Tenofovir Gel for Prevention of Herpes Simplex Virus Type 2 Acquisition: Findings From the VOICE Trial.

BACKGROUND: Genital infection with herpes simplex virus type 2 (HSV-2) is common and increases risk of human immunodeficiency virus (HIV) transmission and acquisition. Pericoital use of tenofovir (TFV) gel provided protection from HSV-2 acquisition in the CAPRISA 004 study. METHODS: We measured estimate of effect of vaginal TFV 1% gel in preventing HSV-2 acquisition among women in VOICE, randomized, double-blinded, placebo-controlled trial assessing daily use of oral and vaginal TFV for HIV-1 preexposure prophylaxis. The TFV level in plasma at the first quarterly visit was used as a measure of gel use. RESULTS: Of 566 participants at risk for HSV-2 acquisition, 532 (94%) had first-quarter plasma TFV and end-of-study HSV-2 serologic data available. Over a follow-up period of 501 person-years, 92 incident cases of HSV-2 acquisition occurred: 77 were in women with no TFV detected in plasma, and 15 occurred in women with TFV detected in plasma (incidence, 20.6 cases/100 person-years [95% confidence interval [CI], 16.2-25.7] vs 11.9 cases/100 person-years [95% CI, 6.6-19.6], respectively). TFV detection in plasma was associated with a trend toward a reduced risk of HSV-2 seroconversion, with an unadjusted hazard ratio (HR) of 0.59 (95% CI, .34-1.02; P = .060) and a HR adjusted for site, age, having ≥2 male sex partners in the past 3 months, use of hormonal contraception, having anal sex in the past 3 months, and HIV status of 0.60 (95% CI, .33-1.08; P = .086). CONCLUSIONS: Detection of TFV in plasma among TFV gel users was associated with a trend toward a reduced risk of HSV-2 acquisition, after controlling for sexual behavior and HIV-1 acquisition.

Herpes Simplex Virus Type 2 Acquisition Among HIV-1-Infected Adults Treated With Tenofovir Disoproxyl Fumarate as Part of Combination Antiretroviral Therapy: Results From the ACTG A5175 PEARLS Study.

Objective: Tenofovir disoproxyl fumarate (TDF) disoproxyl fumarate (TDF) has in vitro activity against herpes simplex virus type 2 (HSV-2) and reduced HSV-2 acquisition as preexposure prophylaxis. Whether TDF-containing antiretroviral therapy (ART) reduces HSV-2 acquisition is unknown. Design: Secondary analysis of AIDS Clinical Trials Group A5175, a randomized, open-label study of 3 ART regimens among 1571 participants. Methods: HSV-2 serostatus was assessed at baseline, at study exit, and before a change in ART regimen. Results: Of 365 HSV-2-seronegative persons, 68 acquired HSV-2, with 24 receiving TDF-containing ART and 44 receiving ART without TDF (HSV-2 seroconversion incidence, 6.42 and 6.63 cases/100 person-years, respectively; hazard ratio, 0.89; 95% confidence interval, .55-1.44). Conclusions: HSV-2 acquisition was not reduced in HIV-infected, HSV-2-uninfected persons during TDF-containing ART.

Prospective Characterization of the Risk Factors for Transmission and Symptoms of Primary Human Herpesvirus Infections Among Ugandan Infants.

BACKGROUND: Human herpesvirus (HHV) infections are common during infancy. Primary infections are frequently asymptomatic and best studied prospectively by using direct viral detection. METHODS: Oropharyngeal swab specimens were collected weekly from Ugandan newborn infants, their mothers, and other children in the household. Blood specimens were collected every 4 months. Samples were tested for herpes simplex virus (HSV) types 1 and 2, Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6A, HHV-6B, and HHV-8, using quantitative polymerase chain reaction. RESULTS: Thirty-two infants, 32 mothers, and 49 other household children were followed for a median of 57 weeks. Seventeen mothers had human immunodeficiency virus type 1 (HIV) infection; no infants acquired HIV-1. The 12-month incidence of postnatal infection was 76% for HHV-6B, 59% for CMV, 47% for EBV, 8% for HSV-1, and 0% for HHV-8. The quantity of oropharyngeal shedding by contacts was associated with HHV-6A or HHV-6B transmission. Maternal HIV-1 infection was associated with EBV transmission, while breastfeeding and younger child contacts were associated with CMV transmission. Except for HSV-1, primary HHV infections were subclinical. CONCLUSIONS: By capturing exposures and acquisition events, we found that the incidence and risk factors of infection vary by HHV type. HSV-1 infection, unlike other HHV infections, caused acute clinical illness in these infants.

Efficacy results of a trial of a herpes simplex vaccine.

BACKGROUND: Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women. METHODS: We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 µg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20. RESULTS: The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], -29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (-8%; 95% CI, -59 to 26). CONCLUSIONS: In a study population that was representative of the general population of HSV-1- and HSV-2-seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; ClinicalTrials.gov number, NCT00057330.).

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.

Daily oral tenofovir and emtricitabine-tenofovir preexposure prophylaxis reduces herpes simplex virus type 2 acquisition among heterosexual HIV-1-uninfected men and women: a subgroup analysis of a randomized trial.

BACKGROUND: Daily oral preexposure prophylaxis (PrEP) using the antiretroviral tenofovir disoproxil fumarate (TDF) alone or in combination with emtricitabine (FTC-TDF) reduces the risk for HIV-1 acquisition. Tenofovir has in vitro activity against herpes simplex virus type 2 (HSV-2). OBJECTIVE: To assess the efficacy of daily oral PrEP with tenofovir and FTC-TDF in the prevention of HSV-2 acquisition. DESIGN: Subgroup analysis of data from a randomized, placebo-controlled trial with concealed allocation. (ClinicalTrials.gov: NCT00557245). SETTING: Multiple sites in Kenya and Uganda. PARTICIPANTS: Heterosexual men and women who were seronegative for HIV-1 and HSV-2 and at high risk for HIV-1 acquisition due to having an HIV-1-infected partner. INTERVENTION: Once-daily oral tenofovir disoproxil fumarate (TDF), alone or combined with emtricitabine (FTC-TDF), compared with placebo. MEASUREMENTS: HSV-2 seroconversion. RESULTS: A total of 131 participants seroconverted to HSV-2 (79 of 1041 assigned to tenofovir or FTC-TDF PrEP [HSV-2 incidence, 5.6 per 100 person-years] and 52 of 481 assigned to placebo [HSV-2 incidence, 7.7 per 100 person-years]). The hazard ratio (HR) for HSV-2 acquisition with daily oral PrEP was 0.70 (95% CI, 0.49 to 0.99; P = 0.047) compared with placebo, and the absolute risk reduction was 2.1 per 100 person-years. Among the 1044 participants with HSV-2-infected partners, the HR for PrEP was 0.67 (CI, 0.46 to 0.98; P = 0.038) compared with placebo, and the absolute risk reduction was 3.1 per 100 person-years. LIMITATION: Randomization was not stratified by HSV-2 status, and diagnostic tests to exclude participants with acute HSV-2 at baseline are not available. CONCLUSION: Daily oral tenofovir-based PrEP significantly reduced the risk for HSV-2 acquisition among heterosexual men and women. Modest protection against HSV-2 is an added benefit of HIV-1 prevention with oral tenofovir-based PrEP. PRIMARY FUNDING SOURCE: Bill & Melinda Gates Foundation.

Daily acyclovir to decrease herpes simplex virus type 2 (HSV-2) transmission from HSV-2/HIV-1 coinfected persons: a randomized controlled trial.

BACKGROUND: Daily suppressive therapy with valacyclovir reduces risk of sexual transmission of herpes simplex virus type 2 (HSV-2) in HSV-2-serodiscordant heterosexual couples by 48%. Whether suppressive therapy reduces HSV-2 transmission from persons coinfected with HSV-2 and human immunodeficiency virus type 1 (HIV-1) is unknown. METHODS: Within a randomized trial of daily acyclovir 400 mg twice daily in African HIV-1 serodiscordant couples, in which the HIV-1-infected partner was HSV-2 seropositive, we identified partnerships in which HIV-1-susceptible partners were HSV-2 seronegative to estimate the effect of acyclovir on risk of HSV-2 transmission. RESULTS: We randomly assigned 911 HSV-2/HIV-1-serodiscordant couples to daily receipt of acyclovir or placebo. We observed 68 HSV-2 seroconversions, 40 and 28 in acyclovir and placebo groups, respectively (HSV-2 incidence, 5.1 cases per 100 person-years; hazard ratio [HR], 1.35 [95% confidence interval, .83-2.20]; P = .22). Among HSV-2-susceptible women, vaginal drying practices (adjusted HR, 44.35; P = .004) and unprotected sex (adjusted HR, 9.91; P = .002) were significant risk factors for HSV-2 acquisition; having more children was protective (adjusted HR, 0.47 per additional child; P = .012). Among HSV-2-susceptible men, only age ≤30 years was associated with increased risk of HSV-2 acquisition (P = .016). CONCLUSIONS: Treatment of African HSV-2/HIV-1-infected persons with daily suppressive acyclovir did not decrease risk of HSV-2 transmission to susceptible partners. More-effective prevention strategies to reduce HSV-2 transmission from HIV-1-infected persons are needed.

Performance of the Focus HerpeSelect-2 enzyme immunoassay for the detection of herpes simplex virus type 2 antibodies in seven African countries.

OBJECTIVE: To compare the performance of the Focus HerpeSelect-2 enzyme immunoassay (EIA) with the gold standard herpes simplex virus (HSV) type 2 western blot, among HIV-1-uninfected men and women in east and southern Africa. METHODS: 3399 HIV-1-uninfected women and men from seven countries in east and southern Africa were tested for HSV-2 antibody using the Focus HerpeSelect-2 EIA. The performance of the HerpesSelect-2 EIA was compared with the gold standard HSV-2-specific western blot. RESULTS: Two-thirds (2294/3399) of participants were male and two-thirds (2242/3399) were from east Africa. By western blot testing, HSV-2 prevalence was 68%; 59% in men and 85% in women. At the manufacturer's recommended cut-off value of greater than 1.1, the HerpeSelect-2 EIA had a sensitivity of 98.3% and specificity of 80.3%. Receiver operating characteristic plot analysis indicated that the optimum cut-off was 2.1 or greater, with sensitivity 93.9% and specificity 90.5%. Diagnostic accuracy was modestly higher for southern Africa (area under the curve (AUC) 0.979, 95% CI 0.970 to 0.988) compared with east Africa (AUC 0.954, 95% CI 0.942 to 0.965; p<0.001 for southern vs east Africa). CONCLUSIONS: The Focus HerpeSelect-2 EIA has acceptable diagnostic accuracy for the determination of HSV-2 serostatus in African HIV-1-uninfected adults. An assay cut-off value of 2.1 or greater results in approximately 90% sensitivity and specificity, against a gold standard HSV-2 western blot. Diagnostic accuracy differed slightly by geographical region.

Performance of commercial herpes simplex virus type-2 antibody tests using serum samples from Sub-Saharan Africa: a systematic review and meta-analysis.

BACKGROUND: Several commercial type-specific serologic tests are available for herpes simplex virus type 2 (HSV-2). Poor specificity of some tests has been reported on samples from sub-Saharan Africa. METHODS: To summarize the performance of the tests using samples from sub-Saharan Africa, we conducted a systematic review of publications reporting performance of commercially available HSV-2 tests against a gold standard (Western Blot or monoclonal antibody-blocking EIA). We used random-effects meta-analyses to summarize sensitivity and specificity of the 2 most commonly evaluated tests, Kalon gG2 enzyme-linked immunosorbent assay (ELISA), and Focus HerpeSelect HSV-2 ELISA. RESULTS: We identified 10 eligible articles that included 21 studies of the performance of Focus, and 12 of Kalon. The primary analyses included studies using the manufacturers' cut-offs (index value = 1.1). Focus had high sensitivity (random effects summary estimate 99%, 95% confidence interval [CI]: 99%-100%) but low specificity (69%, 95% CI: 59%-80%). Kalon had sensitivity of 95% (95% CI: 93%-97%) and specificity of 91% (95% CI: 86%-95%). Specificity of Focus was significantly lower (P = 0.002) among HIV-positive (54%, 95% CI: 40%-68%) than HIV-negative individuals (69%, 95% CI: 56%-82%). When the cut-off optical density index was increased above the recommended value of 1.1 to between 2.2 and 3.5, the specificity of Focus increased to 85% (95% CI: 77%-92%). CONCLUSIONS: Sensitivity and specificity of HSV-2 tests used in sub-Saharan Africa vary by setting, and are lower than reported from studies in the United States and Europe. Increasing the cut-off optical density index may improve test performance. Evaluation of test performance in a given setting may help deciding which test is most appropriate.

Comparison of focus HerpesSelect and Kalon HSV-2 gG2 ELISA serological assays to detect herpes simplex virus type 2 antibodies in a South African population.

INTRODUCTION: Sero-epidemiological studies of herpes simplex virus (HSV) type 2 infection in Africa remain difficult to interpret as a result of the high rate of false-positive results observed when using the new recombinant gG2 HSV-2 ELISA tests. The performance of two widely used gG2 ELISA was compared to derive an appropriate testing algorithm for use in South Africa. METHODS: Sera from 210 women attending family planning clinics in Johannesburg were tested using HerpeSelect and Kalon HSV-2 gG2 assays. Sera from 20 discordant pairs, 44 concordant positive and 33 concordant negative samples were further tested by HSV Western blot. The sensitivity and specificity of each test and of combination algorithms compared with Western blot were calculated. RESULTS: HerpeSelect had a sensitivity of 98% (95% CI 95 to 100) and specificity of 61% (95% CI 48 to 74). Kalon was less sensitive (89%, 95% CI 83 to 94) but more specific (85%, 95% CI 61 to 100). Seroprevalence may have been overestimated by as much as 14% by HerpeSelect. Specificity was improved by raising the cut-off index for the determination of a positive result for HerpeSelect (to >or=3.5), but not for Kalon. HIV-1 infection reduced the specificity of HerpeSelect to 30%. Improved sensitivity and specificity were obtained by a two-test algorithm using HerpeSelect (>or=3.5) as the first test and Kalon to resolve equivocal results (sensitivity 92%, 95% CI 82 to 98; specificity 91%, 95% CI 79 to 98). CONCLUSION: Newer HSV-2 serological tests have low specificity in this South African population with a high HIV-1 prevalence. Two-step testing strategies could provide rational testing alternatives to Western blot.

Herpes simplex virus type-2 seropositivity among ever married women in South and north Vietnam: a population-based study.

OBJECTIVE: To investigate herpes simplex virus type-2 (HSV-2) seropositivity and associated risk factors in Vietnamese women. METHODS: Cross-sectional study with personal interviews and gynecological examinations among population-based samples of ever married women, aged 15 to 69 years, living in Ho Chi Minh City (HCMC) and Hanoi in 1997. Type-specific IgG antibodies against HSV-2 were detected using HerpeSelect ELISA (Focus Diagnostics). Adjusted prevalence ratios were estimated with log-binomial regression. RESULTS: HSV-2 seroprevalence was higher in 1106 women from HCMC (30.8%, 95% CI: 28.1-33.4, age-standardized to 2000 world standard population) than in 1170 women from Hanoi (8.8%, 95% CI: 7.1-10.5). In HCMC, HSV-2 seroprevalence was higher for women who were not married, HPV DNA positive, current hormonal contraceptive users, or had a history of multiple sexual partners or spontaneous abortion. HCMC seroprevalence was inversely associated with educational attainment, age at first intercourse, and age at first pregnancy. In the multivariable model for HCMC, a trend of increasing HSV-2 seroprevalence with age was observed, and prevalence ratios were nearly identical to age-adjusted prevalence ratios for marital status, age at first pregnancy, and HPV DNA positivity. CONCLUSIONS: HSV-2 was notably less prevalent in Hanoi than HCMC, where it was associated with traditional HSV-2 risk factors. These results are likely explained by socio-cultural, historical, economic, and demographic factors related to urban-rural and regional differences. Future population-based studies should include men and never-married women as a next step toward obtaining a more nearly complete picture of HSV-2 epidemiology in Vietnam.

A population-based study of primary human herpesvirus 6 infection.

BACKGROUND: Serologic studies indicate that human herpesvirus 6 (HHV-6) infects 90 percent of children by two years of age. Little is known about the acquisition, virologic course, and clinical manifestations of HHV-6 infection. METHODS: We prospectively studied a cohort of 277 children from birth through the first two years of life to define the pattern of acquisition of HHV-6. The children's saliva was tested weekly for HHV-6 DNA with the use of the polymerase chain reaction. Parents maintained a daily log of signs and symptoms of illness in their children. RESULTS: Primary HHV-6 infection occurred in 130 children, with cumulative percentages of 40 percent by the age of 12 months and 77 percent by the age of 24 months. The peak age of acquisition was between 9 and 21 months. The acquisition of HHV-6 was associated with female sex (adjusted hazard ratio, 1.7; 95 percent confidence interval, 1.2 to 2.4) and having older siblings (adjusted hazard ratio, 2.1; 95 percent confidence interval, 1.4 to 2.9). Among 81 children with a well-defined time of acquisition of HHV-6, 93 percent had symptoms, and 38 percent were seen by a physician. None had seizures. As compared with children who had other illnesses, those with primary HHV-6 infection were more likely to have fever (P=0.003), fussiness (P=0.02), diarrhea (P=0.03), rash (P=0.003), and roseola (P=0.002) and were more likely to visit a physician (P=0.003). CONCLUSIONS: The acquisition of HHV-6 in infancy is usually symptomatic and often results in medical evaluation. Roseola occurs in a minority of patients, and febrile seizures are infrequently associated with primary HHV-6 infection. Older siblings appear to serve as a source of HHV-6 transmission.

Peer Mentoring at the Uganda Cancer Institute: A Novel Model for Career Development of Clinician-Scientists in Resource-Limited Settings.

Cancer centers are beginning to emerge in low- and middle-income countries despite having relatively few oncologists and specialists in related fields. Uganda, like many countries in sub-Saharan Africa, has a cadre of highly motivated clinician-scientists-in-training who are committed to developing the capacity for cancer care and research. However, potential local mentors for these trainees are burdened with uniquely high demands on their time for clinical care, teaching, institutional development, advocacy, and research. Facilitated peer mentoring helps to fill skills and confidence gaps and teaches mentoring skills so that trainees can learn to support one another and regularly access a more senior facilitator/role model. With an added consultant component, programs can engage limited senior faculty time to address specific training needs and to introduce junior investigators to advisors and even potential dyadic mentors. Two years after its inception, our facilitated peer mentoring career development program at the Uganda Cancer Institute in Kampala is successfully developing a new generation of researchers who, in turn, are now providing role models and mentors from within their group. This program provides a practical model for building the next generation of clinical scientists in developing countries.

Seroprevalence of herpes simplex virus type 1 in children in the United States.

OBJECTIVES: To describe HSV-1 seroprevalence in children in the United States and to examine factors associated with herpes simplex virus type 1 (HSV-1) infection in children. STUDY DESIGN: Sera samples available from 2989 children age 6 to 13 years who participated in the National Health and Nutrition Examination Surveys (NHANES) 1999-2002 were tested for HSV-1 antibodies using a type-specific immunodot assay. HSV-1 seroprevalence in children age 12 to 13 years was compared with that reported in an earlier survey (NHANES 1988-1994). RESULTS: Overall, HSV-1 seroprevalence in children age 6 to 13 years was 31.1% (95% confidence interval [CI], 28.6% to 33.9%). Seroprevalence increased with age, from 26.3% in 6- to 7-year-olds to 36.1% in 12-to 13-year-olds, and varied by race/ethnicity, birthplace, and poverty level. Among US-born children age 12 to 13 years, the point estimate of HSV-1 seroprevalence was lower in NHANES 1999-2002 than in NHANES 1988-1994 (34.3% vs 38.1%), but the differences were not statistically significant. CONCLUSIONS: HSV-1 is a common infection in US children, with more than 25% infected by age 7. Race/ethnicity, birthplace, and poverty level are predictors for HSV-1 infection in children.

Herpes simplex virus type 2 and risk of intrapartum human immunodeficiency virus transmission.

OBJECTIVE: To determine whether herpes simplex virus type 2 (HSV-2) infection was associated with risk of intrapartum human immunodeficiency virus type 1 (HIV-1) transmission and to define correlates of HSV-2 infection among HIV-1-seropositive pregnant women. METHODS: We performed a nested case control study within a perinatal cohort in Nairobi, Kenya. Herpes simplex virus type 2 serostatus and the presence of genital ulcers were ascertained at 32 weeks of gestation. Maternal cervical and plasma HIV-1 RNA and cervical HSV DNA were measured at delivery. RESULTS: One hundred fifty-two (87%) of 175 HIV-1-infected mothers were HSV-2-seropositive. Among the 152 HSV-2-seropositive women, nine (6%) had genital ulcers at 32 weeks of gestation, and 13 (9%) were shedding HSV in cervical secretions. Genital ulcers were associated with increased plasma HIV-1 RNA levels (P=.02) and an increased risk of intrapartum HIV-1 transmission (16% of transmitters versus 3% of nontransmitters had ulcers; P = .003), an association which was maintained in multivariable analysis adjusting for plasma HIV-1 RNA levels (P=.04). We found a borderline association for higher plasma HIV-1 RNA among women shedding HSV (P=.07) and no association between cervical HSV shedding and either cervical HIV-1 RNA levels or intrapartum HIV-1 transmission (P=.4 and P=.5, [corrected] respectively). CONCLUSION: Herpes simplex virus type 2 is the leading cause of genital ulcers among women in sub-Saharan Africa and was highly prevalent in this cohort of pregnant women receiving prophylactic zidovudine. After adjusting for plasma HIV-1 RNA levels, genital ulcers were associated with increased risk of intrapartum HIV-1 transmission. These data suggest that management of HSV-2 during pregnancy may enhance mother-to-child HIV-1 prevention efforts. LEVEL OF EVIDENCE: II.

Brief communication: fatal human metapneumovirus infection in stem-cell transplant recipients.

BACKGROUND: Human metapneumovirus (hMPV), a recently discovered respiratory virus, is associated with clinical disease in young and elderly persons. OBJECTIVE: To determine the importance of hMPV in hematopoietic stem-cell transplant recipients. DESIGN: Retrospective survey of patients with consecutive residual bronchoalveolar lavage (BAL) samples. SETTING: Referral cancer center. PATIENTS: Hematopoietic stem-cell transplant recipients who underwent BAL because of lower respiratory tract disease. MEASUREMENTS: Bronchoalveolar lavage specimens were assayed by quantitative real-time polymerase chain reaction methods. RESULTS: Human metapneumovirus was detected in BAL specimens from 5 of 163 patients (3.0%). Persistent viral infection was noted in 3 patients with several samples, and hMPV was detected in 1 of 2 lung specimens tested. Infected patients became symptomatic within the first 40 days after transplantation. Initial symptoms included fever, cough, nasal congestion, and sore throat. Clinical findings included respiratory failure, pulmonary hemorrhage, and culture-negative septic shock. Four of 5 patients died with acute respiratory failure. LIMITATIONS: This retrospective study did not evaluate asymptomatic patients or those with mild disease. CONCLUSION: Human metapneumovirus infection in the lower respiratory tract is associated with respiratory failure in immunocompromised adults who were previously considered to have "idiopathic pneumonia." The infection may result in fulminant respiratory decompensation and shock after transplantation.

Antibody to HSV gD peptide induced by vaccination does not protect against HSV-2 infection in HSV-2 seronegative women.

BACKGROUND: In the HIV-1 vaccine trial RV144, ALVAC-HIV prime with an AIDSVAX® B/E boost reduced HIV-1 acquisition by 31% at 42 months post first vaccination. The bivalent AIDSVAX® B/E vaccine contains two gp120 envelope glycoproteins, one from the subtype B HIV-1 MN isolate and one from the subtype CRF01_AE A244 isolate. Each envelope glycoprotein harbors a highly conserved 27-amino acid HSV-1 glycoprotein D (gD) tag sequence that shares 93% sequence identity with the HSV-2 gD sequence. We assessed whether vaccine-induced anti-gD antibodies protected females against HSV-2 acquisition in RV144. METHODS: Of the women enrolled in RV144, 777 vaccine and 807 placebo recipients were eligible and randomly selected according to their pre-vaccination HSV-1 and HSV-2 serostatus for analysis. Immunoglobulin G (IgG) and IgA responses to gD were determined by a binding antibody multiplex assay and HSV-2 serostatus was determined by Western blot analysis. Ninety-three percent and 75% of the vaccine recipients had anti-gD IgG and IgA responses two weeks post last vaccination, respectively. There was no evidence of reduction in HSV-2 infection by vaccination compared to placebo recipients over 78 weeks of follow-up. The annual incidence of HSV-2 infection in individuals who were HSV-2 negative at baseline or HSV-1 positive and HSV-2 indeterminate at baseline were 4.38/100 person-years (py) and 3.28/100 py in the vaccine and placebo groups, respectively. Baseline HSV-1 status did not affect subsequent HSV-2 acquisition. Specifically, the estimated odds ratio of HSV-2 infection by Week 78 for female placebo recipients who were baseline HSV-1 positive (n = 422) vs. negative (n = 1120) was 1.14 [95% confidence interval 0.66 to 1.94, p = 0.64)]. No evidence of reduction in the incidence of HSV-2 infection by vaccination was detected. CONCLUSIONS: AIDSVAX® B/E containing gD did not confer protection from HSV-2 acquisition in HSV-2 seronegative women, despite eliciting anti-gD serum antibodies.

Herpes simplex virus infection in women in the WIHS: epidemiology and effect of antiretroviral therapy on clinical manifestations.

OBJECTIVE: To determine the prevalence of infection with herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) among women with and at high risk for HIV infection, and to evaluate the effect of HAART on the recurrence of genital lesions. METHODS: We evaluated the epidemiology and clinical manifestations associated with HSV-1 and HSV-2 among 1796 HIV-infected and 476 HIV-uninfected women enrolled in a multisite cohort study. Serum antibodies to HSV-1 and HSV-2 at baseline and self-reported history of genital herpes, reports of recent genital sores and presence of genital ulcers on examination, and use of HAART regimen at each study visit were analyzed. RESULTS: Reactivity to HSV-1 only and HSV-2 only was detected in 18% and 20% of HIV-infected, and in 28% and 18% of HIV-uninfected participants respectively; 58% of HIV-infected women and 45% of HIV-uninfected women were seropositive for both HSV types. Reactivity to HSV-2 was associated with increasing age, more male sexual partners, earlier sexual debut, African-American race, Latina ethnicity, less education and lower income. HIV-uninfected women reported significantly fewer genital sores than HIV-infected women who had used HAART for at least 1 year and had optimal CD4 cell gain and viral suppression (adjusted odds ratio (OR), 0.19; 95% confidence interval (CI), 0.13-0.28). CONCLUSION: Use of HAART and subsequent immune recovery does not completely eliminate the effect of HIV infection on genital lesions among women with concurrent HSV-2 infection.

Prevalence of herpes simplex virus types 1 and 2 among children and adolescents attending a sexual abuse clinic.

BACKGROUND: Children and adolescents with a history of sexual abuse are at risk for acquiring herpes simplex virus (HSV) type 2. We evaluated the prevalence of HSV-1 and HSV-2 and the usefulness for this population of 2 commercially available tests. METHODS: Sera from 150 children seen in a sexual abuse clinic were analyzed for type-specific HSV antibodies using Focus HerpeSelect HSV-2 ELISA (Focus), Biokit HSV-2 Rapid Test (Biokit), and by Western blot (WB). RESULTS: The patient sample was 81% female, had a mean age of 11.6 years (range, 1 to 18 years), and was 46% Caucasian, 28% Hispanic, 25% African American, and 2% other. According to WB, 77 (51%) of the children were HSV-1 seropositive. For HSV-2, there was 1 "true positive" (positive by all 3 tests) and 1 patient whose serum had atypical HSV-2 bands by WB but was positive by Focus. There were 6 sera that were positive by Focus and negative by WB. Index values of these 6 Focus tests were not predictive of WB status. For the 105 samples for which Biokit data were available, all samples were concordant with WB. CONCLUSIONS: The findings of this study suggest that routine screening for HSV-2 in sexually abused children does not have a high yield. The Focus test has an unacceptably high rate of false-positive results in children; however, Biokit may be an acceptable substitute for WB in evaluating children for HSV-2 antibodies.