The Incidence of Herpes Zoster Complications: A Systematic Literature Review.

INTRODUCTION: The objective of this work was to summarize the incidence of herpes zoster (HZ) complications in different populations. METHODS: Systematic literature review of PubMed, Embase, and Virtual Health Library records between January 1, 2002 and October 20, 2022 using search strings for HZ, complications, and frequency measurements. RESULTS: The review included 124 studies, most conducted in the general population (n = 93) and on individuals with comorbidities (n = 41) ≥ 18 years of age. Most studies were conducted in Europe (n = 44), Asia (n = 40), and North America (n = 36). Postherpetic neuralgia (PHN) was the most studied neurological complication. Variable relative PHN incidence was found in the general population (2.6-46.7%) or based on diagnosis: immunocompromised (3.9-33.8%), depression (0-50%), and human immunodeficiency virus (HIV) (6.1-40.2%). High incidence rates were observed in hematological malignancies (HM) and solid organ malignancies (132.5 and 93.7 per 1000 person-years, respectively). Ocular complications were frequently reported with herpes zoster ophthalmicus (HZO). The relative incidence (incidence rate) of HZO in the general population was reported as 1.4-15.9% (0.31-0.35 per 1000 person-years). High relative incidence was observed in HIV (up to 10.1%) and HM (3.2-11.3%). Disseminated HZ was the most frequently reported cutaneous complication. The relative incidence of disseminated HZ was 0.3-8.2% in the general population, 0-0.5% in the immunocompetent, and 0-20.6% in patients with comorbidities. High relative incidence was reported in HM and solid organ transplant (up to 19.3% and 14.8%, respectively). DISCUSSION: Most reported complications were neurological (n = 110), ocular (n = 48), and cutaneous (n = 38). Few studies stratified complications by age or gender (or both). Incidence appeared higher in select immunocompromised populations. Higher incidence was associated with older age in several studies; the general association with gender was unclear. CONCLUSIONS: Variable incidence of HZ complications was reported by population subgroup. Further research is required to quantitatively analyze incidence by age, gender, and location.

Public health impact of herpes zoster vaccination on older adults in Singapore: a modeling study.

In Singapore, population aging and rising life expectancy are increasing herpes zoster (HZ) burden, which may be reduced by vaccination. The present study modeled the public health impact of HZ vaccination in Singapore using ZOster ecoNomic Analysis (ZONA) model adapted with Singapore-specific key model inputs, where available. Base case analysis was conducted in adults ≥ 50 years of age (YOA), exploring three vaccination strategies (no vaccination, recombinant zoster vaccine [RZV], zoster vaccine live [ZVL]) under mass vaccination setting (30% coverage). Scenario and sensitivity analyses were performed. Out of 1.51 million adults in 2021 (base case population), 406,513 (27.0%) cases of HZ, 68,264 (4.5%) cases of post-herpetic neuralgia (PHN), and 54,949 (3.6%) cases of other complications were projected without vaccination. RZV was estimated to avoid 73,129 cases of HZ, 11,094 cases of PHN, and 9,205 cases of other complications over the subjects' remaining lifetime; ZVL would avoid 17,565 cases of HZ, 2,781 cases of PHN, and 1,834 cases of other complications. The number needed to vaccinate to prevent one case of HZ/PHN was lower for RZV (7/41) than ZVL (26/163). Among all five age-stratified cohorts (50-59/60-64/65-69/70-79/≥80 YOA), RZV (versus no vaccination/ZVL) avoided the largest number of cases in the youngest cohort, 50-59 YOA. Results were robust under scenario and sensitivity analyses. Mass vaccination with RZV is expected to greatly reduce the public health burden of HZ among Singapore individuals ≥ 50 YOA. Findings support value assessment and decision-making regarding public health vaccination strategies for HZ prevention in Singapore.

Risk of shingles (herpes zoster) increases with age, especially from 50 years. Shingles is a major public health concern in Singapore, given its rapidly aging population. Vaccination can prevent shingles and reduce its public health burden. Two shingles vaccines are available in Singapore: recombinant zoster vaccine (RZV) since 2021, zoster vaccine live (ZVL) since 2008. To understand the value of preventing shingles via vaccination, this study assessed the public health impact of shingles vaccination. Three vaccination strategies (no vaccination, vaccination with RZV, vaccination with ZVL) were compared in 1.51 million Singapore adults aged 50 years and above. Without vaccination, public health burden of shingles would be high; an estimated 406,513 (27.0%) would have shingles, 68,264 (4.5%) would have shingles-related long-term nerve pain, 54,949 (3.6%) would have other shingles-related complications, and 17,762 (1.2%) would be hospitalized due to shingles. Shingles vaccination could reduce this public health burden: RZV avoided 73,129 cases of shingles, 11,094 cases of shingles-related long-term nerve pain, 9,205 cases of other shingles-related complications, and 2,827 hospitalizations due to shingles, which was 4­6 times that avoided with ZVL (shingles: 17,565; shingles-related long-term nerve pain: 2,781; other shingles-related complications: 1,834; hospitalizations due to shingles: 484). Shingles vaccination for adults aged 50 years and above, especially early vaccination from 50­59 years, could reduce its public health burden more than vaccination at later ages and contribute toward healthy aging, preventive care, and the Healthier SG initiative. Results support local public health value assessments and decision-making for shingles prevention.

Updated Public Health Impact and Cost Effectiveness of Recombinant Zoster Vaccine in Canadian Adults Aged 50 Years and Older.

OBJECTIVES: The aim of this study was to update previously estimated public health impact and cost effectiveness of recombinant zoster vaccine (RZV) for the prevention of herpes zoster (HZ) in Canadians aged ≥50 years using longer-term RZV efficacy and waning data and real-world coverage and completion. METHODS: A multicohort Markov model was used to conduct a cost-utility analysis comparing RZV with no HZ vaccination among Canadians aged ≥50 years. Real-world data were used for first-dose coverage (17.5%) and second-dose completion (65%). Vaccine efficacy and waning data were applied from up to 8-year follow-up from the ZOE-50 and ZOE-70 clinical trials. Incremental costs and benefits were calculated using a lifetime horizon from the healthcare payer (base case) and societal perspectives. A discount rate of 1.5% was applied to costs and quality-adjusted life-years (QALYs). RESULTS: The model estimated that RZV would prevent 303,835 HZ cases, 83,256 post-herpetic neuralgia (PHN) cases, 39,653 other complications, and 99 HZ-related deaths compared with no HZ vaccination. Incremental cost-effectiveness ratios (ICERs) were estimated to be $27,486 and $22,097 per QALY (2022 Canadian dollars [CAN$]) from the healthcare payer and societal perspectives, respectively. The base-case ICER was most sensitive to a lower percentage of initial HZ cases with PHN. Almost all probabilistic sensitivity analysis simulations (98.1%) resulted in ICERs

Differential Utility Losses in Herpes Zoster Cases Between Vaccinated and Unvaccinated Subjects: A Meta-analysis of Three Clinical Trials.

BACKGROUND AND OBJECTIVE: Recombinant zoster vaccine (RZV) is approved in adults for the prevention of herpes zoster. The effect of RZV in moderating the severity of breakthrough cases of herpes zoster has been noted but not explicitly quantified before. In this study, a meta-analysis was undertaken to estimate differential utility losses between unvaccinated (Placebo) and vaccinated (RZV) subjects in breakthrough cases of herpes zoster from three RZV clinical trials. METHODS: Differential utility losses between the two groups were estimated in units of quality-adjusted life-years (QALYs), leveraging aggregate patient data from the ZOE-50 (NCT01165177), ZOE-70 (NCT01165229), and ZOE-HSCT (NCT01610414) clinical trials. Differential utility losses and the ratio of mean utility losses were analyzed using random-effects and fixed-effects meta-regression models. RESULTS: The mean QALY loss differences between the unvaccinated (Placebo) and vaccinated (RZV) groups were 0.008, 0.004, and 0.011 in the ZOE-50, ZOE-70, and ZOE-HSCT studies, respectively, yielding an overall estimated difference of 0.007 (95% confidence interval 0.002-0.012) QALYs. Quality-adjusted life-year loss in the vaccinated group was estimated to be 35.5% of the value in the placebo group. A sensitivity analysis estimated an overall difference of 0.005 (95% confidence interval 0.001-0.009) QALYs, corresponding to 48.6% of the QALY loss value in the placebo group. CONCLUSIONS: Recombinant zoster vaccine is effective in alleviating disease severity in breakthrough cases of herpes zoster. The results may be useful in distinguishing QALY losses between vaccinated and unvaccinated cohorts in health economics studies, particularly cost-effectiveness analyses.

Herpes zoster, also known as shingles, may cause painful rashes and persistent pain for months or even years after the initial episode. Recombinant zoster vaccine is approved for the prevention of shingles. Pivotal recombinant zoster vaccine clinical trials have reported data about the impact of shingles episodes on daily activities and overall health-related quality of life. In this work, we combined data from three recombinant zoster vaccine clinical trials and compared the loss in quality of life­measured in quality-adjusted life-years­incurred by vaccinated and unvaccinated subjects who experienced a shingles episode. We found that vaccinated patients experienced lower quality-adjusted life-year losses when they developed shingles compared with unvaccinated patients. Our results may be useful in assessing quality-adjusted life-year losses between vaccinated and unvaccinated cohorts in future herpes zoster vaccination health economics analyses.

Herpes Zoster Recurrence: A Narrative Review of the Literature.

INTRODUCTION: Herpes zoster (HZ; shingles) is a painful, cutaneous disease caused by reactivation of the varicella zoster virus, which causes varicella (chickenpox) typically during childhood. The considerable healthcare burden of HZ is relatively well documented, with approximately one in three individuals experiencing at least one episode during their lifetime, debilitating symptoms including neuropathic pain, and complications such as post-herpetic neuralgia, vision loss, and rarely, stroke, and increased severity in immunocompromised individuals. However, we are not aware of a comprehensive review of literature specifically examining the burden of HZ recurrence. METHODS: We conducted a PubMed search (1 January 2003-2 February 2023) to assess available literature on the incidence, risk factors, and clinical features of HZ recurrence. RESULTS: The incidence of HZ recurrence reported by the studies identified was wide ranging. Studies in general populations of immunocompetent or immunocompetent/immunosuppressed (mixed) populations with an initial HZ episode estimate that approximately 1.2-9.6% of individuals may experience HZ recurrence, with an incidence rate of 1.7-16.6 cases per 1000 person-years. HZ recurrence was reported in 0.0-18.2% of immunocompromised individuals with HZ, with an incidence rate of 17.0-55 cases per 1000 person-years. Incidence rates varied according to study design, follow-up, and study populations. Recognized risk factors for HZ recurrence include immunocompromised status, female sex, family history, and comorbidities such as diabetes. Other factors that may predispose individuals to recurrence include long-lasting pain after the initial HZ episode and the presence of herpes zoster ophthalmicus. DISCUSSION: Our review underlines that following an initial HZ episode, individuals remain at risk of HZ recurrence, adding to the disease burden in a population. As HZ is preventable by vaccination, national HZ vaccination recommendations should include the need for and timing of vaccination in both immunocompetent and immunocompromised individuals who have a history of HZ.

Herpes zoster (HZ), also known as shingles, results from the same virus that causes chickenpox in childhood. In shingles, the chickenpox virus is reactivated, most commonly causing a painful skin rash. About one in three people have shingles at least once in their lifetime. Neuralgia (a burning, stabbing, and sometimes severe pain along a nerve pathway) may continue for months after the initial rash. Shingles may lead to loss of vision and rarely stroke. Shingles is more severe in people with weakened immunity. We reviewed published information on shingles recurrence (i.e., a second, third, or later episode of shingles), as we were not aware of a broad review of information specifically on recurrence. We focused on the rate of recurrence and factors that increase the risk of recurrence. Overall, in around one-tenth of individuals who experience shingles, the disease may reoccur after complete resolution. The rate of recurrence varied on the basis of how the studies were carried out and the type of patients included in the studies. Well-known factors that increase the risk of shingles recurrence are reduced immunity, female sex, family history, and other conditions (e.g., diabetes). Other factors that may increase the risk of shingles recurrence include pain that lasts for a long time after the first episode of shingles and having herpes zoster ophthalmicus, which leads to eye complications. Our review summarizes available data. As shingles is preventable by vaccination, strategies to prevent this disease should include those who have a history of shingles.

Lifetime risk of herpes zoster in the population of Beijing, China.

Objectives: We aimed to estimate the current and future lifetime risks (LTR) of herpes zoster (HZ) and postherpetic neuralgia (PHN), as well as their respective number of annual incident cases in Beijing, China, if individuals were not vaccinated against HZ. Study design: Mathematical model built in Microsoft Excel, de novo. Methods: A hypothetical cohort of 1,000 people was simulated from age 0-100 or until death to generate LTRs of HZ/PHN in Beijing, China. LTR was defined as the risk of developing HZ/PHN at least once in the person's lifetime. The current number of annual incident HZ/PHN cases were also calculated by multiplying up-to-date population data and the annual age-specific incidence of HZ/PHN. For both LTR and annual incident cases, current estimates were projected into the year 2035 to investigate the impact of an aging population. Scenario and deterministic sensitivity analyses (DSA) were conducted to validate the model outcomes. Results: In Beijing, the current and future LTRs of HZ (PHN) were 32.4% (2.8%) and 34.8% (3.3%), respectively. The current and future annual incident cases of HZ (PHN) of individuals aged ≥50 years were 68,394 (7,801) cases among 7.04 million individuals and 88,676 (9,649) cases among 9.08 million individuals, respectively. The scenario analyses demonstrated that modelled results were likely to underestimate the LTR of HZ. Results were robust under the DSA. Conclusions: Given an aging population, HZ poses a significant, growing burden on individuals, the society, and healthcare system of China, highlighting the need for preventative measures such as vaccination.

Cost-effectiveness of the recombinant zoster vaccine (RZV) against herpes zoster: An updated critical review.

The objective of this study was to critically review the cost-effectiveness (CE) of the recombinant zoster vaccine (RZV) against herpes zoster (HZ). A literature review was conducted in PubMed, Embase, and Cochrane between January 1, 2017, and February 28, 2022, and on select public healthcare agency websites to identify and collect data from CE studies comparing RZV to zoster vaccine live (ZVL) or to no vaccination. Study characteristics, inputs, and outputs were collected. The overall CE of RZV was assessed. RZV vaccination against HZ is cost-effective in 15 out of 18 studies included in the present review. Varying incremental cost-effectiveness ratios (ICERs) observed may be associated with different assumptions on the duration of protection of RZV, as well as different combinations of structural and disease-related study (model) inputs driving the estimation of ICERs.

What is the context?• Herpes zoster, also known as shingles, may cause painful rashes and skin alterations.• Chronic pain, also referred to as post-herpetic neuralgia, may persist for months or even years after the initial rash.• The disease is caused by reactivation of the varicella zoster virus.• The recombinant zoster vaccine (RZV) and the zoster vaccine live (ZVL) are approved for the prevention of herpes zoster and post-herpetic neuralgia.• We reviewed published evidence from the past 5 years on RZV.What is new?• Out of 18 selected studies, RZV vaccination against herpes zoster and post-herpetic neuralgia is cost-effective in 15.• In the 15 studies establishing RZV cost-effectiveness, RZV is always cost-effective or frequently cost-saving in direct comparisons to ZVL, when applicable.• RZV was found cost-saving in several immune-compromised populations.What is the impact?• The overview of the currently available body of evidence related to cost-effectiveness of RZV may help informing decision makers about the value of vaccination against herpes zoster.

Public health impact of herpes zoster vaccination on older adults in Hong Kong.

The growing burden of herpes zoster (HZ) in Hong Kong, due to an aging population with increasing life expectancy, may be reduced by vaccination. This study aimed to estimate public health impact of HZ vaccination in Hong Kong. The ZOster ecoNomic Analysis (ZONA) model was adapted with Hong Kong-specific key model inputs/assumptions, where available. Base case analysis involved adults ≥50 years of age (YOA), exploring three vaccination strategies (no vaccination/recombinant zoster vaccine [RZV]/zoster vaccine live [ZVL]) under private market (5% coverage) and mass vaccination (40% coverage) settings. Scenario and sensitivity analyses were performed. In the base case population (3.13 million), without vaccination, 891,024 HZ (28.4%), 156,097 post-herpetic neuralgia (PHN) (5.0%), and 38,755 (1.2%) HZ ophthalmicus (HZO) were projected over their remaining lifetime. Mass RZV vaccination reduced HZ, PHN, and HZO cases by 204,875 (-23.0%), 31,949 (-20.5%), and 8,471 (-21.9%), respectively, which was 4-5 times that reduced with ZVL. RZV was more efficient than ZVL, with lower number needed to vaccinate to prevent one HZ/PHN/HZO case (RZV: 7/40/148; ZVL: 27/163/709). Among all age cohorts, the greatest reduction in cases was projected for RZV (versus no vaccination/ZVL) in the youngest cohort, 50-59 YOA. Results were robust under scenario and sensitivity analyses. HZ burden in Hong Kong is substantial. Mass RZV vaccination is expected to considerably reduce public health burden of HZ among individuals ≥50 YOA, compared with no vaccination/ZVL. Results may support value assessment and decision-making regarding vaccination strategies for HZ prevention in Hong Kong.

In Hong Kong, the burden of shingles is increasing due to an aging population with increasing life expectancy. Vaccination can prevent shingles and reduce disease burden. Since 2021, two shingles vaccines are available in Hong Kong: zoster vaccine live (ZVL) and recombinant zoster vaccine (RZV). Using mathematical modeling, this study compared the public health impact (the number of cases of disease that would occur) of different shingles vaccination strategies, in a hypothetical population of 3.13 million Hong Kong adults aged ≥50 years in their remaining lifetime. The three strategies compared were no vaccination versus vaccination with ZVL or RZV. With no vaccination, public health burden of shingles would remain high, where an estimated 2 in 7 will have shingles, 1 in 20 will have shingles-related nerve pain, and 1 in 100 will have shingles around the eye. Vaccination (versus no vaccination) was predicted to reduce these cases by 47,477 (shingles), 7,701 (nerve pain), and 1,769 (shingles around the eye) for ZVL; and 204,875 (shingles), 31,949 (nerve pain), and 8,471 (shingles around the eye) for RZV. RZV avoided 4­5 times the number of cases compared with ZVL. Earlier RZV vaccination, from age 50 years, would have a greater public health impact than vaccination at a later age as the percentage of cases avoided with RZV (versus no vaccination) was highest in people aged 50­59 years compared with other age groups. These results may support value assessment and decision-making on public health vaccination strategies for shingles prevention in Hong Kong.

Cost-Effectiveness Analysis Update of the Adjuvanted Recombinant Zoster Vaccine in Japanese Older Adults.

INTRODUCTION: This study aimed to update cost-effectiveness and public health impact estimates of the two-dose recombinant zoster vaccine (RZV) compared with no vaccination against herpes zoster (HZ) in the Japanese population aged 65 years. List price of the vaccine and latest RZV efficacy and waning estimates were incorporated. METHODS: A multicohort static Markov model with a cycle length of 1 year was used to follow a hypothetical cohort of one million people aged 65 years over their remaining lifetime (base case). Age-stratified vaccine efficacy and waning rates were updated on the basis of the latest clinical trial data (interim ZOE-LTFU; NCT02723773). First-dose coverage was assumed at 40%, and second-dose compliance was assumed at 95%. Costs and outcomes were discounted at 2% annually, and the incremental cost-effectiveness ratio (ICER) was calculated from payer and societal perspectives. The societal perspective considered productivity loss due to suffering HZ, or due to suffering HZ and time required for vaccination. Sensitivity analyses explored the overall uncertainties in the model. Scenario analyses for Japanese adults aged 50, 60, 70, 80, ≥ 50, and ≥ 65 years (main scenario) were conducted. An ICER below ¥5-6 million/quality-adjusted life-year (QALY) was considered cost-effective. RESULTS: RZV was estimated to prevent 71,423 HZ cases and 15,858 post-herpetic neuralgia (PHN) cases per million people aged 65 years compared with no vaccine in Japan. The ICER was ¥4,205,515 from a payer perspective and was most sensitive to assumptions regarding vaccine efficacy waning, proportion of patients with HZ developing PHN, and HZ incidence. From societal perspectives, ICERs were ¥3,854,192 (productivity loss from suffering HZ only) and ¥4,622,212 (productivity loss from suffering HZ and time required for vaccination). Overall, the results were considered robust under extensive sensitivity and scenario analyses. CONCLUSION: Vaccination against HZ with RZV is cost-effective compared with no vaccination in Japanese adults aged 65 years.

When Is an In Silico Representation a Digital Twin? A Biopharmaceutical Industry Approach to the Digital Twin Concept.

Digital twins (DTs) are expected to render process development and life-cycle management much more cost-effective and time-efficient. A DT definition, a brief retrospect on their history and expectations for their deployment in today's business environment, and a detailed financial assessment of their attractive economic benefits are provided in this chapter. The argument that restrictive guidelines set forth by regulatory agencies would hinder the adoption of DTs in the (bio)pharmaceutical industry is revisited, concluding that those companies who collaborate with the agencies to further their technical capabilities will gain significant competitive advantage. The analyzed process development examples show high methodological readiness levels but low systematic adoption of technology. Given the technical feasibilities, financial opportunities, and regulatory encouragement, concerns regarding intellectual property and data sharing, though required to be taken into account, will at best delay an industry-wide adoption of DTs. In conclusion, it is expected that a strategic investment in DTs now will gain an advantage over competition that will be difficult to overcome by late adopters.