Terri Warren

Reactivation of Genital Herpes Simplex Virus Type 2 Infection in Asymptomatic Seropositive Persons

BACKGROUND Most persons who have serologic evidence of infection with herpes simplex virus (HSV) type 2 (HSV-2) are asymptomatic. Historically, it has been assumed that these persons have less frequent viral reactivation than those with symptomatic infection. METHODS We conducted a prospective study to investigate genital shedding of HSV among 53 subjects who had antibodies to HSV-2 but who reported having no history of genital herpes, and we compared their patterns of viral shedding with those in a similar cohort of 90 subjects with symptomatic HSV-2 infection. Genital secretions of the subjects in both groups were sampled daily and cultured for HSV for a median of 94 days. RESULTS HSV was isolated from the genital mucosa in 38 of the 53 HSV-2-seropositive subjects (72 percent) who reported no history of genital herpes, and HSV DNA was detected by the polymerase-chain-reaction assay in cultures prepared from genital mucosal swabs in 6 additional subjects. The rate of subclinical shedding of HSV in the subjects with no reported history of genital herpes was similar to that in the subjects with such a history (3.0 percent vs. 2.7 percent). Of the 53 subjects who had no reported history of genital herpes, 33 (62 percent) subsequently reported having typical herpetic lesions; the duration of their recurrences in these subjects was shorter (median, three days vs. five days; P<0.001) and the frequency lower (median, 3.0 per year vs. 8.2 per year; P<0.001) than in the 90 subjects with previously diagnosed symptomatic infection. Only 1 of these 53 subjects had no clinical or virologic evidence of HSV infection. CONCLUSIONS Seropositivity for HSV-2 is associated with viral shedding in the genital tract, even in subjects with no reported history of genital herpes.

Genital Shedding of Herpes Simplex Virus Among Symptomatic and Asymptomatic Persons with HSV-2 Infection

CONTEXT Since herpes simplex virus type 2 (HSV-2) antibody tests have become commercially available, an increasing number of persons have learned that they have genital herpes through serologic testing. The course of natural history of HSV-2 in asymptomatic, seropositive persons is uncertain. OBJECTIVE To evaluate the virologic and clinical course of HSV genital shedding among individuals with symptomatic and asymptomatic HSV-2 infection. DESIGN, SETTING, AND PARTICIPANTS Cohort of 498 immunocompetent HSV-2-seropositive persons enrolled in prospective studies of genital HSV shedding at the University of Washington Virology Research Clinic, Seattle, and Westover Heights Clinic, Portland, Oregon, between March 1992 and April 2008. Each participant obtained daily self-collected swabs of genital secretions for at least 30 days. MAIN OUTCOME MEASURE The rate of viral shedding measured by quantitative real-time fluorescence polymerase chain reaction for HSV DNA from genital swabs. RESULTS Herpes simplex virus type 2 was detected on 4753 of 23,683 days (20.1%; 95% confidence interval [CI], 18.3%-22.0%) in 410 persons with symptomatic genital HSV-2 infection compared with 519 of 5070 days (10.2%; 95% CI, 7.7%-13.6%) in 88 persons with asymptomatic infection (P < .001). Subclinical shedding rates were higher in persons with symptomatic infection compared with asymptomatic infection (2708 of 20,735 days [13.1%; 95% CI, 11.5%-14.6%) vs 434 of 4929 days [8.8%; 95% CI, 6.3%-11.5%]) (P < .001). However, the amount of HSV detected during subclinical shedding episodes was similar (median, 4.3 [interquartile range, 3.1-5.6] log(10) copies in the symptomatic infection group vs 4.2 [interquartile range, 2.9-5.5] in the asymptomatic infection group, P = .27). Days with lesions accounted for 2045 of 4753 days (43.0%; 95% CI, 39.8%-46.5%) with genital viral shedding among persons with symptomatic genital HSV-2 infection compared with 85 of 519 days (16.4%; 95% CI, 11.2%-23.9%) among persons with asymptomatic infection (P < .001). CONCLUSION Persons with asymptomatic HSV-2 infection shed virus in the genital tract less frequently than persons with symptomatic infection, but much of the difference is attributable to less frequent genital lesions because lesions are accompanied by frequent viral shedding.

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.

From the NIH: proceedings of a workshop on the importance of self-obtained vaginal specimens for detection of sexually transmitted infections.

On June 27, 2006, the NIH conducted a workshop to review published data and current field practices supporting the use of self-obtained vaginal swabs (SOVs) as specimens for diagnosis of sexually transmitted infections (STIs). The workshop also explored the design of studies that could support FDA clearance of SOVs for STI testing, particularly for specimens collected in nonclinical settings including patients’ homes. This report summarizes the workshop findings and recommendations. Participants concluded that self-obtained vaginal swabs are well accepted by women of all ages and that SOVs perform as well as or better than other specimen types for Chlamydia trachomatis and Neisseria gonorrhoeae detection using transcription-mediated amplification. In addition, workshop participants recommended the validation of SOV testing by public health practitioners and manufacturers of STI diagnostic tests to expedite incorporation of SOVs as a diagnostic option in clinical and nonclinical settings for Chlamydia trachomatis and Neisseria gonorrhoeae testing. Similarly, SOVs should be explored for use in the diagnosis of other sexually transmitted pathogens.

Topical resiquimod 0.01% gel decreases herpes simplex virus type 2 genital shedding: A randomized, controlled trial

BACKGROUND Resiquimod, an investigational immune response modifier and Toll-like receptor (TLR) 7 and 8 agonist, stimulates production of cytokines that promote an antigen-specific T helper type 1 (Th1)--acquired immune response. In animal models, induction of Th1-specific responses modifies experimental herpes simplex virus (HSV) infection. METHODS We conducted a randomized, double-blind, vehicle-controlled trial to assess the efficacy of resiquimod 0.01% gel for reducing human anogenital HSV-2 mucosal reactivation. Adults with genital HSV-2 applied resiquimod or vehicle topically to herpes lesions 2 times weekly for 3 weeks and then collected daily anogenital swabs for 60 days for HSV DNA polymerase chain reaction. Recurrences during the subsequent 7 months were treated with study gel. During the final treatment-free 60 days, participants again collected daily swabs to assess shedding. RESULTS The median lesion and shedding rates were lower for resiquimod compared with vehicle recipients during the initial sampling period (10% vs. 16% [P=.03] and 10% vs. 17% [P=.08], respectively) and during the final sampling period (3% vs. 22% [P<.001] and 10% vs. 26% [P=.009], respectively). Resiquimod did not influence recurrence length. CONCLUSIONS These findings suggest that the immunological control of HSV-2 reactivation and lesion clearance may differ and that TLR7 and TLR8 agonists can reduce the frequency of mucosal HSV-2 reactivation.

Valacyclovir for the Suppression of Recurrent Genital Herpes in Human Immunodeficiency Virus–Infected Subjects

To determine the efficacy and safety of valacyclovir (500 mg twice daily) for the suppression of recurrent genital herpes simplex virus infections in human immunodeficiency virus (HIV)-infected subjects, a randomized, double-blind, placebo-controlled, multicenter international trial was conducted. A total of 293 HIV-seropositive subjects receiving antiretroviral therapy were enrolled. The proportion of subjects who did not have a recurrence of genital herpes at 6 months was 65% among valacyclovir recipients versus 26% among placebo recipients (relative risk, 2.5; 95% confidence interval, 1.8-3.5). The time to first genital herpes recurrence was significantly shorter in the placebo group (median, 59 days) than in the valacyclovir group (median, >180 days). Valacyclovir was well tolerated; the incidence of adverse events for the 2 treatment groups was similar when the duration of treatment was considered. There were no episodes of thrombotic microangiopathy. Valacyclovir was safe and effective for the suppression of recurrent genital herpes infection in HIV-infected individuals.

Genital Shedding of Herpes Simplex Virus among Men

Epidemiologic studies suggest that most sexual transmission of genital herpes occurs when persons shed virus but lack lesions. This study assessed 79 men (63 with a history of genital herpes simplex virus [HSV] type 2 infection, 5 with a history of genital HSV-1 infection, and 11 with HSV-2 antibodies but no history of genital herpes) and obtained daily swabs for viral culture. HSV was isolated at least once from 60 (81%) HSV-2-seropositive men. The total viral shedding rate in HSV-2-seropositive men was 5%; the subclinical shedding rate was 2.2%. Of 11 HSV-2-seropositive men without a genital herpes history, 7 recognized typical recurrences and HSV was detected in 10. The shedding rate among men with genital HSV-2 was significantly higher than among men with genital HSV-1 infection (odds ratio, 4.4; 95% confidence interval, 1.2-15.3). The frequency of viral shedding in men with genital herpes appears comparable with that in women.

Helicase-primase inhibitor pritelivir for HSV-2 infection

BACKGROUND Pritelivir, an inhibitor of the viral helicase-primase complex, exhibits antiviral activity in vitro and in animal models of herpes simplex virus (HSV) infection. We tested the efficacy and safety of pritelivir in otherwise healthy persons with genital HSV-2 infection. METHODS We randomly assigned 156 HSV-2-positive persons with a history of genital herpes to receive one of four doses of oral pritelivir (5, 25, or 75 mg daily, or 400 mg weekly) or placebo for 28 days. Participants obtained daily swabs from the genital area for HSV-2 testing, which was performed with a polymerase-chain-reaction assay. Participants also maintained a diary of genital signs and symptoms. The primary end point was the rate of genital HSV shedding. RESULTS HSV shedding among placebo recipients was detected on 16.6% of days; shedding among pritelivir recipients was detected on 18.2% of days among those receiving 5 mg daily, 9.3% of days among those receiving 25 mg daily, 2.1% of days among those receiving 75 mg daily, and 5.3% of days among those receiving 400 mg weekly. The relative risk of viral shedding with pritelivir, as compared with placebo, was 1.11 (95% confidence interval [CI], 0.65 to 1.87) with the 5-mg daily dose, 0.57 (95% CI, 0.31 to 1.03) with the 25-mg daily dose, 0.13 (95% CI, 0.04 to 0.38) with the 75-mg daily dose, and 0.32 (95% CI, 0.17 to 0.59) with the 400-mg weekly dose. The percentage of days with genital lesions was also significantly reduced, from 9.0% in the placebo group to 1.2% in both the group receiving 75 mg of pritelivir daily (relative risk, 0.13; 95% CI, 0.02 to 0.70) and the group receiving 400 mg weekly (relative risk, 0.13; 95% CI, 0.03 to 0.52). The rate of adverse events was similar in all groups. CONCLUSIONS Pritelivir reduced the rates of genital HSV shedding and days with lesions in a dose-dependent manner in otherwise healthy men and women with genital herpes. (Funded by AiCuris; ClinicalTrials.gov number, NCT01047540.).

Comparative efficacy of famciclovir and valacyclovir for suppression of recurrent genital herpes and viral shedding.

Background: Daily antiviral therapy with famciclovir and valacyclovir has been shown to be effective in reducing both symptomatic and asymptomatic reactivation of herpes simplex virus type 2 (HSV-2) when compared to placebo. However, few comparative studies between the 2 antivirals have been performed. Objectives: To compare the clinical and virologic effects of famciclovir and valacyclovir administered as daily suppressive therapy for persons with genital herpes. Study Design: Two randomized, double-blind, placebo-controlled studies comparing daily famciclovir 250 mg bid with valacyclovir 500 mg qd were performed. Study 1 randomized 320 participants and compared the clinical effect of the drugs given for 16 weeks, and study 2 enrolled 70 HSV-2 seropositive subjects and compared the virologic effect of the drugs given for 10 weeks. Results: In study 1, the time to first recurrence was similar in famciclovir and valacyclovir recipients, hazard ratio (HR) 1.17 (95% CI, 0.78–1.76), but time to first virologically confirmed recurrence was shorter among famciclovir recipients, HR = 2.15 (95% CI, 1.00–4.60). In study 2, HSV was detected on 3.2% of days among famciclovir recipients and 1.3% of days among valacyclovir recipients, relative risk 2.33 (95% CI, 1.18–4.89). Conclusion: Valacyclovir appear to be somewhat better than famciclovir for suppression of genital herpes and associated shedding. Further comparative trials of antiviral drugs for various indications should be performed as acyclovir and penciclovir appear to have different ability to abrogate HSV reactivation.

Association of Major Histocompatibility Complex Determinants with the Development of Symptomatic and Asymptomatic Genital Herpes Simplex Virus Type 2 Infections

The clinical spectrum of herpes simplex virus (HSV) infections, ranging from asymptomatic to frequently distressing outbreaks, suggests that there may be immunologic determinants of disease severity that are associated with human leukocyte antigen (HLA) expression. A controlled, prospective study identified several major histocompatibility complex (MHC) class I and II antigens whose frequencies are associated with HSV-2 infection or with frequent symptomatic genital recurrences. Previous studies were hampered by the inability to serologically identify patients with asymptomatic HSV-2 infection. Clinical evaluation and Western blot assay were used to identify 3 subject cohorts: 1 with no prior HSV infections, 1 with HSV-2 antibodies but no recognized symptoms, and 1 with HSV-2 antibodies and frequent genital recurrences. Statistical comparisons of HLA frequencies among these cohorts showed associations of HLA-B27 and -Cw2 with symptomatic disease. Also, HLA-Cw4 was significantly associated with HSV-2 infection. These associations indicate that immunologic factors linked to the MHC influence the risk of HSV-2 infection and disease expression.