Effect of Valacyclovir on Viral Shedding in Immunocompetent Patients With Recurrent Herpes Simplex Virus 2 Genital Herpes: A US-Based Randomized, Double-Blind, Placebo-Controlled Clinical Trial
Kenneth H. FifeTerri WarrenRené FerreraDouglas YoungScott E. JustusCatherine K. HeitmanScott Burroughs
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Viral Shedding
Subclinical infection
Objective: To assess the effect of the antiviral drug acyclovir on the frequency of subclinical shedding of herpes simplex virus (HSV) in the genital tract. Design: A double-blind, placebo-controlled, crossover clinical trial. Setting: A university-based virology research clinic. Patients: 34 women with herpes simplex virus type 2 (HSV-2) antibody only and genital herpes of less than 2 years' duration. Intervention: Participants were randomly assigned to receive either acyclovir, 400 mg twice daily for 70 days, followed by a 14-day washout period, and then placebo for 70 days, or the study medications in the reverse order. Measurements: Women collected daily genital swabs of the vulvar, cervicovaginal, and perianal areas for HSV culture, maintained a diary of genital lesions, and were examined at the time of recurrences. Results: In an intent-to-treat analysis of the initial treatment period, 15 of the 17 women who received placebo and 3 of the 17 women who received acyclovir had at least 1 day of subclinical shedding (P < 0.001). Among the participants who received placebo, subclinical shedding occurred on 64 of 928 (6.9%) days compared with 3 of 1057 (0.3%) days among the participants who received acyclovir (P < 0.001). The relative risk for subclinical shedding was 0.09 (95% CI, 0.03 to 0.35) for the women who received acyclovir compared with the women who received placebo. In a paired analysis of 26 women who completed both arms of the study, acyclovir therapy was associated with a decrease in the frequency of subclinical shedding; subclinical shedding occurred on 83 of 1439 (5.8%) days with placebo, and on 6 of 1611 (0.37%) days with acyclovir (P < 0.001)—a 94% reduction. The frequency of subclinical shedding was reduced at all anatomic sites and in all patients. Conclusions: Daily therapy with oral acyclovir suppresses subclinical shedding of HSV-2 in the genital tract, suggesting that studies to evaluate the use of acyclovir in preventing HSV-2 transmission are warranted.
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Background Influenza viral shedding studies provide fundamental information for preventive strategies and modelling exercises. We conducted a prospective household study to investigate viral shedding in seasonal and pandemic influenza between 2007 and 2011 in Berlin and Munich, Germany. Methods Study physicians recruited index patients and their household members. Serial nasal specimens were obtained from all household members over at least eight days and tested quantitatively by qRT-PCR for the influenza virus (sub)type of the index patient. A subset of samples was also tested by viral culture. Symptoms were recorded daily. Results We recruited 122 index patients and 320 household contacts, of which 67 became secondary household cases. Among all 189 influenza cases, 12 were infected with seasonal/prepandemic influenza A(H1N1), 19 with A(H3N2), 60 with influenza B, and 98 with A(H1N1)pdm09. Nine (14%) of 65 non-vaccinated secondary cases were asymptomatic/subclinical (0 (0%) of 21 children, 9 (21%) of 44 adults; p = 0.03). Viral load among patients with influenza-like illness (ILI) peaked on illness days 1, 2 or 3 for all (sub)types and declined steadily until days 7–9. Clinical symptom scores roughly paralleled viral shedding dynamics. On the first day prior to symptom onset 30% (12/40) of specimens were positive. Viral load in 6 asymptomatic/subclinical patients was similar to that in ILI-patients. Duration of infectiousness as measured by viral culture lasted approximately until illness days 4–6. Viral load did not seem to be influenced by antiviral therapy, age or vaccination status. Conclusion Asymptomatic/subclinical infections occur infrequently, but may be associated with substantial amounts of viral shedding. Presymptomatic shedding may arise in one third of cases, and shedding characteristics appear to be independent of (seasonal or pandemic) (sub)type, age, antiviral therapy or vaccination; however the power to find moderate differences was limited.
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Background. Patients with newly acquired genital herpes simplex virus 2 (HSV-2) infection have virus frequently detected at the genital mucosa. Rates of genital shedding initially decrease over time after infection, but data on long-term viral shedding are lacking. Methods. For this study, 377 healthy adults with history of symptomatic genital HSV-2 infection collected anogenital swabs for HSV-2 DNA polymerase chain reaction for at least 30 consecutive days. Results. Time since first genital herpes episode was significantly associated with reduced genital shedding. Total HSV shedding occurred on 33.6% of days in participants <1 year, 20.6% in those 1–9 years, and 16.7% in those ≥10 years from first episode. Subclinical HSV shedding occurred on 26.2% of days among participants <1 year, 13.1% in those 1–9 years, and 9.3% in those ≥10 years from first episode. On days with HSV detection, mean quantity was 4.9 log10 copies/mL for those <1 year, 4.7 log10 copies/mL among those 1–9 years, and 4.6 log10 copies/mL among those ≥10 years since first episode. Conclusions. Rates of total and subclinical HSV-2 shedding decrease after the first year following the initial clinical episode. However, viral shedding persists at high rates and copy numbers years after infection, and therefore may pose continued risk of HSV-2 transmission to sexual partners.
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Antigen (Ag)-specific immune responses to chronic infections, such as herpes simplex virus type-2 (HSV), in HIV/HSV co-infected persons may sustain HIV tissue reservoirs by promoting T-cell proliferation but are poorly studied in women on antiretroviral therapy (ART). Mixed anogenital swabs and cervical secretions were self-collected by nine HIV/HSV-2 co-infected women during ART for 28 days to establish subclinical HSV DNA shedding rates and detection of HIV RNA by real-time PCR. Typical herpes lesion site (TLSB) and cervical biopsies were collected at the end of the daily sampling period. Nucleic acids (NA) isolated from biopsies had HIV quantified, HIV envC2-V5 single-genome amplification (SGA), and TCR repertoires assessed. Women had a median CD4 count of 537 cells/uL ((IQR): 483-741) at enrollment and HIV plasma viral loads <40copies/mL. HSV DNA was detected on 12% of days (IQR: 2-25%) from anogenital specimens. Frequent subclinical HSV DNA shedding was associated with increased HIV DNA tissue concentrations and increased divergence from the most recent common ancestor (MRCA), an indicator of HIV replication. Distinct predominant TCR clones were detected in cervix and TLSB in a woman with frequent HSV DNA shedding, with mixing of minor variants between her tissues; more limited TCR repertoire mixing was observed in two women with less frequent subclinical HSV DNA shedding. Subclinical HSV shedding in HIV/HSV co-infected women during ART may sustain HIV tissue reservoirs via Ag-exposure or HIV replication. This study provides evidence supporting further study of interventions targeting suppression of Ag-specific immune responses as a component of HIV cure strategies.IMPORTANCE Persons with HIV infection are frequently co-infected with chronic herpes viruses, which periodically replicate and produce viable herpes virions, particularly in anogenital and cervical tissues. Persistent protein expression results in proliferation of CD8+ and CD4+ T cells; the latter could potentially expand and sustain HIV tissue reservoirs. We found HSV genital shedding rates were positively correlated with HIV DNA concentrations and HIV divergence from ancestral sequences in tissues. Our work suggests that immune responses to common co-infections, such as herpes viruses, may sustain HIV tissue reservoirs during suppressive ART, suggesting future cure strategies should study interventions to suppress replication or reactivation of chronic herpes infections.
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Abstract Primary herpes simplex virus 1 (HSV‐1) and varicella‐zoster virus (VZV) infection leads to a life‐long latent infection of ganglia innervating the oral mucosa. HSV‐1 and VZV reactivation is more common in immunocompromised individuals and may result in viral shedding in saliva. We determined the kinetics and quantity of oral HSV‐1 and VZV shedding in HSV‐1 and VZV seropositive individuals infected with HIV and to assess whether HSV‐1 shedding involves reactivation of the same strain intra‐individually. HSV‐1 and VZV shedding was determined by real‐time PCR of sequential daily oral swabs (n = 715) collected for a median period of 31 days from 22 individuals infected with HIV. HSV‐1 was genotyped by sequencing the viral thymidine kinase gene. Herpesvirus shedding was detected in 18 of 22 participants. Shedding of HSV‐1 occurred frequently, on 14.3% of days, whereas solely VZV shedding was very rare. Two participants shed VZV. The median HSV‐1 load was higher compared to VZV. HSV‐1 DNA positive swabs clustered into 34 shedding episodes with a median duration of 2 days. The prevalence, duration and viral load of herpesvirus shedding did not correlate with CD4 counts and HIV load. The genotypes of the HSV‐1 viruses shed were identical between and within shedding episodes of the same person, but were different between individuals. One‐third of the individuals shed an HSV‐1 strain potentially refractory to acyclovir therapy. Compared to HSV‐1, oral VZV shedding is rare in individuals infected with HIV. Recurrent oral HSV‐1 shedding is likely due to reactivation of the same latent HSV‐1 strain. J. Med. Virol. 85:1669–1677, 2013 . © 2013 Wiley Periodicals, Inc.
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Herpes Labialis
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Cytomegalovirus (CMV) almost universally infects persons with HIV (PWH), and it is a driver of persistent inflammation and HIV persistence. The mechanisms underlying the association between CMV (and possibly other herpesviruses) and HIV persistence are unclear. Serially collected blood samples were obtained from men who have sex with men (MSM) who started antiretroviral therapy (ART) within 1 year of their estimated date of HIV infection (EDI). Total CMV and Epstein-Barr virus (EBV) DNA were quantified in peripheral blood mononuclear cells by droplet digital PCR (ddPCR). Deep sequencing of the HIV DNA partial
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Herpes Simplex Virus Shedding and Plasma Human Immunodeficiency Virus RNA Levels in Coinfected Women
Asymptomatic herpes simplex virus (HSV) shedding was described in a cohort of human immunodeficiency virus (HIV)-infected women, and the association of HSV shedding with changes in plasma HIV RNA load was investigated. Genital, rectal, and oral swabs were obtained daily during a 4-week period for polymerase chain reaction and culture, and concomitant plasma specimens were drawn 3 times weekly for determination of HIV RNA load. During the study, 70% and 79% of subjects shed HSV from the oral cavity and genital area, respectively. Shedding of HSV occurred for a mean of 3.2 days for oral shedding and 5.4 days for genital shedding. Mean plasma HIV RNA loads during periods of HSV shedding and nonshedding and for periods 3 days after the cessation of shedding were compared; no significant differences were found (P=.74). In women who shed HSV, as evaluated by detection of virus, plasma HIV RNA load did not fluctuate with HSV shedding.
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