, 95% CI 1.04-1.44, P = 0.017). Analyses stratifying HSV-2 prevalence for individual education level by area-based SES showed the highest prevalence of HSV-2 in women with the lowest education level residing in the highest SES areas. This pattern was not evident in men, with a greater concordance between individual and area-based SES. CONCLUSION: HSV-2 seroprevalence is not consistently distributed across individual and area measures of SES, suggesting that upward and downward mixing between social strata in men and women is an important mode of HSV-2 transmission.

HSV-2 serologic testing in an HMO population: uptake and psychosocial sequelae.

OBJECTIVES: To prospectively measure the uptake of Herpes simplex virus Type 2 (HSV-2) testing and psychosocial response to a new serologic diagnosis of HSV-2 in a health maintenance organization (HMO) population. STUDY DESIGN: Randomly selected urban HMO enrollees were invited to be tested for HSV-2 antibody at a research clinic. Participants had blood drawn and completed demographic and psychosocial questionnaires. RESULTS: Of 3111 eligible enrollees contacted, 344 (11%) were tested. Eighty-seven (26%) tested HSV-2 seropositive, and 44 (51%) of these did not report a prior genital herpes diagnosis. Distress, measured by the total mood disturbance, was 6.5 points higher on average following a new genital herpes diagnosis relative to baseline (actual range = 109 points, P = 0.003) but not statistically different from HSV-2 negative or previously diagnosed participants. CONCLUSIONS: HMO enrollees unexpectedly testing HSV-2 positive showed short-term psychosocial distress that resolved during 6-month follow-up. Findings suggest that concerns about psychosocial burden should not deter voluntary serologic HSV-2 testing in primary care settings.

Burden of infection and fat mass in healthy middle-aged men.

OBJECTIVE: Our aim was to study the effect of exposure to four infections on fat mass. RESEARCH METHODS AND PROCEDURES: This was a cross-sectional study of healthy middle-aged men from the general population (n = 74). Each study subject's serum was tested for specific IgG class antibodies against herpes simplex virus (HSV)-1, HSV-2, enteroviruses, and Chlamydia pneumoniae through the use of quantitative in vitro enzyme-linked immunosorbent assays (ELISAs). A total pathogen burden score based on these seropositivities [Quantitative Seropositivity Index (QSI)] was constructed. Fat mass was measured by bioelectrical impedance. RESULTS: We observed significant relationships between the HSV-1 titer and fat mass and percentage fat mass. The associations were stronger when considering the infection burden. The QSI was significantly associated with fat mass (r = 0.30, p = 0.009) and percentage fat mass (r = 0.27, p = 0.01). Those subjects in the highest tertile of fat mass showed significantly higher QSI (259.5 +/- 74.1 vs. 206.9 +/- 78.2, p = 0.007). In subjects that were seropositive for Enteroviruses, the relationship between the QSI and fat mass was strengthened (r = 0.51, p = 0.02). In a multivariate regression analysis, the QSI, independently of age and C-reactive protein, contributed to 9% of fat mass variance. DISCUSSION: Pathogen burden showed an association with fat mass. Subjects with increased fat mass could be more susceptible to developing multiple infections resulting in a chronic low-grade inflammation. We can not exclude the possibility that exposure to multiple infections leads to increased fat mass.

The cost-effectiveness of routine antenatal screening for maternal herpes simplex virus-1 and -2 antibodies.

OBJECTIVE: The purpose of this study was to determine the cost-effectiveness of routine antenatal screening for herpes simplex virus 1 and 2 in women without a known history of genital herpes. STUDY DESIGN: Decision analysis was used to compare 3 treatment strategies to prevent neonatal herpes infection in women without a known history of genital herpes simplex virus: (1) the current standard of care (no herpes simplex virus screening), (2) antepartum herpes simplex virus-1 and -2 antibody screening of the pregnant woman and her male partner with appropriate counseling, and (3) antepartum herpes simplex virus-1 and -2 antibody screening with appropriate counseling and acyclovir prophylaxis at 36 weeks of gestation in seropositive women. RESULTS: Our model predicts that using current guidelines, 1 of 5469 women will have a herpes-infected neonate. Strategy 2 and 3 cost $5,812,819 and $4,130,297, respectively, for every significant neurologic sequela or death prevented. The cost-effectiveness of these strategies, expressed as cost per quality life-year gained, was $219,513 and $155,988 respectively. These results were robust in the sensitivity analysis. CONCLUSION: Routine herpes simplex virus screening in pregnancy is not cost-effective.

Psychosocial impact of serological diagnosis of herpes simplex virus type 2: a qualitative assessment.

OBJECTIVES: To assess the emotional and psychosocial responses to a serological diagnosis of HSV-2 infection in individuals without previous history of genital herpes. METHODS: 24 individuals who had a positive HSV-2 serology by western blot and no clinical history of disease were recruited from four clinics (sexually transmitted disease, maternal and infant care, family medicine, and virology research) over a 10 month period. In-depth qualitative interviews were conducted to elicit an individual's responses to the HSV-2 diagnosis. RESULTS: Three categories of themes were identified from the interviews. Short term emotional responses included surprise, denial, confusion, distress, sadness, disappointment, and relief to know. Short term psychosocial responses included fear of telling sex partners, anger at the source partner, guilt about acquiring or transmitting, and concern about transmitting to a child. Perceived ongoing responses included fear of telling future partners, concern about transmitting to a sex partner, feeling sexually undesirable, feeling socially stigmatised, feeling like "damaged goods," sex avoidance due to social responsibility, fear of transmitting to a newborn, and relationship concerns relating to the diagnosis. CONCLUSIONS: Individuals exhibit strong emotional and psychosocial responses to a serological diagnosis of HSV-2 infection. Many of the negative responses may be time limited and influenced by factors that are potentially amenable to counselling.

Sexual behaviour and social class in Australian women.

Sexual behaviour is determined by social, cultural and personal factors. Sexual behaviour studies have been conducted in many countries. However, information from Australia is limited. This study was conducted in Obstetrics Department, Westmead Hospital, Sydney. Questionnaire-derived demographic and behavioural characteristics for public and private patients were compared using bivariate and logistic regression analyses. Of the patients, 3036 were public, and 595 private. On bivariate analysis some significant differences were private patients more likely to be born in Australia and have a higher education level whereas public patients were more likely to have had a greater number of lifetime sexual partners and younger age at first sex. Public patients were more likely to be herpes simplex virus type 2 (HSV-2) antibody positive (12%) than private patients (6%). On logistic regression significant variables included country of birth, being HSV-2 antibody positive, and age at first sex. A number of sexual and social variables were significantly different, comparing patients in the public and private sectors. Evaluation of interventions to reduce the sexual risk to women in the public sector should be considered, including encouraging young women to delay their sexual debut, and reducing the number of sexual partners.

Debate: the argument against. Should every STD clinic patient be considered for type-specific serological screening for HSV?

While initially attractive, the idea that all individuals attending sexually transmitted disease or genitourinary medicine clinics should be offered type-specific screening for herpes simplex virus may be impractical, and even undesirable, for a number of reasons. These include the lack of a cost-effective and sufficiently specific and sensitive screening test, the absence of an intervention that benefits the health of the individual or reduces the risk of onward transmission and, not least, the psychological, social and sexual sequelae of an unexpectedly positive result.

Evaluation of confirmatory strategies for detection of type-specific antibodies against herpes simplex virus type 2.

In this study, the optimal combination of three commercial glycoprotein G-2 (gG-2)-based herpes simplex virus type 2 (HSV-2) type-specific enzyme-linked immunosorbent assays (Euroimmun anti-HSV-2 immunoglobulin G [IgG] ELISA [Eu2], Gull HSV-2-specific IgG ELISA [Gu2], and Radim HSV-2 IgG ELISA [Ra2]) and one gG-2-based HSV-2-specific immunoblot (Euroimmun anti-HSV-1/HSV-2 gG Western blot [EuW]) was determined with regard to diagnostic performance and cost efficiency. Two hundred fifty serum samples were included in this study, 194 of which were from female prostitutes. When a formal primary "gold standard" was defined based on majority agreement of the commercial tests, with EuW being decisive in stand-off situations, the sensitivity and specificity of the assays in the samples from prostitutes were as follows: Eu2, 100 and 89.22%; Gu2, 94.44 and 96.08%; Ra2, 61.18 and 95.10%; and EuW, 98.90 and 100%. The most cost-effective confirmatory strategy in the samples from prostitutes was screening with Eu2, retesting positive and equivocal samples with Gu2, and resolving the remaining discordant results with EuW (estimated additional costs per sample, 79.02%; sensitivity, 100%; positive predictive value, 96.81%). Applying a self-developed gG-2-independent assay to the discordant and concordant negative samples in the samples from prostitutes suggested that the primary gold standard may have missed six HSV-2-positive samples. In conclusion, confirmatory strategies based on commercial gG-2-dependent seroassays result in an increase in the specificity of HSV-2-specific serology. However, further improvement of the sensitivity of current HSV-2-specific serology may require the additional exploitation of the gG-2-independent type-specific antibody response.

Use of a glycoprotein G-based type-specific assay to detect antibodies to herpes simplex virus type 2 among persons attending sexually transmitted disease clinics.

BACKGROUND: Most genital herpes simplex virus type 2 (HSV-2) infections are unrecognized, thus, strategies to reduce the sexual transmission of HSV-2 are partly dependent on serologic screening. GOAL: To define performance characteristics of the Gull/ Meridian glycoprotein G-based HSV-2 enzyme-linked immunosorbent assay among sexually transmitted disease clinic attendees and correlates of test acceptance. STUDY DESIGN: The cross-sectional study was conducted during two periods. Serologic testing was offered at a US $15 charge during the first period and at no charge during the second period. Sera were tested by a type-specific glycoprotein G enzyme-linked immunosorbent assay and Western blot analysis, with the latter test used as the reference standard. RESULTS: Acceptance of HSV-2 testing was associated with free testing (odds ratio, 7.5; 95% CI, 6.0-9.9), older age, and white race. Sensitivity of the HSV-2 assay was 80.5% and specificity was 98.5%. The HSV-2 positive and negative predictive values were 95.8% (95% CI, 91.6-98.0%) and 92.2% (95 % CI, 89.6 -94.2%), respectively. Antibodies to HSV-2 were detected in 25.9% of 606 persons with no history of genital herpes. CONCLUSION: Acceptance of HSV-2 serologic testing was cost sensitive. In this high-prevalence population, the positive predictive value of the enzyme-linked immunosorbent assay was sufficient to warrant its use without a confirmatory test. This assay could be useful in the screening of sexually active adults to detect unrecognized HSV-2 infection.

Epidemiology in the pharmaceutical industry: a perspective for infectious diseases.

As access to observational data and databases expands so does the need for epidemiologists in industry. As an example, in the U.K. arm of the Department of Epidemiology at GlaxoWellcome Research and Development, the number of PhD-trained epidemiologists increased from zero in 1996 to eight in 1999. Their remit is often broad, including designing and co-ordinating, pharmacoepidemiologic research, studies of risk factors for disease and disease progression and pregnancy registries. Where appropriate, existing data sources, such as research databases, are employed for studies. Otherwise, primary data collection is pursued using standard methodology, for example, cross-sectional, case-control and cohort studies. This paper describes a structure for epidemiologic research in the pharmaceutical industry, the role of the industry epidemiologist and the scope of epidemiological studies. Two examples of observational studies of HSV-2/HIV interactions are given, and implications for research agendas discussed. The pharmaceutical industry is becoming increasingly committed to epidemiological research, and research agendas often involve extensive collaboration with leading external academic and public health groups.