Healthcare resource utilisation pattern and costs associated with herpes simplex virus diagnosis and management: a systematic review.

OBJECTIVES: Little is known about the economic burden of herpes simplex virus (HSV) across countries. This article aims to summarise existing evidence on estimates of costs and healthcare resource utilisation associated with genital and neonatal HSV infection. DESIGN: Systematic literature review. DATA SOURCES: Seven databases were searched from inception to 31 August 2020. A focused search was performed to supplement the results. ELIGIBILITY CRITERIA: Studies which reported either healthcare resource utilisation or costs associated with HSV-related healthcare, including screening, diagnosis and treatment of genital HSV infection and neonatal herpes prevention and treatment. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed the risk of bias using the Larg and Moss's checklist. All data were summarised narratively. RESULTS: Out of 11 443 articles, 38 were included. Most studies (35/38, 94.6%) were conducted in high-income countries, primarily the United States, and were more often related to the prevention or management of neonatal herpes (n=21) than HSV genital ulcer disease (n=17). Most analyses were conducted before 2010. There was substantial heterogeneity in the reporting of HSV-related healthcare resource utilisation, with 74%-93% individuals who sought care for HSV, 11.6%-68.4% individuals who received care, while neonates with herpes required a median of 6-34 hospitalisation days. The costs reported were similarly heterogeneous, with wide variation in methodology, assumptions and outcome measures between studies. Cost for screening ranged from US$7-100, treatment ranged from US$0.53-35 for an episodic therapy, US$240-2580 yearly for suppressive therapy, while hospitalisation for neonatal care ranged from US$5321-32 683. CONCLUSIONS: A paucity of evidence exists on healthcare resource utilisation and costs associated with HSV infection, especially among low-income and middle-income countries. Future research is needed on costs and healthcare utilisation patterns to improve overall understanding of the global economic burden of HSV.

Phytochemical Characterization of Olea europea Leaf Extracts and Assessment of Their Anti-Microbial and Anti-HSV-1 Activity.

Owing to the richness of bioactive compounds, Olea europea leaf extracts exhibit a range of health effects. The present research evaluated the antibacterial and antiviral effect of leaf extracts obtained from Olea europea L. var. sativa (OESA) and Olea europea var. sylvestris (OESY) from Tunisia. LC-DAD-ESI-MS analysis allowed the identification of different compounds that contributed to the observed biological properties. Both OESA and OESY were active against Gram-positive bacteria (MIC values between 7.81 and 15.61 µg/mL and between 15.61 and 31.25 µg/mL against Staphylococcus aureus ATCC 6538 for OESY and OESA, respectively). The antiviral activity against the herpes simplex type 1 (HSV-1) was assessed on Vero cells. The results of cell viability indicated that Olea europea leaf extracts were not toxic to cultured Vero cells. The half maximal cytotoxic concentration (CC50) values for OESA and OESY were 0.2 mg/mL and 0.82 mg/mL, respectively. Furthermore, both a plaque reduction assay and viral entry assay were used to demonstrate the antiviral activity. In conclusion, Olea europea leaf extracts demonstrated a bacteriostatic effect, as well as remarkable antiviral activity, which could provide an alternative treatment against resistant strains.

[Herpes simplex virus infections during pregnancy: epidemiology, clinical presentation and management]. / Infections par les virus herpes simplex pendant la grossesse : épidémiologie, aspects cliniques et prise en charge.

The incidence of herpes simplex virus (HSV) neonatal infection is estimated to be 8.9 per 100,000 live births in Europe. Early treatment with intravenous acyclovir has transformed the prognosis but this infection remains severe since, despite the treatment, mortality is frequent in disseminated diseases and neurological sequelae are frequent when central nervous system is involved. The major risk factor for transmission is the type of maternal infection. In women shedding the virus in their genital tract during childbirth, neonatal infection rates are 44 %, 25 % and 1.3 % in primary, non-primary and recurrent infections, respectively. The goals for the management of this infection during pregnancy encompass 1) the prevention of any contact between the newborn and the maternal virus by suppressing viral replication in the genital tract in late pregnancy and recommending a cesarean section in cases of genital lesions at delivery, and 2) the development of strategies allowing rapid identification and treatment of infected newborns.

Enhanced acyclovir delivery using w/o type microemulsion: preclinical assessment of antiviral activity using murine model of zosteriform cutaneous HSV-1 infection.

The present study was aimed to develop and evaluate a microemulsion-based dermal drug delivery of an antiviral agent, acyclovir. A water-in-oil microemulsion was prepared using isopropyl myristate, Tween 20, Span 20, water and dimethylsulphoxide. It was characterized for drug content, stability, globule size, pH, viscosity and ex vivo permeation through mice skin. In vivo antiviral efficacy of optimized formulation was assessed in female Balb/c mice against herpes simplex virus-I (HSV-I)-induced infection. It was observed that optimized formulation when applied 24-h post-infection could completely inhibit the development of cutaneous herpetic lesions vis-à-vis marketed cream.

Drugs in development for herpes simplex and varicella zoster virus.

The alpha-herpesviruses varicella zoster virus (VZV) and herpes simplex virus (HSV) share common features including lifelong persistence in sensory ganglia and the risk of recurrences. For both HSV and VZV, standard-of-care (SoC) is based on nucleoside analogs (NAs), which require specific activation in infected cells. These existing drugs exhibit substantial limitations, warranting the development of new and more effective drugs.

Hospital risk management of cutaneous herpes simplex virus infection.

BACKGROUND: The epidemiology of cutaneous herpes simplex infection (CHSI) has dramatically changed over the past several decades. Valaciclovir is one of a new generation of antiviral medications that has expanded treatment options for the most common cutaneous manifestations of herpes simplex virus. However, the efficacy and safety of formulations with different doses of valaciclovir remain unclear. AIM: To carry out hospital risk management by ascertaining the incidence and risk of CHSI in patients during treatment with varying doses of valaciclovir. METHODS: The PubMed, MEDLINE and Web of Science electronic databases were systematically searched from database inception to date of searching. Efficacy of drug treatment was measured by average easement score (AES). Safety was characterized as the proportion of patients with drug adverse reactions (DARs) such as fever, dizziness, headache, anxiety, irritability and yellowing of the skin. Outcomes for continuous and dichotomous data were estimated by standard mean difference (SMD) and risk ratio (RR), respectively. RESULTS: Five randomized controlled trials involving 1753 randomized participants for efficacy assessment and 1874 randomized participants for safety assessment were identified. Valaciclovir dose increasing from 1000 mg/day improved AES only moderately, but significantly promoted the incidence of DARs. Twice-daily treatment showed no increase in therapeutic effect but greatly increased DAR incidence. The valaciclovir dose that produced a reduction in AES was 1000 mg/day: SMD = -0.73 (95% CI -0.98 to 0.48; P < 0.01) and RR = 0.95 (95% CI 0.81-1.09; P < 0.002). CONCLUSIONS: Increasing the daily dose of valaciclovir does not substantially improve therapeutic efficacy for CHSI but may raise DAR incidence. Drug doses of 1000 and 2000 mg/day show no significant difference in efficacy scores, but the latter exhibits a higher incidence of DARs. The dose-dependent, long-term efficacy and safety of valaciclovir remain to be explored.

Hospitalization cost per case of neonatal herpes simplex virus infection from claims data.

The purpose of this study was to estimate the average excess inpatient cost of neonatal herpes simplex virus (NHSV) infection from 2005 to 2009 insurance claims data. The estimated adjusted average excess inpatient cost for neonate admissions with HSV diagnosis and >7 days of hospitalization was $40,044 [95% confidence interval (CI), $33,529-$47,775]. When disaggregated by the days of admission, cost estimates were: 8-13 days, $23,918 [CI, $19,490-$29,282]; 14-21 days, $44,358 [CI, $34,654-$56,673]; >21 days, $68,916 [CI, $49,905-$94,967]). Although these estimates are not representative of the entire US, they can inform future economic evaluation studies on NHSV interventions.

Antibody-based concepts for multipurpose prevention technologies.

Because of the versatility and specificity of monoclonal antibodies, they are candidates for multipurpose prevention technologies when formulated as topical (gels, films, rings) or injectable drugs and as vaccines. This review focuses on antibody-based proof of concept studies for the human immunodeficiency virus, herpes simplex virus and sperm. Opportunities and challenges in antibody evasion/resistance, manufacturing, regulatory, and pharmacoeconomics are discussed. This article is based on a presentation at the "Product Development Workshop 2013: HIV and Multipurpose Prevention Technologies," held in Arlington, Virginia on February 21-22, 2013. It forms part of a special supplement to Antiviral Research.

Evaluation of the febrile young infant: an update.

The febrile young infant is commonly encountered in the emergency department, and the incidence of serious bacterial infection in these patients is as high as 15%. Undiagnosed bacterial infections such as meningitis and bacteremia can lead to overwhelming sepsis and death or neurologic sequelae. Undetected urinary tract infection can lead to pyelonephritis and renal scarring. These outcomes necessitate the evaluation for a bacterial source of fever; therefore, performance of a full sepsis workup is recommended to rule out bacteremia, urinary tract infection, and bacterial meningitis in addition to other invasive bacterial diseases including pneumonia, bacterial enteritis, cellulitis, and osteomyelitis. Parents and emergency clinicians often question the necessity of this approach in the well-appearing febrile young infant, and it is important to understand and communicate the evidence that guides the approach to these patients. Recent studies examining the risk of serious bacterial infection in young infants with bronchiolitis and the role of viral testing in the febrile young infant will also be discussed in this review.

Accounting for misclassified outcomes in binary regression models using multiple imputation with internal validation data.

Outcome misclassification is widespread in epidemiology, but methods to account for it are rarely used. We describe the use of multiple imputation to reduce bias when validation data are available for a subgroup of study participants. This approach is illustrated using data from 308 participants in the multicenter Herpetic Eye Disease Study between 1992 and 1998 (48% female; 85% white; median age, 49 years). The odds ratio comparing the acyclovir group with the placebo group on the gold-standard outcome (physician-diagnosed herpes simplex virus recurrence) was 0.62 (95% confidence interval (CI): 0.35, 1.09). We masked ourselves to physician diagnosis except for a 30% validation subgroup used to compare methods. Multiple imputation (odds ratio (OR) = 0.60; 95% CI: 0.24, 1.51) was compared with naive analysis using self-reported outcomes (OR = 0.90; 95% CI: 0.47, 1.73), analysis restricted to the validation subgroup (OR = 0.57; 95% CI: 0.20, 1.59), and direct maximum likelihood (OR = 0.62; 95% CI: 0.26, 1.53). In simulations, multiple imputation and direct maximum likelihood had greater statistical power than did analysis restricted to the validation subgroup, yet all 3 provided unbiased estimates of the odds ratio. The multiple-imputation approach was extended to estimate risk ratios using log-binomial regression. Multiple imputation has advantages regarding flexibility and ease of implementation for epidemiologists familiar with missing data methods.

Efficacy and tolerability assessment of a topical formulation containing copper sulfate and hypericum perforatum on patients with herpes skin lesions: a comparative, randomized controlled trial.

BACKGROUND: Topical Acyclovir has moderate efficacy on recurrent HSV symptoms, requiring repeat applications for several days. Topical Dynamiclear, which requires only a single dose application, may provide a more effective and convenient treatment option for symptomatic management of HSV. OBJECTIVES: The study assessed the comparative efficacy and tolerability of a single use, topical formulation containing copper sulfate pentahydrate and Hypericum perforatum that is marketed as Dynamiclear™ to a topical 5% Acyclovir cream standard preparation and use. METHODS: A prospective, randomized, multi-centered, comparative, open-label clinical study was conducted. A total of 149 participants between 18 and 55 years of age with active HSV-1 and HSV-2 lesions were recruited for the 14-day clinical trial. Participants were randomized into two groups: A (n=61), those receiving the Dynamiclear formulation, and B (n=59), those receiving 5% Acyclovir. Efficacy parameters were assessed via physical examination at baseline (day 1), day 2, 3, 8, and 14. Laboratory safety tests were conducted at baseline and on day 14. RESULTS: Use of the Dynamiclear formulation was found to have no significant adverse effects and was well tolerated by participants. All hematological and biochemical markers were within normal range for the Dynamiclear group. Statistically, odds for being affected by burning and stinging sensation were 1.9 times greater in the Acyclovir group in comparison to the Dynamiclear group. Similarly, the odds of being affected by symptoms of acute pain, erythema and vesiculation were 1.8, 2.4, and 4.4 times higher in the Acyclovir group in comparison to the Dynamiclear group. CONCLUSIONS: The Dynamiclear formulation was well tolerated, and efficacy was demonstrated in a number of measured parameters, which are helpful in the symptomatic management of HSV-1 and HSV-2 lesions in adult patients. Remarkably, the effects seen from this product came from a single application.

Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management.

Herpes simplex viruses (HSV) type 1 and type 2 are responsible for recurrent orolabial and genital infections. The standard therapy for the management of HSV infections includes acyclovir (ACV) and penciclovir (PCV) with their respective prodrugs valacyclovir and famciclovir. These compounds are phosphorylated by the viral thymidine kinase (TK) and then by cellular kinases. The triphosphate forms selectively inhibit the viral DNA polymerase (DNA pol) activity. Drug-resistant HSV isolates are frequently recovered from immunocompromised patients but rarely found in immunocompetent subjects. The gold standard phenotypic method for evaluating the susceptibility of HSV isolates to antiviral drugs is the plaque reduction assay. Plaque autoradiography allows the associated phenotype to be distinguished (TK-wild-type, TK-negative, TK-low-producer, or TK-altered viruses or mixtures of wild-type and mutant viruses). Genotypic characterization of drug-resistant isolates can reveal mutations located in the viral TK and/or in the DNA pol genes. Recombinant HSV mutants can be generated to analyze the contribution of each specific mutation with regard to the drug resistance phenotype. Most ACV-resistant mutants exhibit some reduction in their capacity to establish latency and to reactivate, as well as in their degree of neurovirulence in animal models of HSV infection. For instance, TK-negative HSV mutants establish latency with a lower efficiency than wild-type strains and reactivate poorly. DNA pol HSV mutants exhibit different degrees of attenuation of neurovirulence. The management of ACV- or PCV-resistant HSV infections includes the use of the pyrophosphate analogue foscarnet and the nucleotide analogue cidofovir. There is a need to develop new antiherpetic compounds with different mechanisms of action.

Congenital anomalies and resource utilization in neonates infected with herpes simplex virus.

BACKGROUND: Neonatal herpes simplex virus (HSV) infection, while uncommon, is associated with substantial morbidity and mortality. However, there is little nationally representative data describing resource utilization. METHODS: This retrospective cohort study was conducted using the Pediatric Health Information System, an administrative database that contains discharge diagnosis and resource utilization data from 35 free-standing children's hospitals. Patients

Cost-effectiveness analysis of herpes simplex virus testing and treatment strategies in febrile neonates.

OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of testing for and empirically treating herpes simplex virus (HSV) infection in neonates with fever aged from birth to 28 days. DESIGN: Cost-effectiveness analysis. SETTING: Decision model. PATIENTS: Neonates with fever with no other symptoms and neonates with fever with cerebrospinal fluid (CSF) pleocytosis. INTERVENTIONS: Four clinical strategies: (1) HSV testing and empirical treatment while awaiting test results; (2) HSV testing and treatment if test results were positive for HSV or the patient had symptoms of HSV; (3) treatment alone without testing; or (4) no HSV testing or treatment unless the patient exhibited symptoms. The 2 HSV testing methods used were CSF HSV polymerase chain reaction (PCR) and comprehensive evaluation with blood HSV PCR, CSF HSV PCR, and multiple viral cultures. MAIN OUTCOME MEASURES: Twelve-month survival and quality-adjusted life expectancy with a cost-effectiveness threshold of $100,000 per quality-adjusted life year (QALY) gained. RESULTS: Clinical strategy 1, when applied in febrile neonates with CSF pleocytosis, saved 17 lives per 10,000 neonates and was cost-effective using CSF HSV PCR testing ($55,652/QALY gained). The cost-effectiveness of applying clinical strategy 1 in all febrile neonates depended on the cost of the CSF HSV PCR, prevalence of disease, and parental preferences for neurodevelopmental outcomes. Clinical strategies using comprehensive HSV testing were not cost-effective in febrile neonates ($368,411/QALY gained) or febrile neonates with CSF pleocytosis ($110,190/QALY gained). CONCLUSIONS: Testing with CSF HSV PCR and empirically treating with acyclovir sodium saves lives and is cost-effective in febrile neonates with CSF pleocytosis. It is not a cost-effective use of health care resources in all febrile neonates.

Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management.

Eight of the more than 80 known herpesviruses are human pathogens. Human herpes simplex virus (HSV) is a contagious infection with a large reservoir in the general population. It has a potential for significant complications in the immunocompromised host. In addition, psychological distress caused by the negative stigma associated with genital herpes and visible facial lesions in those experiencing frequent outbreaks renders it a challenging clinical dilemma. This article reviews the epidemiology, pathogenesis, and diagnostic features of HSV infections, providing the clinician with an up-to-date understanding of the available management strategies for mucocutaneous HSV-induced disease.

Real-time polymerase chain reaction detection of herpes simplex virus in cerebrospinal fluid and cost savings from earlier hospital discharge.

Neonatal herpes simplex virus (HSV) can be a devastating illness and may be difficult to diagnose in those cases without a typical skin rash. As a result, physicians often rely on HSV polymerase chain reaction of cerebrospinal fluid to rule out HSV encephalitis. We developed a real-time polymerase chain reaction assay for HSV using the SmartCycler II (Cepheid, Sunnyvale, CA). End point dilution studies showed sensitivity comparable to that of two national reference laboratories that use LightCycler. In-house turnaround time was approximately 1.5 days versus approximately 5.2 days for sending the test to a reference laboratory. We hypothesized that the rapid availability of a negative test result would allow physicians to discharge appropriate patients earlier. Six months after implementation, clinical case analysis identified 12 pediatric patients who were discharged earlier based on more rapid test results, with a projected savings of approximately 55.2 hospital days throughout the first year. Actual length of stay for patients tested in-house was significantly less than that of historical controls and was projected to save approximately 70.2 hospital days in the first year. Including projected annual laboratory cost/test savings of approximately $11,000, a total savings of $38,000 to $43,000 was estimated for the first year of implementation, more than offsetting startup instrument and development cost.

Neonatal herpes should be a reportable disease.

Neonatal herpes is a devastating disease, the most serious complication of genital herpes, one of the most common serious congenital or perinatal infections, and the most frequent complication of sexually transmitted infections among children. Nevertheless, neonatal herpes is not reportable to health authorities in most states. The potential for prevention has been enhanced by recent diagnostic and therapeutic advances, and the disease meets widely accepted criteria for reporting, including incidence rates that exceed those of comparable conditions, epidemiologic instability, disease severity, direct and indirect socioeconomic costs, concern by persons at risk, the potential for prevention by public health interventions, and the prospect that the resulting data would influence public health policy. The absence of national surveillance contributes to beliefs by healthcare providers and the public health community that genital and neonatal herpes are uncommon conditions that affect small segments of society, beliefs that directly interfere with prevention. Neonatal herpes should be a reportable condition.