Elizabeth Krantz

Acute Hepatitis C in a Contemporary US Cohort: Modes of Acquisition and Factors Influencing Viral Clearance

BACKGROUND Acute hepatitis C virus (HCV) infection is often asymptomatic; thus, its epidemiology and natural history are difficult to define. METHODS Acute HCV infection was identified on the basis of HCV seroconversion within 1 year (n=45), new anti-HCV seropositivity with clinical acute hepatitis (n=21), or HCV strain sequencing after an iatrogenic exposure (n=1). Risk factors were assessed with a baseline questionnaire, and participants were followed up prospectively with serial measurement of viral loads. RESULTS Of 67 persons with acute HCV infection, most were asymptomatic (64%) and injection drug users (66%). Thirteen had an unknown mode of transmission; of these, 11 reported high-risk sexual behavior. Ten acquired acute HCV infection within 3 months of an iatrogenic exposure; 3 had confirmed iatrogenic infection, and 4 had no other risk factors identified. The spontaneous viral clearance rate after 6 months of infection was 18% (95% confidence interval, 11%-31%). The rate of viral clearance varied significantly by sex (34% vs. 3% for women vs. men; P<.001). CONCLUSIONS High-risk sexual or iatrogenic exposures may be important contemporary risk factors for HCV infection. The spontaneous viral clearance rate (18%) in this contemporary study was similar to that reported for past studies of transfusion-associated HCV infection. Women were more likely to clear acute HCV infection than men.

The relationship between condom use and herpes simplex virus acquisition

Context We need other means to reduce the risk for transmitting genital herpes (herpes simplex virus type 2 [HSV-2]). Are condoms effective? Content In a trial of an ineffective HSV-2 vaccine, 1843 participants were divided into 3 groups according to the frequency of condom use (for 0% to 25%, 25% to 75%, and >75% to 100% of sexual acts). Frequent condom users had fewer HSV-2 infections. Compared with participants in the next lowest category, participants in a category had a 26% lower risk for HSV-2 infection. Limitation In this observational cohort study, many unmeasured factors could also contribute to altered rates of HSV-2 acquisition. Conclusion Condom use is associated with a lower rate of acquisition of HSV-2. The Editors Genital herpes is a common sexually transmitted infection that can be transmitted during episodes of recurrent lesions and during subclinical shedding (1). In the absence of an effective vaccine, condoms have been routinely recommended for prevention of transmission, and a recent study showed that daily antiviral therapy also decreases the risk for transmission of herpes simplex virus type 2 (HSV-2) in discordant couples (2, 3). In a previous study of monogamous HSV-2discordant couples who were enrolled in an ineffective candidate HSV-2 vaccine trial, we showed that condoms protect women from HSV-2 infection (4). However, very few cases of genital HSV-2 occurred among men who were sexual partners of women infected with HSV-2, precluding definitive conclusions about the effectiveness of condoms for prevention of transmission to men. We present data from a concurrent trial of the candidate vaccine among HSV-2seronegative persons attending sexually transmitted disease clinics (5). A total of 1862 participants were enrolled in this study; 85 cases of genital herpes were documented in men, and 33 cases were documented in women. We analyzed the effect of condom use on HSV acquisition in this prospectively followed cohort of men and women. Methods Study Sample Participants included in this analysis took part in a randomized, double-blind, placebo-controlled efficacy trial of a candidate subunit HSV-2 vaccine that was subsequently shown to be ineffective (5). The trial involved 22 centers located at sexually transmitted disease clinics and enrolled 1862 participants. Initial serologic testing was done at screening; participants who were seronegative for HIV and HSV-2 and reported 4 or more sexual partners in the past year or 1 or more sexually transmitted diseases in the past year were eligible to enroll. The effectiveness of condom use among the 528 discordant couples enrolled in a parallel vaccine study was reported previously (4, 5). Participants were enrolled and followed for 18 months, during which they were evaluated at 11 study visits. At enrollment, we collected demographic information and information about sexual history. At each study visit, we took blood samples and recorded the following information about sexual history, which described behavior since the last visit: frequency of sexual activities, defined as vaginal or anal intercourse; frequency of condom use; number of partners; number of new partners; and number of partners with a known history of genital herpes. The information regarding number of partners was gender-specific. In addition, participants were counseled routinely about safer sexual behavior and were offered condoms at each study visit. Genitourinary signs and symptoms were evaluated as needed at additional interim visits. Laboratory Methods The Western blot assay done at the University of Washington, Seattle, Washington, established HSV serologic status at study entry and was used to document seroconversion (6). Type-specific cultures using standard techniques were done at local study sites. Statistical Analysis Acquisition of HSV-2 was defined by seroconversion on the Western blot assay or by a positive culture for HSV-2. Time to HSV-2 acquisition was defined as the number of days from screening to the first positive culture for HSV-2 or as the midpoint between the last negative result of the HSV-2 antibody test and the first positive result of the HSV-2 antibody test. In this analysis of condom use and HSV acquisition, we included the time from screening to enrollment in the study, whereas in the vaccine trial participants were followed beginning at enrollment. Thus, our report includes 109 participants who were not included in the efficacy analysis of the original vaccine trial. Twenty of these participants seroconverted to HSV-2 during the screening period before enrollment, and 89 were lost to follow-up after enrollment. Participants who did not acquire HSV-2 were censored at the last blood draw taken during the study or at enrollment if they did not report any sexual activity thereafter. Participants who reported no sexual activity for the entire time from screening to study termination were excluded from the analysis because they were not at risk for HSV-2 infection. Participants with follow-up longer than 65 days beyond the 18 months specified in the protocol (3%) were censored at day 605. Participants who were seronegative for HSV type 1 (HSV-1) and HSV-2 at screening were included in the analysis of HSV-1. Time to HSV-1 acquisition was defined as the number of days from screening to the first positive culture for HSV-1 or the midpoint between the last negative result of the HSV-1 antibody test and the first positive result of the HSV-1 antibody test. Participants who did not acquire HSV-1 were censored at the last blood draw or at enrollment if they did not report any sexual activity thereafter. Participants who reported no sexual activity for the duration of the study were excluded from the analysis of HSV-1. KaplanMeier curves, log-rank tests, and univariate and multivariate Cox regression models were used to determine baseline risk factors associated with HSV-2 acquisition. To relate sexual behavior to HSV-2 acquisition during the study, we constructed time-dependent covariate Cox regression models. The analysis time was divided into four 150-day intervals, and information about sexual history collected at interim visits was used to calculate covariate summaries for each period. Because continuous variables did not satisfy the assumption of a linear effect in the log hazard, they were categorized. Our choice for the cut-points was motivated by maintaining equal numbers of participants in each category (for example, age was split at the median value, 27 years), by consistency with observed risk patterns, or by interpretation considerations. Frequency of sexual activity was expressed as the average number of sexual acts per week in the time period, calculated by averaging the reported estimates over the visits for each interval. This average was then categorized as greater than 2 versus 2 or fewer to correspond to observed risk patterns. Use of condoms during the study period was described categorically in each interval (used for 0% to 25%, for 25% to 75%, or for >75% of sexual acts). This grouped linear parameterization was chosen to remain consistent with published analyses (4) while allowing a doseresponse relationship, assuming constant change in the risk with increasing category of condom use. The use of condoms was not evaluated during intervals for which the participants did not report any sexual activity. The number of partners reported was summarized for each period and was modeled in a binary fashion. Partner cut-points were chosen for interpretation reasons to describe ways in which this patient group may differ from monogamous couples who were studied in a previously published report addressing condom use and infection with HSV (4). Total number of partners was modeled as more than 1 versus 1 or fewer, and both new partners and partners with a history of genital herpes were modeled as any versus none. These analyses did not adjust for receipt of placebo versus receipt of vaccine, because this factor was not statistically significant in acquisition of HSV and did not influence the covariates of interest for this study. An interaction term between condom use and gender was used to check the hypothesis of a difference in the effect of condoms by gender and to provide gender-specific estimates of condom use. Two-sided P values for model covariates were calculated by using the likelihood ratio test. The same methods were used to explore baseline risk factors and time-varying risk factors for time to infection with HSV-1. Poisson regression was used to provide P values for comparisons involving incidence rates. Tests for changes in sexual behavior with time used generalized estimating equations. Statistical analyses were done by using Stata statistical software (version 8.1, Stata Corp., College Station, Texas). Role of the Funding Source The funding for the analyses for this study was provided by federal grants; design, data analysis, and interpretation were done at the University of Washington. The initial clinical trial was funded by Chiron Corporation. This study was supported in part by National Institutes of Health Herpes Program Project Grant AI-30731 and Centers for Disease Control and Prevention Research Initiative UR6/CCU017828-02. Results Of the 1862 participants who enrolled for the vaccine trial, 19 did not report any sexual activity during the entire study and thus were excluded from this analysis. The remaining 1843 participants included 1365 men and 478 women. The median age of the participants was 27 years. Sixty-two percent were white, 32% were African American, and 6% were people of other races; 1184 participants (64%) were seropositive for HSV-1 at study entry. Most men and women qualified for the study by reporting 4 or more partners in the past year (66% of men, 70% of women); some reported 1 or more sexually transmitted diseases in the past year (12% of men, 19% of women); and the remainder met both criteria (22% of men, 1

Valacyclovir and acyclovir for suppression of shedding of herpes simplex virus in the genital tract

BACKGROUND Valacyclovir exhibits better oral absorption and higher, more prolonged serum concentrations than oral acyclovir. The efficacy of valacyclovir and acyclovir on genital herpes simplex virus (HSV) shedding was assessed in a double-blind, 3-period crossover trial. METHODS Sixty-nine immunocompetent participants with genital HSV-2 received oral valacyclovir, acyclovir, and matching placebo in random order for 7-week periods. Participants provided daily genital mucosal swabs for HSV detection by viral culture and polymerase chain reaction (PCR). RESULTS HSV was detected at least once in 62 (90%) participants by culture and in 68 (98%) by PCR. During placebo, the total HSV shedding rate was 15.4% of days by culture (PCR, 40.2%); the subclinical shedding rate was 6.6% by culture (PCR, 27.1%). Both antivirals were associated with lower HSV shedding by culture (relative risk [RR], 0.03 [95% confidence interval [CI], 0.01-0.07] for valacyclovir and RR, 0.05 [95% CI, 0.03-0.10] for acyclovir) and PCR (RR, 0.18 [95% CI, 0.12-0.26] for valacyclovir and RR, 0.20 [95% CI, 0.15-0.28] for acyclovir), compared with placebo. No significant differences in frequency and quantity of HSV were detected by PCR between the valacyclovir and acyclovir arms. CONCLUSIONS Although the suppression of viral replication is not complete, valacyclovir and acyclovir are highly effective in suppressing the frequency and quantity of genital HSV shedding.

Natural history of genital herpes simplex virus type 1 infection.

Background Herpes simplex virus type 1 (HSV-1) has been increasingly reported as a cause of genital herpes, yet there have been few studies on the long-term natural history of this infection. Goal The goal was to examine the clinical course of genital HSV-1 infection. Study Design This was a cohort study of patients presenting with culture-proven primary genital HSV-1 infection. Results The median follow-up of the 77 patients was 736 days. The overall rate of recurrences was 1.3/year in the first year of infection, decreasing to 0.7/year in the second year. In the first year of infection, 43% of study patients did not have a recurrence. In the second year of infection, 67% of study patients did not have a recurrence. Conclusion Genital HSV-1 recurs infrequently in most patients, and the rate decreases further in the subsequent years of infection. Because the prognoses of genital HSV-1 and HSV-2 infections differ, determination of the viral type is important for patient counseling.

Valganciclovir for Suppression of Human Herpesvirus 8 Replication: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial

BACKGROUND Human herpesvirus-8 (HHV-8) replication is critical in the induction and maintenance of Kaposi sarcoma, primary effusion lymphoma, and some cases of Castleman disease. In vitro and observational studies suggest that ganciclovir inhibits HHV-8 replication, but no randomized clinical trials have been conducted. METHODS A total of 26 men infected with HHV-8 were randomized to receive 8 weeks of valganciclovir administered orally (900 mg once per day) or 8 weeks of placebo administered orally. After a 2-week washout period, participants in each group received the study drug they had not yet taken (either valganciclovir or placebo), for 8 additional weeks. Oral swab samples were collected daily during the study, and HHV-8 and CMV DNA were quantified by real-time PCR. RESULTS A total of 16 human immunodeficiency virus (HIV)-positive men and 10 HIV-negative men enrolled in and completed the study. Of the 3,439 swab samples that participants had been expected to provide, 3029 (88%) were available for analysis. HHV-8 was detected on 44% of swabs collected from participants who were receiving placebo, compared with 23% of swabs collected from participants who were receiving valganciclovir (relative risk [RR], 0.54 [95% confidence interval {CI}, 0.33-0.90]; P = .02). Valganciclovir reduced oropharyngeal shedding of cytomegalovirus by 80% (RR, 0.20 [95% CI, 0.08-0.48]; P < .001). Shedding of HHV-8 and shedding of cytomegalovirus were independent. Hematologic, renal, or hepatic toxicities were no more common among participants who received the active drug, compared with those who received placebo, though participants who received valganciclovir reported more days of diarrhea. CONCLUSIONS Valganciclovir administered orally once per day is well tolerated and significantly reduces the frequency and quantity of HHV-8 replication.

Knowledge of Partners’ Genital Herpes Protects against Herpes Simplex Virus Type 2 Acquisition

BACKGROUND Prospective studies of herpes simplex virus type 2 (HSV-2) infection in discordant couples have shown a low rate of transmission. However, unlike partners with genital herpes in prospectively monitored couples, most persons who transmit genital herpes are not aware of having the infection. METHODS Because HSV has a short incubation period and most persons who acquire genital herpes can identify the transmitting partner, a time-to-event design was used to assess risks of HSV acquisition among patients with newly acquired genital herpes. RESULTS Among 199 persons with laboratory-documented newly acquired genital herpes, the median duration of the sexual relationship with the transmitting partner was 3.5 months, and the median number of sex acts before transmission was 40. The median time to HSV-2 acquisition was greater among participants whose partners disclosed that they had genital herpes, compared with participants whose partners did not disclose their status (270 vs. 60 days; P = .03). In multivariate models, having a partner who disclosed that he or she had genital herpes remained a strong protective factor against genital HSV-2 acquisition (hazard ratio, 0.48 [95% confidence interval, 0.25-0.91]). CONCLUSION These findings suggest that testing persons with HSV type-specific serologic assays and encouraging disclosure may result in a decreased risk of HSV-2 transmission to sex partners.

Frequent reactivation of herpes simplex virus among HIV-1-infected patients treated with highly active antiretroviral therapy

The effect of highly active antiretroviral therapy (HAART) on control of herpes simplex virus (HSV) in human immunodeficiency virus (HIV) type 1-infected subjects is not known. Among 28 HAART-treated and 49 untreated subjects with HIV-1 and HSV-2 infections, mucosal HSV shedding (median, 18% and 29% of days positive for HSV DNA, respectively; P=.08) and HSV DNA level (median, 56,250 and 50,000 copies/mL, respectively; P=.20) were similar. Treated subjects reported significantly fewer days with HSV lesions, compared with untreated subjects (2.8% vs. 11.3% of days, respectively; P=.001). Thus, mucosal HSV shedding and HSV-2 reactivation were still frequent among treated subjects, even though HAART was associated with fewer days with HSV lesions.

A pooled analysis of the effect of condoms in preventing HSV-2 acquisition.

BACKGROUND The degree of effectiveness of condom use in preventing the transmission of herpes simplex virus 2 (HSV-2) is uncertain. To address this issue, we performed a large pooled analysis. METHODS We identified prospective studies with individual-level condom use data and laboratory-defined HSV-2 acquisition. Six studies were identified through a review of publications through 2007: 3 candidate HSV-2 vaccine studies, an HSV-2 drug study, an observational sexually transmitted infection (STI) incidence study, and a behavioral STI intervention study. Study investigators provided us individual-level data to perform a pooled analysis. Effect of condom use was modeled using a continuous percentage of sex acts during which a condom was used and, alternatively, using absolute numbers of unprotected sex acts. RESULTS A total of 5384 HSV-2-negative people at baseline contributed 2 040 894 follow-up days; 415 persons acquired laboratory-documented HSV-2 during follow-up. Consistent condom users (used 100% of the time) had a 30% lower risk of HSV-2 acquisition compared with those who never used condoms (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.40-0.94) (P = .01). Risk for HSV-2 acquisition increased steadily and significantly with each unprotected sex act (HR, 1.16; 95% CI, 1.08-1.25) (P < .001). Condom effectiveness did not vary by gender. CONCLUSIONS To our knowledge, this is the largest analysis using prospective data to assess the effect of condom use in preventing HSV-2 acquisition. Although the magnitude of protection was not as large as has been observed with other STIs, we found that condoms offer moderate protection against HSV-2 acquisition in men and women.

Time course of seroconversion by HerpeSelect ELISA after acquisition of genital herpes simplex virus type 1 (HSV-1) or HSV-2.

Background HerpeSelect HSV-1 and HSV-2 ELISAs are glycoprotein G–based, type-specific antibody detection tests that are approved by the US Food and Drug Administration for diagnosis of genital herpes. Goal The goal was to determine seroconversion times by means of HerpeSelect ELISAs. Study Design Four-hundred thirteen sera from 113 patients with recently acquired genital herpes were tested by HerpeSelect ELISAs and Western blot (WB). Thirty-one patients had primary genital HSV-1 (group 1), 56 had primary HSV-2 (group 2), and 26 had prior HSV-1 antibodies and newly acquired HSV-2 (group 3). Results Median interval from onset of symptoms to seroconversion was 25 days, as determined by HerpeSelect HSV-1, versus 33 days by WB for group 1; 21 days by HerpeSelect HSV-2 versus 40 days by WB (group 2;P = 0.0005); and 23 days by HerpeSelect HSV-2 ELISA versus 47 days by WB (group 3;P = 0.02). In long-term follow-up, transient reversion to HerpeSelect negativity occurred in 3 of 31 HSV-1-infected subjects (10%) and in 2 of 82 HSV-2-infected subjects (2%). Conclusion Seroconversion to HSV-2 was determined faster by HerpeSelect than by WB.

Frequent and Asymptomatic Oropharyngeal Shedding of Human Herpesvirus 8 among Immunocompetent Men

BACKGROUND Little is known about the clinical and virologic manifestations of human herpesvirus (HHV)-8 infection in immunocompetent persons in the absence of malignancy. METHODS A total of 46 human immunodeficiency virus-negative, HHV-8-seropositive men collected saliva daily, and 25 recorded 15 common symptoms daily (gastrointestinal, constitutional, and oropharyngeal) and absences from work or school. Quantitative polymerase chain reaction measured HHV-8 DNA in saliva. RESULTS Some 44 (96%) of 46 men reported having sex with men (MSM). Of the 44 MSM, 27 (61%) had HHV-8 detected in saliva on > or = 1 day; heterosexual men also shed HHV-8. In analyses restricted to MSM, HHV-8 DNA was detected on 636 (22%) of 2897 days. Among MSM with HHV-8 detected in saliva, the median rate was 20% (range, 1%-100%), with 30% shedding on > 50% of days, and the median quantity was 4.5 log10 copies/mL (range, 2.0-7.3 log10 copies/mL). The quantity of HHV-8 shed was lower in nonwhites (P<.001) and younger participants (P=.03). The frequency of HHV-8 detection and quantity were correlated (r=0.62; P<.001). Symptoms were reported on 10 (9%) of 114 days when HHV-8 was present, compared with 78 (9%) of 830 days without (odds ratio, 0.93 [95% confidence interval, 0.30-2.88]; P=.9). CONCLUSIONS HHV-8 is detected frequently and intermittently in the saliva of chronically infected immunocompetent MSM, but this infection is asymptomatic.