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Genital herpes, caused by herpes simplex virus (HSV) type 1 or type 2, is a prevalent sexually transmitted infection (STI). Given that HSV is an incurable infection, there are important concerns about appropriate use of diagnostic tools, management of infection, prevention of transmission to sexual partners, and appropriate counseling. In preparation for updating the Centers for Disease Control and Prevention (CDC) STI treatment guidelines, key questions for management of genital herpes infection were developed with a panel of experts. To answer these questions, a systematic literature review was performed, with tables of evidence including articles that would change guidance assembled. These data were used to inform recommendations in the 2021 CDC STI treatment guidelines.

BackgroundIn women, genital herpes simplex virus type 2 (HSV-2) infection is associated with increased risk for recurrent bacterial vaginosis (BV), but causal relationships are unclear.MethodsWomen with a self-reported history of BV and HSV-2 seropositivity self-collected vaginal and anogenital swabs for 2 nonconsecutive 28-day periods, in the absence or presence of valacyclovir suppressive therapy (500 mg daily). HSV polymerase chain reaction was performed on anogenital swabs; vaginal swabs were used for assessment of BV by Nugent score and quantification of vaginal microbiota. Days with BV, defined by Nugent score ≥7, were compared during the observational period and valacyclovir treatment.ResultsForty-one women collected swabs for a median of 28 days (range, 20–32 days) each study period. The HSV-2 shedding rate decreased from 109 of 1126 days (9.7%) presuppression to 6 of 1125 days (0.05%) during valacyclovir (rate ratio [RR], 0.06 [95% confidence interval {CI}, .02–.13]). BV occurred on 343 of 1103 days (31.1%) during observation and 302 of 1091 days (27.7%) during valacyclovir (RR, 0.90 [95% CI, .68–1.20]). The median per-person Nugent score was 3.8 during observation and 4.0 during valacyclovir. Average log10 concentrations of vaginal bacterial species did not change significantly during valacyclovir treatment.ConclusionsShort-term HSV-2 suppression with valacyclovir did not significantly affect the Nugent score or the vaginal microbiome despite potent suppression of HSV-2 shedding.

Background There is significant unmet need of novel therapeutics for Alzheimer’s Disease (AD). A growing body of evidence suggests a role for herpesviruses in the development of AD and reduced risk of AD among patients receiving antivirals. We investigated the association between herpes simplex virus type 1 (HSV-1) diagnoses, antiviral use, and AD using real-world data. Methods In a matched case-control study, AD patients aged ≥ 50 years diagnosed between 2006 and 2021 were identified from IQVIA PharMetrics Plus® claims database using International Classification of Disease (ICD) codes (ICD 9 331.0; ICD 10 G30.x). Controls without any history of neurological disorders were matched in a 1:1 ratio with AD subjects on age, sex, region, database entry year, and healthcare visit numbers. HSV-1 diagnoses were identified using relevant ICD codes. Conditional logistic regression was used to evaluate the association between HSV-1 and AD. The association between antiviral use (e.g., acyclovir, famciclovir, valacyclovir) and AD was assessed by multivariate Cox proportional hazards model in patients with HSV-1 diagnosis. Results The study included 344,628 AD patient-control pairs. Most patients were female (65%) with a mean age of 73 (± 5) years. AD patients had more comorbidities (50% vs. 45% with ≥ 2 comorbidities) and shorter follow up time (median of 33 vs. 48 months) when compared to controls. History of HSV-1 diagnosis was present in 1507 (0.44%) AD patients vs. 823 (0.24%) controls. HSV-1 diagnosis was associated with AD (adjusted odds ratio [OR] 1.80; 95% confidence interval [CI] 1.65-1.96). In a stratified analysis, this association was more pronounced in the older age group (75+ years: OR 2.10, 95% CI 1.88-2.35; 71-74 years: OR 1.51, 95% CI 1.27-1.80; 50-70 years: OR 1.14, 95% CI 0.91-1.44). Patients with HSV-1 who used antivirals were less likely to have AD compared to those who did not use antivirals (adjusted hazard ratio 0.83, 95% CI 0.74-0.92). Similar results were observed when the analysis was extended to include all patients with AD-related dementia and matched controls. The association between herpes simplex virus type 1 (HSV-1) and Alzheimer’s Disease (AD)/AD-related Dementia(ADRD) Conclusion Findings from this large real-world data study is consistent with emerging literature on HSV-1 and risk of AD and the possible protective role of antiviral drugs. Disclosures Luke Liu, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Christine Johnston, MD, MPH, AbbVie: Advisor/Consultant|Gilead: Grant/Research Support|GSK: Advisor/Consultant Simon P. Fletcher, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Shahed Iqbal, PhD, MBBS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds.

Background In the United States, booster vaccines for persons 18 years and older were approved under Emergency Use Authorization (EUA) in September 2021. Waning immunity following SARS-CoV-2 primary vaccination series led to recommendations for booster vaccination. Emerging data suggest that providing boosters different from the primary series (heterologous vaccination) may provide a broader immune response than boosting with the same vaccine (homologous vaccination). CDC recommended the Pfizer-BioNTech BNT162b2 30-μg mRNA booster vaccine to clinical trial participants >6 months post study vaccines if not planned for boosting within the study. Methods We conducted an observational study of persons who received 2 doses of Novavax protein-based NVX-CoV2373 vaccine 21 days apart, in a Phase 3 clinical trial, and subsequently received a Pfizer BNT162b2 booster vaccine under EUA. Serologic assays, including the Roche anti-nucleocapsid (N) IgG and anti-Spike (S) IgG, were performed on blood collected pre-booster (D0) and on days 18 (D18) and 34 (D34) post-booster vaccine. The anti-S IgG geometric means (GMTs) were calculated over study time points. Wilcoxon signed rank test was performed to compare anti-S IgG response between D0 and D18 and D0 and D34. Results Of 26 participants enrolled, 16 (57%) were women; the median age was 47 years (range 29-67). Roche anti-N antibodies were negative at all visits. Time from second NVX-CoV2373 vaccine to Pfizer BNT162b2 booster was a median of 10.4 months in 54% of participants and 7 months in 46% of participants. Anti-S IgG GMTs were 222 BAU/ml D0, 24,723 BAU/ml D18, and 24,584 BAU/ml D34 (p< 0.0001 for comparisons of D0 with D18 & D34). Overall, participants tolerated the booster vaccine without significant adverse events. Cell mediated immunity and D614G pseudovirus neutralizing antibody assays are in progress. Figure 1.Anti-S IgG titers pre and post-booster vaccine 16 participants included with all 3-time study time points for comparison. Conclusion Two doses of NVX-CoV2373 vaccine followed by the Pfizer BNT162b2 booster vaccine resulted in ∼100-fold increase in anti-S IgG against SARS-CoV-2. No participant had evidence of prior SARS-CoV-2 infection by anti-N IgG. Two doses of NVX-CoV2373 vaccine followed by one dose of Pfizer BNT162b2 vaccine is an effective and well-tolerated regimen for boosting anti-S IgG against SARS-CoV-2. Disclosures Christine Johnston, MD, MPH, AbbVie: Advisor/Consultant|Gilead: Grant/Research Support|GSK: Advisor/Consultant Kerry J. Laing, PhD, Curevo Vaccine: Advisor/Consultant|MaxHealth Biotechnology: Advisor/Consultant|Sanofi Pasteur: Grant/Research Support David M. Koelle, MD, Curevo Vaccines: Advisor/Consultant|MaxHealth LLC: Advisor/Consultant|Oxford Immunotec: gift of reagents|Sanofi: Grant/Research Support|Sensei: Grant/Research Support Alexander L. Greninger, MD, PhD, Abbott: Contract Testing|Cepheid: Contract Testing|Gilead: Grant/Research Support|Gilead: Contract Testing|Hologic: Contract Testing|Merck: Grant/Research Support|Novavax: Contract Testing|Pfizer: Contract Testing Anna Wald, MD, MPH, Aicuris: Advisor/Consultant|Auritec: Advisor/Consultant|Crozet: Advisor/Consultant|DXNow: Advisor/Consultant|GSK: Grant/Research Support|Merck: Advisor/Consultant|sanofi: Grant/Research Support|VIR: Advisor/Consultant|X-Vax: Advisor/Consultant.

Background Prevention interventions for coronavirus disease (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), are currently limited to non-pharmaceutical strategies. Observational and laboratory data suggested that hydroxychloroquine (HCQ) had biologic activity against SARS-CoV-2. A blinded trial of HCQ in persons with confirmed exposure and virologic and clinical endpoints is needed. Methods We conducted a national, householdrandomized, double-blind, controlled trial of HCQ post-exposure prophylaxis, with entirely remote study procedures. We enrolled close contacts exposed to persons with SARS-CoV-2 infection in the past 96 hours. Participants were randomized to either HCQ (400 mg daily for three days followed by 200 mg daily for eleven days) or ascorbic acid (500 mg followed by 250 mg daily), as a placebo-equivalent control. Participants self-collected mid-turbinate swabs daily (days 1–14) for SARS-CoV-2 PCR testing. The primary outcome was PCR-confirmed, incident SARS-CoV-2 infection among persons SARS-CoV-2 negative at enrollment. Symptoms were assessed using criteria from the US CDC. Results From March-August 2020, 623 households were randomized; 311 households (381 participants) to the HCQ group and 312 households (400 participants) to the control group. Ninety- one percent of participants were retained up to day 14 and 9,595 of 10,588 (91%) of swabs were tested. Among participants who were SARS-CoV-2 negative at baseline (n=626/781, 80%), the cumulative incidence of SARS-CoV-2 was 14.5% (95% CI: 11.6–17.4) and the cumulative incidence of COVID-19 symptoms was 11.6% (95% CI: 8.9–14.2) at day 14. By day 14, there was no difference between the HCQ group and control group in SARS-CoV-2 acquisition (46 vs. 43 events, aHR= 0.99, 95% CI 0.64–1.52, p=0.95) or symptomatic disease (40 vs. 32 events, aHR= 1.23, 95% CI: 0.76–1.99, p=0.40). The adverse event frequency was similar between groups (59 [15.5%] participants in the HCQ and 45 [11.3%] in the control group, p=0.092). Cumulative incidence of RT-PCR-confirmed SARS-CoV-2 infection among close contacts of diagnosed cases, by study group Conclusion This randomized, double-blind, controlled trial among persons with recent exposure and high incidence of SAR-CoV2 provides strong evidence that HCQ post-exposure prophylaxis did not prevent SARS-CoV-2 infection or modify clinical disease. Disclosures Anna Bershteyn, PhD, Bill and Melinda Gates Foundation (Grant/Research Support)Gates Ventures (Consultant)National Institutes of Health (Grant/Research Support) Kristopher M. Paolino, MD, MTM&H, Nothing to disclose Raphael J. Landovitz, MD, MSc, Gilead (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Roche (Other Financial or Material Support, Speaker Honoraria) Anna Wald, MD, MPH, Aicuris (Individual(s) Involved: Self): Consultant; Gilead (Individual(s) Involved: Self): Consultant; GlaxoSmithKline (Individual(s) Involved: Self): Scientific Research Study Investigator; Merck (Individual(s) Involved: Self): DSMB participation; provision of vaccine for a study, Other Financial or Material Support; Sanofi (Individual(s) Involved: Self): Scientific Research Study Investigator; X-Vax (Individual(s) Involved: Self): Consultant Helen Y. Chu, MD MPH, Cepheid (Grant/Research Support)Ellume (Grant/Research Support)Glaxo Smith Kline (Consultant)Merck (Consultant)Sanofi-Pasteur (Grant/Research Support)

As coronavirus disease 2019 cases and deaths continue to expand globally, there is an urgent need to develop, test, and approve effective antiviral therapies. Currently, a majority of clinical trials are evaluating therapies in patients who are already hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infection. Given that the median time between development of symptoms and need for hospitalization is 1 week, a golden opportunity to intervene early is being missed. Indeed, for many other viral infections, early treatment soon after development of symptoms is associated with decreased mortality, lower hospitalization rates, and lower likelihood of transmission to others. In this study, we advocate for randomized, double-blind, placebo controlled, clinical trials to evaluate promising agents early during SARS CoV-2 infection.

Background. The ubiquitous human pathogens, herpes simplex virus (HSV)-1 and HSV-2, are distinct viral species that diverged approximately 6 million years ago. At least 4 small, ancient HSV-1 × HSV-2 interspecies recombination events have affected the HSV-2 genome, with recombinants and nonrecombinants at each locus circulating today. However, it is unknown whether interspecies recombination can affect other loci and whether new recombinants continue to be generated. Methods. Using 255 newly sequenced and 230 existing HSV genome sequences, we comprehensively assessed interspecies recombination in HSV. Results. Our findings show that the sizes and locations of interspecies recombination events in HSV-2 are significantly more variable than previously appreciated and that they can impact species-specific T-cell recognition of HSV. Conclusions. We describe 2 large (>5 kb) recombination events, one of which arose in its current host, demonstrating that interspecies recombination continues to occur today. These results raise concerns about the use of live-attenuated HSV-2 vaccines in high HSV-1 prevalence areas.

Background Tenofovir is a potent anti-human immunodeficiency virus (HIV) agent that decreased risk of herpes simplex virus type 2 (HSV-2) acquisition in HIV pre-exposure prophylaxis trials. Whether tenofovir has utility in established HSV-2 disease is unclear. Methods We randomized immunocompetent women with symptomatic HSV-2 infection to oral tenofovir disoproxil fumarate (TDF)/placebo vaginal gel, oral placebo/tenofovir (TFV) vaginal gel, or double placebo (ratio 2:2:1) in a one-way cross-over trial. Women collected genital swabs twice daily for HSV PCR during 4-week lead-in and 5-week treatment phases. The primary intent-to-treat end point was within-person comparison of genital HSV shedding and lesion rates. Results 64 women completed the lead-in phase and were randomized. Neither TDF nor TFV gel decreased overall shedding or lesion rate in the primary analysis; TFV gel decreased quantity of HSV DNA by -0.50 (-0.86-0.13) log10 copies/mL. In the per-protocol analysis, TDF reduced shedding (relative risk [RR] = 0.74, P = .006) and lesion rates (RR = 0.75, P = .032); quantity of virus shed decreased by 0.41 log10 copies/mL. Conclusions Oral TDF modestly decreased HSV shedding and lesion rate, and quantity of virus shed when used consistently. Vaginal TFV gel decreased quantity of virus shed by 60%. In contrast to effects on HSV-2 acquisition, tenofovir is unlikely to provide clinically meaningful reductions in the frequency of HSV shedding or genital lesions. Clinical trials registration NCT01448616.

Background. Genital shedding of herpes simplex virus (HSV) type 2 occurs frequently. Anatomic patterns of genital HSV-2 reactivation have not been intensively studied. Methods. Four HSV-2-seropositive women with symptomatic genital herpes attended a clinic daily during a 30-day period. Daily samples were collected from 7 separate genital sites. Swab samples were assayed for HSV DNA by quantitative polymerase chain reaction. Anatomic sites of clinical HSV-2 recurrences were recorded. Results. HSV was detected on 44 (37%) of 120 days and from 136 (16%) of 840 swab samples. Lesions were documented on 35 (29%) of 120 days. HSV was detected at >1 anatomic site on 25 (57%) of 44 days with HSV shedding (median, 2 sites; range, 1-7), with HSV detected bilaterally on 20 (80%) of the 25 days. The presence of a lesion was significantly associated with detectable HSV from any genital site (incident rate ratio [IRR], 5.41; 95% confidence interval [CI], 1.24-23.50; P = .02) and with the number of positive sites (IRR, 1.19; 95% CI, 1. 01-1.40; P = .03). The maximum HSV copy number detected was associated with the number of positive sites (IRR, 1.62; 95% CI, 1.44-1.82; P