Characteristics of Prescreened Patients Who Did Not Participate in the Zoster Eye Disease Study.

PURPOSE: The Zoster Eye Disease Study (ZEDS) is a multicenter randomized clinical trial (RCT) funded by the National Eye Institute aiming to determine the efficacy of suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) that enrolled fewer participants than planned (527/780, 67.6%). Understanding reasons for nonparticipation of likely eligible prescreened patients provides insights into patient populations that are not represented by ZEDS and barriers in clinical trials. METHODS: In this retrospective cohort study, HZO adults likely eligible for ZEDS with a history of a typical rash and a medical record within the past year of an episode of epithelial or stromal keratitis or iritis were prescreened at activated Participating Clinical Centers from 2017 to 2022 using a standard prescreening log. De-identified data including demographic information, reasons for exclusion because of ineligibility, and patient refusal were retrospectively entered into REDCap and analyzed. RESULTS: Prescreening logs with reasons for nonconsent (1244/1706, 72.9%) were included in the data set. Patients were excluded from the study (915/1244, 73.6%) because they did not meet all inclusion criteria (619/915, 67.7%) or met an exclusion criterion (296/915, 32.3%). Among the 12 exclusion criteria for the ZEDS study, immunocompromise (76/296, 25.7%) and renal insufficiency (50/296, 16.9%) were most frequently reported. Patient refusal to participate (327/1,244, 26.3%) was common. CONCLUSION: The most common reasons for ineligibility were immunocompromise and renal insufficiency. There may be benefits to long-term antiviral use in these populations not captured in ZEDS. A quarter (26.3%) of prescreened patients refused participation, showing the substantial impact of patient preferences on trial participation.

Baseline Participant Characteristics at Enrollment in the Zoster Eye Disease Study.

PURPOSE: The Zoster Eye Disease Study (ZEDS) is the first randomized clinical trial to study the efficacy of long-term (1 year) suppressive valacyclovir treatment on herpes zoster ophthalmicus (HZO) outcomes. This article details the baseline characteristics of participants. SETTING: The study was set at 95 participating clinical centers in 33 states, Canada, and New Zealand. STUDY POPULATION: Immunocompetent adults with a history of a characteristic HZO unilateral rash and documentation of an episode of active dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, or iritis within the preceding year, enrolled in ZEDS from November 2017 to January 2023. INTERVENTION: Participants were randomized to double-masked oral valacyclovir 1 gm daily versus placebo for 1 year of treatment and followed for 18 months. RESULTS: Five hundred twenty-seven participants were enrolled across 4 strata according to age at HZO onset (younger or older than 60 years) and duration of HZO at enrollment (less or greater than 6 months), with an even distribution of men and women and a median age of 60 years. More participants with recent (57%, 300/527) than chronic HZO and younger than 60 years at HZO onset (54%, 286/527) were enrolled. Most participants were treated acutely with a recommended antiviral regimen (91%, 480/527) and had not been vaccinated against zoster (79%, 418/527). CONCLUSIONS: The broad ZEDS study population enhances the likelihood that ZEDS will provide generalizable high-quality evidence regarding the efficacy and safety of suppressive valacyclovir for HZO immunocompetent adults and whether it should become standard of care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03134196.

Apparent lack of association of COVID-19 vaccination with Herpes Zoster.

Purpose: Herpes zoster (HZ) has been identified as a potential association with the BNT162b2 COVID-19 vaccination. This study evaluated this possible association in a cohort of patients receiving the vaccination. Methods: Epic electronic health records of adult patients who received at least one COVID-19 vaccination between January 12, 2020 and 9/30/2021 within the NYU Langone Health were reviewed to analyze a new diagnosis of herpes zoster within 3 months before compared to 3 months after vaccination. Results: Of the 596,111 patients who received at least one COVID-19 vaccination, 716 patients were diagnosed with HZ within three months prior to vaccination, compared to 781 patients diagnosed within 3 months afterwards. Using the chi-square test for independence of proportions, there was not a statistically significant difference in frequency of HZ before (proportion: 0.0012, 95% CI: [0.0011, 0.0013]) vs. after vaccination (proportion: 0.0013, 95% CI: [0.0012, 0.0014]); (p = 0.093). Conclusions and importance: This study did not find evidence of an association between COVID-19 vaccination and a new diagnosis of HZ. We encourage health care professionals to strongly recommend COVID-19 vaccinations per Centers for Disease Control (CDC) recommendations and vaccination against HZ according to Food and Drug Administration (FDA) approval for the recombinant zoster vaccine.

Zoster Eye Disease Study: Rationale and Design.

PURPOSE: The purpose of this study was to describe the rationale and design of the Zoster Eye Disease Study (ZEDS). METHODS: ZEDS is a National Eye Institute-supported randomized clinical trial designed to determine whether 1 year of suppressive valacyclovir in patients with herpes zoster ophthalmicus (HZO) reduces complications because there is currently no high-quality evidence to support its use. Eligible patients are 18 years and older, immunocompetent, have a history of a typical rash at disease onset, and have had a record of active epithelial or stromal keratitis or iritis within 1 year before enrollment. Exclusion criteria include estimated glomerular filtration rate less than 45 or pregnancy. The primary endpoint is the time to first occurrence of new or worsening dendriform epithelial keratitis, stromal keratitis without or with ulceration, endothelial keratitis, or iritis due to HZO during 12 months of study treatment requiring prespecified treatment changes. The study has 80% power to detect a 30% difference between treatment groups, with a 30% rate of endpoints by 1 year assumed among controls. Secondary and exploratory questions include whether there is a persistent treatment benefit during the 6 months after treatment, whether development of postherpetic neuralgia varies by treatment group, and whether vaccinations against herpes zoster affect study outcomes and coronavirus disease 19 status. RESULTS: Over approximately 4 years, over 400 study participants have been enrolled. CONCLUSIONS: ZEDS aims to provide scientific evidence on whether suppressive valacyclovir treatment improves outcomes in HZO and should become the standard of care.

Meeting the challenges of retention and enrollment of study participants in clinical trials during the COVID-19 pandemic from the study leadership perspective: Experience from the Zoster Eye Disease Study (ZEDS).

PURPOSE: To describe steps taken that enabled a high rate of retention and early resumption of enrollment in the Zoster Eye Disease Study (ZEDS), a randomized controlled trial funded by the National Eye Institute, during the first 13 months (3/1/2020-3/31/2021) of the COVID-19 pandemic. METHODS: A number of responses were implemented in ZEDS when the focus shifted to retention of study participants at the beginning of the pandemic including frequent communication with the participating clinical centers (PCCs) about remote visits, local lab work, shipping study medication, and completion of revised case report forms. Additional payments were provided to the PCCs. Remote activation of PCCs continued. Screening and enrollment visits gradually resumed when allowed. RESULTS: Communication with PCCs increased, and average attendance at monthly coordinator teleconferences went up from 17 to 47. Remote visits peaked in April 2020, accounting for 75% (33/44) of study visits, then declined to less than 10% of study visits beginning August 2020. Overall, 97% (590/609) of study visits were completed. Only 5.5% (9/165) of study participants withdrew consent, and 2.4% (4/165) were lost to follow-up. Enrollment returned to pre-pandemic levels by September 2020. DISCUSSION: Strong communication and unwavering commitment, combined with the technological capability for remote work, visits, and shipment of study medication, were key to the successful retention of study participants and resumption of enrollment. CONCLUSIONS: Rapid responses to challenges to trials caused by the COVID-19 pandemic can enable them to continue successfully and provide insights into the planning of future trials.

Herpes Zoster: A Brief Definitive Review.

ABSTRACT: This brief definitive review of herpes zoster (HZ) will cover the current state of knowledge and questions that remain to be answered regarding HZ in general and HZ ophthalmicus in particular. A question-and-answer format will be used to address various important topics related to this common and serious disease. Questions to be addressed relate to common misconceptions, contagiousness of infection, unknowns regarding pathogenesis, rising incidence, risk factors and complications, relationship with temporal arteritis, vaccination, and current and future antiviral treatment. In addition, the importance of the Zoster Eye Disease Study to determine the efficacy of suppressive valacyclovir treatment in preventing complications of HZ ophthalmicus and the need to support enrollment will be discussed.

Enrollment in the Zoster Eye Disease Study.

PURPOSE: To present the results of a survey of the Zoster Eye Disease Study (ZEDS) investigators regarding barriers to the enrollment of study participants and approaches to overcome them. METHODS: ZEDS is a multicenter randomized clinical trial supported by the National Eye Institute to determine whether prolonged suppressive valacyclovir reduces the complications of herpes zoster ophthalmicus (HZO), relative to placebo. Enrollment of study participants is currently far below expectations. An institutional review board-approved anonymous internet survey was conducted of ZEDS investigators to study their experiences and opinions regarding barriers to enrollment and various approaches to overcome them. RESULTS: The overall survey response rate was 54% (79/145). Only 29% (23/79) agreed that it is easy to enroll study participants. Regarding patient barriers, 69% (55/79) agreed that HZO patients want to be treated with antiviral medication and 69% (54/78) agreed that HZO patients on antivirals do not want to be randomized. Regarding personal barriers facing investigators, 91% (72/79) agreed that antivirals are effective and 100% that the research questions ZEDS is designed to answer are very important. Fewer than 30% of respondents believed that steps taken to increase enrollment have been very helpful. Over half (54%, 42/78) believed that advertising on social media would be moderately or very effective. CONCLUSIONS: Belief among ZEDS investigators that antivirals are effective, and the preference of patients to be treated with antivirals rather than be randomized in ZEDS, are major barriers to enrollment. New approaches to overcoming barriers are necessary to develop an evidence-based standard of care for treatment of HZO.

Current Practice Patterns and Opinions on the Management of Recent-Onset or Chronic Herpes Zoster Ophthalmicus of Zoster Eye Disease Study Investigators.

PURPOSE: To determine practices and opinions among study investigators in the Zoster Eye Disease Study (ZEDS) regarding suppressive valacyclovir treatment for recent-onset and chronic herpes zoster ophthalmicus (HZO). METHODS: An Internet-based survey was distributed to 170 ZEDS study investigators with questions regarding treatment practices for stromal keratitis in HZO and opinions regarding the efficacy of prolonged antiviral prophylaxis. RESULTS: The response rate was 72.4% (123/170). Topical steroids and oral antivirals were used by the majority of respondents for stromal keratitis in both recent-onset (69.1%, 85/123) and chronic HZO (63.4%, 78/123) (P = 0.86). The duration of treatment was similar in both recent-onset and chronic HZO (P = 0.58) with 50.4% (124/246) of ZEDS investigators using prolonged treatment for stromal keratitis due to recent-onset or chronic HZO. The majority of ZEDS respondents believe that oral antivirals are effective during treatment (70.7%, 87/123). CONCLUSIONS: Approximately half of ZEDS investigators treat HZO with prolonged oral antivirals, in addition to topical steroids, and two-thirds believe that it is effective. Completion of ZEDS is feasible and necessary to determine whether or not these practices are effective. Participation in this study is necessary to obtain evidence to support treatment that many ophthalmologists use and believe is effective.

Evaluating Physician Attitudes and Practices Regarding Herpes Zoster Vaccination.

PURPOSE: To investigate the knowledge, attitudes, and practice patterns of primary care physicians regarding administration of the herpes zoster (HZ) vaccine at NYU Langone Health (NYULH). METHODS: A cross-sectional online survey was distributed from January to March 2017 to all physicians in the Division of General Internal Medicine and Clinical Innovation at NYULH across 5 different practice settings. RESULTS: The response rate was 26% (138 of 530). Of the surveyed physicians, 76% (100/132) agreed that the HZ vaccine was an important clinical priority, compared with 93% and 94% for influenza and pneumococcal vaccination, respectively (P < 0.001). Only 35% (47/132) strongly agreed that it was important, compared with 68% (90/132) and 74% (98/132) who strongly agreed that pneumococcal and influenza vaccines, respectively, were important. Respondents estimated that 43% of their immunocompetent patients aged 60 or older received the HZ vaccine, whereas only 11% of patients aged 50 to 59 received the HZ vaccine (P < 0.001). The rate of HZ vaccination was lower in public hospitals (26%) than in the NYULH faculty group practice (46%) (P = 0.007). A greater percent (67% and 72%) of their patients have received influenza and pneumococcal vaccines, respectively (P < 0.001). Almost all doctors (99%, 131/132) consider the Centers for Disease Control and Prevention recommendations important in determining vaccination practices. CONCLUSIONS: HZ vaccination rates remain relatively low compared with rates of influenza and pneumonia vaccination. The recommendation for vaccination against zoster by the Centers for Disease Control and Prevention for individuals aged 50 years and older and stronger recommendations by primary care physicians for administration of zoster vaccines are needed to increase HZ vaccination rates.

Development of Herpes Simplex Virus Infectious Epithelial Keratitis During Oral Acyclovir Therapy and Response to Topical Antivirals.

PURPOSE: To describe 3 cases of herpes simplex virus (HSV) vesicular blepharitis that progressed to infectious epithelial keratitis despite treatment with oral acyclovir, but responded to topical antiviral therapy. METHODS: Retrospective review of a small case series. RESULTS: One adult and 2 children presented with unilateral HSV vesicular blepharitis without evidence of corneal involvement. Each patient was placed on a therapeutic dose of oral acyclovir. While taking oral antiviral therapy, the patients developed HSV infectious epithelial keratitis, which was treated with trifluridine 1% solution 9 times daily in the adult and ganciclovir 0.15% ophthalmic gel 5 times daily in the 2 children. All 3 cases showed resolution of epithelial keratitis within 3 to 10 days after initiation of topical antiviral treatment while oral acyclovir was continued. CONCLUSIONS: Oral antiviral therapy alone may not adequately prevent progression of infectious ocular HSV blepharoconjunctivitis. Topical antiviral therapy appeared to enable resolution of HSV epithelial keratitis that arose during oral acyclovir treatment.

Persistent dilemmas in zoster eye disease.

Herpes zoster ophthalmicus (HZO) is a common, vision and potentially life-threatening disease caused by the reactivation of the varicella-zoster virus (VZV) in the distribution of the first division of cranial nerve V. Although the rate of herpes zoster increases with age, over half of the people with zoster in general, including HZO, are under age 60. In addition, over 90% of people with zoster are immunocompetent, even though the disease is more common and severe in immunocompromised patients. The incidence of zoster is increasing worldwide for unknown reasons. The epidemiology has not yet been impacted by the zoster vaccine (ZV). The lack of a strong recommendation by physicians for this vaccine is a major barrier to its use. An unresolved dilemma regards the optimum timing for this vaccine. In the USA, the current recommendation by the Centers for Disease Control and Prevention (CDC) is for eligible people age 60 and older, despite its greater efficacy in reducing the incidence of disease and Food and Drug Administration (FDA) approval for age 50-59. Although there is a consensus regarding use of acute high-dose oral antiviral treatment to reduce ocular complications, there is limited evidence for prolonged treatment. The rationale for a proposed randomised controlled trial (RCT) of suppressive antiviral treatment to reduce chronic eye disease and postherpetic neuralgia (PHN) includes evidence that zoster is followed by chronic active VZV infection and similarities between HZO and herpes simplex virus (HSV) eye infection, where this treatment is effective and is the standard of care.

Management and Prevention of Herpes Zoster Ocular Disease.

Herpes zoster (HZ) is caused by reactivation of latent varicella zoster virus (VZV) in people who have had chicken pox, usually resulting in a painful, unilateral, dermatomal, vesicular rash. Herpes zoster ophthalmicus occurs when the first division of cranial nerve V is involved. HZ is common, with approximately 1 million new cases per year in the United States, and occurs in 1 in 3 persons. Although the rate of HZ increases with age, over half of all cases occur under the age of 60 years. Complications of herpes zoster ophthalmicus include eye disease, postherpetic neuralgia (PHN), and strokes. VZV has also been found in temporal arteritis biopsies. There is growing evidence that HZ is followed by chronic active VZV infection contributing to these complications. In view of this, and the efficacy of suppressive antiviral treatment in reducing recurrent herpes simplex keratitis, a randomized controlled trial of suppressive valacyclovir to reduce new or worsening anterior segment disease and/or PHN is needed. The zoster vaccine (ZV) is safe and effective in reducing the burden of illness, severity of PHN, and incidence of HZ. It is Centers for Disease Control and Prevention recommended for persons aged 60 years and above without impaired cellular immunity, and Food and Drug Administration approved for those aged 50 and older. It is most effective in preventing HZ in recipients in their 50s. Because of underusage of the ZV, it has not impacted the epidemiology of the disease. Barriers to its use include cost, variable reimbursement, frozen storage, and lack of a strong recommendation by doctors.

Physician survey for study of suppressive antiviral treatment to reduce chronic ocular disease and postherpetic neuralgia after herpes zoster ophthalmicus.

OBJECTIVES: The purpose of this study was to develop a consensus regarding the appropriate regimen to evaluate long-term suppressive antiviral treatment to reduce complications from herpes zoster ophthalmicus (HZO) and identify potential study sites. METHODS: In January 2013, a survey of 13 questions was distributed among cornea fellowship directors, board members of the Cornea Society and Ocular Microbiology and Immunology Group, and Kera-net Listserv members. Questions identified respondents' preferred antiviral regimens to administer for chronic or recurrent HZO, gauged the level of interest in participation in a planned randomized clinical trial, and assessed the number of HZO patients treated among specialists in the past year. RESULTS: Of the 171 respondents who completed the questionnaire, the majority identified as Kera-net Listserv members (107 of 171, 63%) and cornea fellowship directors (46 of 171, 27%). First choice of treatment was valacyclovir 500 mg 2 times per day (61 of 171, 36%), followed by acyclovir 800 mg 2 times per day (56 of 171, 33%), and then valacyclovir 1,000 mg daily (26.9%, 46 of 171). Among the choices, famciclovir consistently placed last among all the respondents (7 of 171, 4%). A majority (106 of 171, 62%) of all respondents, including 70% (26 of 37) of U. S. respondents of the high-volume practices, were interested in participating in a future randomized clinical trial evaluating whether treatment with oral antiviral medications for 1 year decreases complications of HZO. CONCLUSIONS: This survey highlights the strong interest in and support for further study of suppressive antiviral treatment regimens to reduce complications of HZO.

Improving adherence to national recommendations for zoster vaccination through simple interventions.

OBJECTIVE: In 2011, 15.8% of eligible patients in the United States were vaccinated against herpes zoster (HZ). To increase the usage of the HZ vaccine by studying physicians' knowledge, attitudes, practices, and perceived obstacles after interventions to overcome barriers. METHODS: General internal medicine physicians were surveyed with a cross-sectional internet survey from October to December 2011 before interventions to increase the use of the HZ vaccine and 1 year later. Interventions included education, increasing availability at the medical center pharmacy, and electronic medical record reminders. Outcome measures included changes in knowledge, attitudes, and practices, and perceived barriers. McNemar chi-square tests were used to compare the changes from the baseline survey for physicians who completed the follow-up survey. RESULTS: Response rate for the baseline study was 33.5% (89/266) and for the follow-up was 29.8% (75/252). Fifty-five completed both surveys. There was a decrease from 57% at baseline to 40% at follow-up in the proportion of physicians who reported that less than 10% of their patients were vaccinated. They were more likely to know the HZ annual incidence (30% baseline; 70% follow-up; P=0.02), and report having educational information for physicians (7% baseline; 27% follow-up; P=0.003). The top helpful intervention was nursing administration of the vaccine. Average monthly HZ vaccine usage in the affiliated outpatient pharmacy increased in 10 months between surveys by 156% compared with the 3 months before the baseline survey. CONCLUSIONS: Interventions implemented during the study led to an increase in physicians' basic knowledge of the HZ vaccine and an increase in usage at the affiliated pharmacy.