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Purpose: Herpes zoster (HZ) is caused by endogenous reactivation of latent varicella-zoster virus (VZV) that persists in sensory ganglia after primary infection. The incidence and severity of HZ increases during immunosuppression. Especially immunocompromised patients are at high risk of developing a cutaneous rash and suffering from delayed healing of lesions. Bromovinyl deoxyuridine (brivudin), one of the most potent oral inhibitors of VZV replication, is widely used in therapy of HZ in adult patients, particularly in Europe. In this study, we investigated the efficacy of brivudin in immunocompromised children to provide an outpatient treatment option. Methods: In this prospective study, we included 64 immunocompromised pediatric patients with a median age of 14 years. Forty-seven patients received immunosuppressive therapy as part of hematopoietic stem cell transplantation and 17 patients as part of chemotherapy. Primary diagnosis was made clinically by examining the nature and the localization of the skin lesions. Laboratory confirmation was conducted based on the detection of VZV DNA in vesicle fluid and blood samples. Brivudin was administered orally at a single dose of 2-5 mg/kg per day. We monitored the patients’ response for the full time of treatment and observed the time of full crusting of lesions, loss of crusts, and any adverse effects that occurred. Results: Patients received medication for 7-21 days (median: 14 days). All children responded promptly to antiviral treatment and recovered completely from their HZ infections without complications.Crusting of lesions was reached after 3-14 days (median: 6 days). Full healing of skin lesions was ascertained within 7-21 days (median: 12 days). Overall, brivudin therapy was well tolerated. No clinical side effects during or after the treatment were observed. High compliance was achieved due to the once-daily dosing regimen. All patients were treated in an outpatient manner. Conclusion: Oral brivudin was a very effective and well-tolerated therapy in immunocompromised children with HZ infection. The oral administration offers potential for outpatient treatment of HZ in these patients.

Diese Leitlinie richtet sich an Dermatologen, Ophthalmologen, HNO-Arzte, Padiater, Neurologen, Virologen sowie Infektiologen, Anasthesisten und Allgemeinmediziner in Klinik und Praxis und dient zur Information fur andere medizinische Fachrichtungen, die an der Behandlung des Zoster beteiligt sind. Daruber hinaus soll die Leitlinie Kostentragern und politischen Entscheidungstragern zur Orientierung dienen. Die Leitlinie wurde im formellen Konsensusverfahren (S2k) von Dermatologen, Virologen/Infektiologen, Ophthalmologen, HNO-Arzten, Neurologen, Padiatern und Anasthesisten/Schmerzmedizinern erstellt. Die Leitlinie stellt einen Uberblick uber die klinische und molekulare Diagnostik sowie den Antigennachweis, die Antikorperkultur und Viruskultur dar. Diagnostisch besondere Situationen und komplizierte Verlaufe der Erkrankung finden ebenfalls Berucksichtigung. Die antivirale Therapie des Zoster und der Postzosterneuralgie wird im Allgemeinen und fur besondere Situationen dargelegt. Detaillierte Angaben zur Schmerzbehandlung finden Erwahnung und sind in einer Ubersicht dargestellt. Ebenso werden die lokaltherapeutischen Masnahmen thematisiert.

Introduction Several chronic underlying conditions (UCs) are known to be risk factors for developing herpes zoster (HZ) and to increase the severity of HZ and its risk of recurrence. The aim of this study was to investigate the incidence and recurrence of HZ in adult patients with one or multiple UCs. Methods A retrospective cohort study based on claims data representing 13% of the statutory health insurance population from 2007 to 2018 in Germany was performed. Patients aged ≥ 18 years were included when at least one of the following UCs was diagnosed: asthma, chronic heart failure, chronic obstructive pulmonary disease (COPD), coronary heart disease (CHD), depression, diabetes mellitus type 1 or 2, and rheumatoid arthritis (RA). Exact matching was used to account for differences in the distribution of age and sex between the case and matched control cohorts. Multi-morbidity was considered in sensitivity analyses by analyzing patients with only one UC. Results Patients with asthma, CHD, COPD, depression, and RA had, on average, a 30% increased risk of developing acute HZ compared to patients without any UC. RA was found to have the highest odds ratio among these conditions, varying from 1.37 to 1.57 for all age groups. Patients with depression also showed a high risk of developing HZ. Analysis of recurrence indicated that patients with at least one UC in the age groups 18–49 years and 50–59 years had the highest risk for a recurrent HZ. After experiencing a first recurrence, patients, regardless of age group, had a two- to threefold higher risk for a second recurrence. Conclusion This study of representative claims data shows a higher HZ incidence and recurrence frequency in patients with UCs. These results provide relevant information for national health care guidelines and disease management programs. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-021-00535-7., Plain Language Summary Shingles is caused by the reactivation of the chickenpox virus and is characterized by a painful skin rash with blisters, commonly occurring on the trunk. Underlying conditions (UCs) are conditions that persist for a long time, require ongoing medical attention, and are rarely completely cured (chronic conditions). UCs can increase the severity, the risk, and the frequency of shingles. Here, data from a large German health care insurance provider was used to investigate whether patients with one or more UCs have a higher risk for getting shingles compared to healthy people. In particular, patients with asthma, chronic heart failure, chronic obstructive pulmonary disease, coronary heart disease, depression, diabetes, and rheumatoid arthritis were investigated. The study shows that patients with asthma, coronary heart disease, chronic obstructive pulmonary disease, depression, and rheumatoid arthritis have, on average, a 30% higher risk of developing shingles, regardless of their age. The risk of developing shingles two or more times is also higher for patients with at least one UC, with those aged 18–59 experiencing an even greater risk. It was found that patients with an UC are more exposed to develop shingles and that younger patients have a higher risk of a recurrent episode. The findings provide important information for the development or adaption of national health care guidelines and shingles vaccination recommendations. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-021-00535-7.

Diese Leitlinie richtet sich an Dermatologen, Ophthalmologen, HNO-Ärzte, Pädiater, Neurologen, Virologen sowie Infektiologen, Anästhesisten und Allgemeinmediziner in Klinik und Praxis und dient zur Information für andere medizinische Fachrichtungen, die an der Behandlung des Zoster beteiligt sind. Darüber hinaus soll die Leitlinie Kostenträgern und politischen Entscheidungsträgern zur Orientierung dienen. Die Leitlinie wurde im formellen Konsensusverfahren (S2k) von Dermatologen, Virologen/Infektiologen, Ophthalmologen, HNO-Ärzten, Neurologen, Pädiatern und Anästhesisten/Schmerzmedizinern erstellt. Die Leitlinie stellt einen Überblick über die klinische und molekulare Diagnostik sowie den Antigennachweis, die Antikörperkultur und Viruskultur dar. Diagnostisch besondere Situationen und komplizierte Verläufe der Erkrankung finden ebenfalls Berücksichtigung. Die antivirale Therapie des Zoster und der Postzosterneuralgie wird im Allgemeinen und für besondere Situationen dargelegt. Detaillierte Angaben zur Schmerzbehandlung finden Erwähnung und sind in einer Übersicht dargestellt. Ebenso werden die lokaltherapeutischen Maßnahmen thematisiert.

Background Varicella and herpes zoster (HZ), diseases both caused by the varicella zoster virus (VZV), are vaccine-preventable. However, the hypothesis that childhood varicella vaccination may increase the incidence of HZ hinders varicella universal routine vaccination (URV) implementation in many countries. Methods This non-systematic and narrative review of the literature considers the burden of varicella and HZ, and the effectiveness of the respective vaccines. We present the factors involved in the interplay between varicella vaccination and HZ incidence, including the roles of exogenous and endogenous boosting. We review HZ incidence model predictions, and compare these with real-world evidence, which has accumulated since varicella URV was introduced. Conclusion Although more research and longer surveillance are needed, available real-world evidence has not confirmed the model-predicted increase in HZ incidence, associated with childhood varicella URV. Although there is a rising incidence of HZ globally, this trend appears to be predominantly the result of an aging population. Vaccination against varicella in childhood provides significant benefits with respect to the medical, societal and economic burdens of the disease. Therefore, a theoretical concern of an increased burden of HZ with varicella vaccination programs should not prevent children from being protected against the disease.

Italy (in pilot regions) and Germany (nationwide) were the first European countries to introduce universal varicella vaccination (UVV) programs. A systematic review was performed to assess varicella epidemiology before UVV programs and the impact of 1-dose and 2-dose UVV programs in Italy and Germany. Italy implemented 1- or 2-dose UVV programs successively in eight pilot regions between 2003 and 2011 and nationwide in 2017. Germany implemented 1- and 2-dose UVV programs in 2004 and 2009, respectively. While Italy had two nationwide surveillance systems in place for varicella in the pre-vaccination era, in Germany, a mandatory notification system for varicella was only introduced in the New Federal States 2 years before the 1-dose UVV implementation. Substantial reductions in moderate/severe varicella and varicella-related hospitalization incidence occurred during the 1-dose era. Further reductions were reported in Italy and Germany after the recommendation of a second dose in a long or short schedule, respectively. Different benefit-risk evaluations of a tetravalent varicella-containing vaccine (MMRV) used as a first dose led to different recommendations (MMRV versus MMR+V) in these countries. Vaccination strategies in both countries tailored to country-specific needs and goals led to a reduction in varicella-related health care hospitalization costs.

The present guidelines are aimed at residents and board-certified specialists in the fields of dermatology, ophthalmology, ENT, pediatrics, neurology, virology, infectious diseases, anesthesiology, general medicine and any other medical specialties involved in the management of patients with herpes zoster. They are also intended as a guide for policymakers and health insurance funds. The guidelines were developed by dermatologists, virologists, ophthalmologists, ENT physicians, neurologists, pediatricians and anesthesiologists/pain specialists using a formal consensus process (S2k). Readers are provided with an overview of the clinical and molecular diagnostic workup, including antigen detection, antibody tests and viral culture. Special diagnostic situations and complicated disease courses are discussed. The authors address general and special aspects of antiviral therapy for herpes zoster and postherpetic neuralgia. Furthermore, the guidelines provide detailed information on pain management including a schematic overview, and they conclude with a discussion of topical treatment options.

Herpes zoster (HZ, shingles) is a frequent medical condition which may severely impact the quality of life of affected patients. Different therapeutic approaches to treat acute HZ are available. The aim of this European project was the elaboration of a consensus-based guideline on the management of patients who present with HZ, considering different patient populations and different localizations. This interdisciplinary guideline aims at an improvement of the outcomes of the acute HZ management concerning disease duration, acute pain and quality of life of the affected patients and at a reduction in the incidence of postherpetic neuralgia (PHN) and other complications. The guideline development followed a structured and pre-defined process, considering the quality criteria for guidelines development as suggested by the AGREE II instrument. The steering group was responsible for the planning and the organization of the guideline development process (Division of Evidence-Based Medicine, dEBM). The expert panel was nominated by virtue of clinical expertise and/or scientific experience and included experts from the fields of dermatology, virology/infectiology, ophthalmology, otolaryngology, neurology and anaesthesiology. Recommendations for clinical practice were formally consented during the consensus conference, explicitly considering different relevant aspects. The guideline was approved by the commissioning societies after an extensive internal and external review process. In this second part of the guideline, therapeutic interventions have been evaluated. The expert panel formally consented recommendations for the treatment of patients with HZ (antiviral medication, pain management, local therapy), considering various clinical situations. Users of the guideline must carefully check whether the recommendations are appropriate for the context of intended application. In the setting of an international guideline, it is generally important to consider different national approaches and legal circumstances with regard to the regulatory approval, availability and reimbursement of diagnostic and therapeutic interventions.

The highest burden of pediatric vaccine-preventable disease is found in developing nations where resource constraints pose the greatest challenge, impacting disease diagnosis and surveillance as well as the implementation of large scale vaccination programmes. In November 2012, a Working Group Meeting convened in Casablanca to describe and discuss the status with respect to 8 vaccine-preventable diseases (pertussis, pneumococcal disease, measles-mumps-rubella-varicella (MMRV), rotavirus and meningococcal meningitis) to identify and consider ways of overcoming obstacles to pediatric vaccine implementation. Experts from Europe, Russia, the Commonwealth of Independent States, the Middle East, Africa and South East Asia participated in the meeting. A range of region-specific needs and barriers to uptake were discussed. The aim of this article is to provide a summary of the ongoing status with respect to pediatric vaccine preventable disease in the countries represented, and the experts' opinions and recommendations with respect to pediatric vaccine implementation.

Background A controversy exists about the potential effect of childhood varicella vaccination on Herpes Zoster (HZ) incidence. Mathematical models projected temporary HZ incidence increase after vaccine introduction that was not confirmed by real-world evidence. These models assume that absence of contacts with infected children would prevent exogenous boosting of Varicella-Zoster-Virus (VZV) immunity and they do not include an endogenous VZV immunity-boosting mechanism following asymptomatic VZV reactivation. This study aims to explore the effect of various assumptions on exogenous and endogenous VZV immunity-boosting on HZ incidence in the general population after introduction of routine childhood varicella vaccination. Methods An age-structured dynamic transmission model was adapted and fitted to the seroprevalence of varicella in France in absence of vaccination using the empirical contact matrix. A two-dose childhood varicella vaccination schedule was introduced at 12 and 18 months. Vaccine efficacy was assumed at 65%/95% (dose 1/dose 2), and coverage at 90%/80% (dose 1/dose 2). Exogenous boosting intensity was based on assumptions regarding HZ-immunity duration, age-dependent boosting effect, and HZ reactivation rates fitted to observed HZ incidence. Endogenous boosting was the same as pre-vaccination exogenous boosting but constant over time, whilst exogenous boosting depended on the force of infection. Five scenarios were tested with different weightings of exogenous (Exo) - endogenous (Endo) boosting: 100%Exo–0%Endo, 75%Exo–25%Endo, 50%Exo–50%Endo, 25%Exo–75%Endo, 0%Exo–100%Endo. Results HZ incidence before varicella vaccination, all ages combined, was estimated at 3.96 per 1000 person-years; it decreased by 64% by year 80 post vaccine introduction, for all boosting assumptions. The 100%Exo-0%Endo boosting scenario, predicted an increase in HZ incidence for the first 21 years post vaccine introduction with a maximum increase of 3.7% (4.1/1000) at year 9. However, with 0%Exo-100%Endo boosting scenario an immediate HZ decline was projected. The maximum HZ incidence increases at 10, 3, and 2 years post vaccination were 1.8% (75%Exo-25%Endo), 0.8% (50%Exo-50%Endo) and 0.2% (25%Exo-75%Endo), respectively. Conclusions Assuming modest levels of endogenous boosting, the increase in HZ incidence following childhood varicella vaccination was smaller and lasted for a shorter period compared with 100%Exo-0%Endo boosting assumption. Endogenous boosting mechanism could partly explain the divergence between previous HZ-incidence projections and real-world evidence. Electronic supplementary material The online version of this article (10.1186/s12879-019-3759-z) contains supplementary material, which is available to authorized users.

Varicella, although a frequently benign childhood disease, nevertheless represents a considerable health burden. WHO recommends including varicella vaccines in universal routine vaccination programs, and maintaining coverage80%. Many countries have successfully introduced varicella vaccination and have benefited from lower disease burden, but many others have not adopted the vaccine. Reasons include cost commitment for a 'mild childhood disease' or concerns that vaccination will shift varicella to older age groups or increase herpes zoster incidence. Areas covered: This literature review summarizes the effectiveness and epidemiological impact of varicella immunization programs. Expert commentary: Varicella vaccines are immunogenic with acceptable safety profiles. One and two dose schedules are highly effective against varicella and large reductions in disease incidence, particularly moderate-severe disease, have been widely reported. There is currently no evidence to suggest that the introduction of varicella vaccination results in a shift of varicella disease burden to older age groups. Although epidemiological studies have shown an increased incidence of herpes zoster since the vaccines were launched, there are many other contributing factors, and indeed, this secular trend was evident before their introduction. In conclusion, varicella vaccination easily fits into existing immunization programs and significantly reduces the often underestimated burden of varicella.

Commercial serologic assays for varicella-zoster virus (VZV), which enable reliable determination of VZV immune status and are amenable to automation, are needed. The present study compares the automated performance of the VZV whole-cell enzyme-linked immunosorbent assay (ELISA) Enzygnost anti-VZV/IgG, the Euroimmun anti-VZV ELISA (IgG) based on highly purified viral proteins, and the VZV glycoprotein (gp)-based Serion ELISA Classic VZV IgG. The fluorescent-antibody-to-membrane-antibody (FAMA) test was used as a reference. A total of 638 serum samples from VZV-negative children, blood donors, varicella vaccinees, and bone marrow transplant recipients were included. The Enzygnost anti-VZV/IgG and the Serion ELISA Classic VZV IgG showed sensitivities of 99.6% and 99.2%, respectively, and the Euroimmun anti-VZV ELISA (IgG) had a significantly lower sensitivity of 90.5%. Specificity was calculated as 100% for both the Euroimmun anti-VZV ELISA (IgG) and for the Enzygnost anti-VZV/IgG, and the Serion ELISA Classic VZV IgG had a significantly lower specificity of 89.4%. Quantitative results of all ELISAs correlated well, but there was a poor quantitative correlation between the ELISAs and FAMA. In conclusion, this study does not show any superiority of a gp- and a protein-based ELISA compared to a whole-cell ELISA for the automated detection of VZV-specific IgG. The automated performance of the Enzygnost anti-VZV/IgG assay correlated best with the FAMA reference assay.

Die Deutsche Vereinigung zur Bekampfung der Viruskrankheiten (DVV) e.V. und die Gesellschaft fur Virologie (GfV) e.V. geben nach unserem Wissen erstmalig in Europa konkrete Empfehlungen zum Einsatz von HIV-positiven Mitarbeiterinnen und Mitarbeitern im Gesundheitswesen. Grundsatzlich gelten fur HIV-positives medizinisches Personal klar definierte Auflagen. Bei einer dauerhaften Viruslast von ≤ 50 Kopien/ml konnen unter der Einhaltung der festgelegten Masnahmen (z. B. Tragen doppelter Handschuhe, regelmasige arbeitsmedizinische Betreuung, mindestens vierteljahrliche Kontrollen der HI-Viruslast, regelmasige Betreuung durch einen in der HIV-Therapie erfahrenen Arzt) von dem HIV-positiven medizinischen Beschaftigten alle operativen und invasiven Tatigkeiten durchgefuhrt werden. Die uneingeschrankte Tatigkeit des HIV-positiven medizinischen Beschaftigten ist jedoch nur dann moglich, wenn Adharenz bei der antiretroviralen Therapie besteht und wenn alle zur Vermeidung einer Infektionsubertragung erforderlichen Masnahmen regelrecht eingehalten werden. Unter Einhaltung der Vorgaben dieser Empfehlungen gehen von dem HIV-positiven medizinischen Beschaftigten mit an Sicherheit grenzender Wahrscheinlichkeit keine Gefahren fur Patienten aus.

Varicella-zoster virus strains of European genotypes have developed a high variability of open reading frame (ORF) 62 during their occurrence over many years in Germany. M1 strains in Germany display a uniform ORF 62 pattern, suggesting that these strains were introduced from Africa and/or Asia via few sources during the last years.

Global warming is believed to induce a gradual climate change. Hence, it was predicted that tropical insects might expand their habitats thereby transmitting pathogens to humans. Although this concept is a conclusive presumption, clear evidence is still lacking--at least for viral diseases. Epidemiological data indicate that seasonality of many diseases is further influenced by strong single weather events, interannual climate phenomena, and anthropogenic factors. So far, emergence of new diseases was unlinked to global warming. Re-emergence and dispersion of diseases was correlated with translocation of pathogen-infected vectors or hosts. Coupled ocean/atmosphere circulations and 'global change' that also includes shifting of demographic, social, and economical conditions are important drivers of viral disease variability whereas global warming at best contributes.

BK viruses (BKV) comprise four subtypes that are distinguishable by serological and molecular methods with the latter indicating up to four subgroups within subtype I. In this study, the phylogeny of all BKV subtypes was analyzed. Phylogenetic analyses of the viral structural protein VP1, concatenated sequences including the T-Ag, t-Ag, VP1 and VP2 genes and the entire coding region of BKV, each employing several tree inference methods, consistently revealed seven strongly supported clades that correlate with BKV subtypes and subgroups. In general, subtype II and III viruses were found to be sister groups, the genetic distances between which were significantly lower than those between either and the other BKV subtypes. Two benchmarks of human evolution (emergence of modern humans, 200,000 years ago; out-of-Africa migration, 100,000 years ago) were assumed for the internal calibration of BKV evolution. Utilization of either calibration point resulted in the diversification of most BKV subgroups coinciding with human radiation less than 50,000 years ago. Another approach, external calibration by linking BKV divergence to the evolution of mammals, was rejected as it advances BKV divergence prior to the emergence of modern humans.

SUMMARYAcute parvovirus B19 infection is a risk for pregnant women. After vertical transmission the infected fetus may develop hydrops fetalis. Since B19 infection occurs mainly during childhood, children represent a main source for virus transmission. In order to determine whether certain groups in the German population show increased risks for B19 infection we analysed the seroprevalence using 6583 sera collected from adults in former Eastern and Western Germany during the German National Health Survey and 649 sera from healthy Thuringian children and adolescents. In adults the overall seroprevalence was 72·1%, rising from 20·4% in children (1–3 years) and 66·9% in adolescents (18–19 years) to 79·1% in the elderly (65–69 years). Significant differences were observed between females (73·3%) and males (70·9%) and between inhabitants of small (74·8%) and big cities (69·0%) but not between people of the former Eastern (72·8%) and Western states (72·0%) of Germany. For women during childbearing age (18–49 years) highest values were observed in those living together with two or more children (81·6%) and in women with occupational contact with children aged 6 years and adolescents (63·8%).

Cardiovascular diseases are the major cause of human death and have been linked to many different risk factors. Among them, coxsackievirus B3 (CVB3), as a member of the enterovirus group, is one of the most important infectious agents of virus-induced myocarditis. Despite the fact that the molecular structure of this pathogen has been characterized very precisely, there is no virus-specific preventive or therapeutic procedure against CVB3-induced heart disease in clinical use today. A promising approach to prevent CVB3-caused myocarditis represents the mutation of the viral genome in a way that coding sequences of cytokines are integrated into the viral RNA. Recombinant cytokine-expressing CVB3 variants were established to increase the local cytokine concentration and to modulate TH1-/TH2-specific immune responses. Especially protective against CVB3-induced murine myocarditis is the application of an interferon-γ (IFN-γ)-expressing recombinant coxsackievirus variant. The local and simultaneous expression of an immuno-relevant cytokine by the virus itself induces a strong and long-lasting immune response which protects laboratory animals against lethal infections.

European porcine H1N2 influenza viruses arose after multiple reassortment steps involving a porcine influenza virus with avian-influenza-like internal segments and human H1N1 and H3N2 viruses in 1994. In Germany, H1N2 swine influenza viruses first appeared in 2000. Two German H1N2 swine influenza virus strains isolated from pigs with clinical symptoms of influenza are described. They were characterized by the neutralization test, haemagglutination inhibition (HI) test and complete sequencing of the viral genomes. The data demonstrate that these viruses represent a novel H1N2 reassortant. The viruses showed limited neutralization by sera raised against heterologous A/sw/Bakum/1832/00-like H1N2 viruses. Sera pools from recovered pigs showed a considerably lower HI reaction, indicative of diagnostic difficulties in using the HI test to detect these viruses with A/sw/Bakum/1832/00-like H1N2 antigens. Genome sequencing revealed the novel combination of the human-like HAH1 gene of European porcine H1N2 influenza viruses and the NAN2 gene of European porcine H3N2 viruses.

Objectives: The objectives of this study were (i) to apply computer-based technologies to evaluate the structure of 48 N,N 0 -(bis-5-nitropyrimidyl)dispirotripiperazines which belong to a new class of highly active antiviral compounds binding to cell surface heparan sulphates, (ii) to understand the chemical– biological interactions governing their activities, and (iii) to design new compounds with strong antiviral activity. Methods: The logarithm of 50% cytotoxic concentration (CC50) in GMK cells, of 50% inhibitory concentration (IC50) against herpes simplex virus type 1, and of selectivity index (SI = CC50/IC50) was used to develop quantitative structure–activity relationships (QSARs) based on simplex representation of molecular structure. The QSAR model was applied to design new compounds. Two of these compounds were synthesized, physico-chemically characterized and tested for cytotoxicity and antiviral activity. Results: Statistic characteristics for partial least squares models allow the prediction of CC50 ,I C 50 and SI values. The QSAR results demonstrate a high impact of individual structural fragments for antiviral activity. Molecular fragments that promote and interfere with antiviral activity were defined on the basis of the obtained models. Electrostatic factors (38%) and hydrophobicity (34%) were the most important determinants of antiherpetic activity. Using the established method, new potential dispirotripiperazine derivatives were computationally designed. Two of these computationally designed compounds were synthesized. The biological test results confirm the computationally predicted values of these compounds. Conclusions: The established QSAR model is suitable for the design of new antiherpetic compounds and prediction of their activity.

ObjectiveRoutine influenza vaccination is currently recommended in several countries for people aged more than 60 or 65 years or with high risk of complications. A lower age threshold of 50 years has been recommended in the United States since 1999. To help policymakers consider whether such a policy should be adopted more widely, we conducted an economic evaluation of lowering the age limit for routine influenza vaccination to 50 years in Brazil, France, Germany, and Italy.MethodsThe probabilistic model was designed to compare in a single season the costs and clinical outcomes associated with two alternative vaccination policies for persons aged 50 to 64 years: reimbursement only for people at high risk of complications (current policy), and reimbursement for all individuals in this age group (proposed policy). Two perspectives were considered: third-party payer (TPP) and societal. Model inputs were obtained primarily from the published literature and validated through expert opinion. The historical distribution of annual influenza-like illness (ILI) incidence was used to simulate the uncertain incidence in any given season. We estimated gains in unadjusted and quality-adjusted life expectancy, and the cost per quality-adjusted life-year (QALY) gained. Deterministic and probabilistic sensitivity analyses were conducted.ResultsComparing the proposed to the current policy, the estimated mean costs per QALY gained were R$4,100, &U20AC;13,200, &U20AC;31,400 and &U20AC;15,700 for Brazil, France, Germany, and Italy, respectively, from a TPP perspective. From the societal perspective, the age-based policy is predicted to yield net cost savings in Germany and Italy, whereas the cost per QALY decreased to R$2800 for Brazil and &U20AC;8000 for France. The results were particularly sensitive to the ILI incidence rate, vaccine uptake, influenza fatality rate, and the costs of administering vaccination. Assuming a cost-effectiveness threshold ratio of &U20AC;50,000 per QALY gained, the probabilities of the new policy being cost-effective were 94% and 95% for France, 72% and near 100% for Germany, and 89% and 99% for Italy, from the TPP and societal perspectives, respectively.ConclusionExtending routine influenza vaccination to people more than 50 years of age is likely to be cost-effective in all four countries studied.

There are currently no drugs available for the treatment of enterovirus (EV)-induced acute and chronic diseases such as the common cold, meningitis, encephalitis, pneumonia, and myocarditis with or without consecutive dilated cardiomyopathy. Here, we report the discovery and characterization of pyrazolopyrimidines, a well-tolerated and potent class of novel EV inhibitors. The compounds inhibit the replication of a broad spectrum of EV in vitro with IC50 values between 0.04 and 0.64 μM for viruses resistant to pleconaril, a known capsid-binding inhibitor, without affecting cytochrome P450 enzyme activity. Using virological and genetics methods, the viral capsid was identified as the target of the most promising, orally bioavailable compound 3-(4-trifluoromethylphenyl)amino-6-phenylpyrazolo[3,4-d]pyrimidine-4-amine (OBR-5-340). Its prophylactic as well as therapeutic application was proved for coxsackievirus B3-induced chronic myocarditis in mice. The favorable pharmacokinetic, toxicological, and pharmacodynamics profile in mice renders OBR-5-340 a highly promising drug candidate, and the regulatory nonclinical program is ongoing.

Recently, it was demonstrated that the coxsackievirus B3 variant PD (CVB3 PD) is able to infect coxsackievirus-adenovirus receptor (CAR)-lacking cells by using heparan sulfates (HS) as additional receptors (A. E. Zautner, U. Korner, A. Henke, C. Badorff, and M. Schmidtke, J. Virol. 77: 10071-10077, 2003). For this study, competition experiments with growth factors binding to known HS sequences as well as with specifically desulfated heparins were performed with Chinese hamster ovary cells (CHO-K1) to determine the structural requirements of HS for interaction with CVB3. Hepatocyte growth factor interacting with HS sequences containing [IdUA-GlcNSO 3 (6OSO 3 )] n , but not basic fibroblast growth factor binding to [HexUA-GlcNSO 3 -HexUA-GlcNSO 3 -IdUA(2OSO 3 )] n , was shown to compete effectively with CVB3 PD for cell surface HS. Whereas unmodified heparin and 2-O-desulfated heparin strongly inhibited the CVB3 PD-induced cytopathic effect, the antiviral activity was markedly reduced after N-, O- and 6-O-desulfation of heparin. Taken together, these results indicate that 6-O- and N-sulfation of GlcNAc of HS is crucial for HS interaction with CVB3 PD and that the disaccharide [IdUA-GlcNSO 3 (6OSO 3 )] n is involved in viral binding. Results from experiments with various inhibitors of endocytic pathways suggest that HS-mediated virus internalization is pH dependent. Despite the fact that CVB3 PD initiates infection about four times slower by making use of HS as a receptor than by using CAR, the time required for a complete viral life cycle in Chinese hamster ovary cells was independent of the utilized receptor.

A promising approach to protect susceptible individuals against severe diseases is the inoculation of plasmids. Such DNA vaccines against influenza virus infections were quite efficient in different animal models; but still this procedure is not in clinical use until today. The present study reports the generation and characterization of bicistronic plasmids which enables the expression of influenza A virus gene sequences together with immunostimulatory cytokines demonstrating that among these cytokines especially interleukin-2 (IL-2) was efficient to prevent a lethal influenza virus infection in mice.

This study was designed to gain insight into amantadine susceptibility of porcine influenza A viruses isolated in Germany between 1981 and 2001. The 12 studied H1N1, H1N2, and H3N2 porcine influenza virus strains were isolated in chicken eggs and passaged once in MDCK cells. Plaque reduction assays were applied to examine virus susceptibility to amantadine. Genotyping was used to confirm drug resistance. In the results of these antiviral studies, only 3 of the 12 isolates were shown to be amantadine-susceptible. All resistant strains contained the AA substitutions G16E, S31N, and R77Q in the membrane protein 2 (M2). Additionally, L27A was detected in two H1N1 strains. S31N and/or L27A are well-known amino acid substitutions in M2 that confer amantadine resistance. The role of the pig as an intermediate host of avian and human influenza A viruses, the possible involvement of genetic reassortment, and the high incidence of naturally amantadine-resistant porcine influenza A viruses suggest a real risk of emergence of amantadine resistant human viruses. Therefore, drug susceptibility monitoring appears to be warranted for effective application of those drugs.

A yeast two-hybrid study was conducted to catalogue the protein–protein interactions of the Porcine teschovirus non-structural proteins. Five homodimer, three reciprocal heterodimer and four unidirectional heterodimer interactions were observed. While several interactions are similar to those described in previous studies using enteroviruses, such as homo- and heterodimeric interactions of the 2B, 3CD and 3D proteins, several were not found previously. Among these is the binding of the leader protein L to the proteinases 3C and 3CD. Unlike the poliovirus 3C, the teschovirus 3C proteinase dimerizes and interacts with 2BC, 3CD and 3D. The strongest interactions were observed for L–3C, L–3CD and 3C–3CD.

Objectives At present, most promising compounds to treat enterovirus-induced diseases are broad-spectrum capsid function inhibitors which bind into a hydrophobic pocket in viral capsid protein 1 (VP1). Coxsackievirus B3 (CVB3) Nancy was the only prototypic enterovirus strain shown to be pleconaril-resistant. This study was designed to better understand the polymorphism of the hydrophobic pocket in CVB3 laboratory strains and clinical isolates and its implications for treatment with the capsid function inhibitor pleconaril. Methods Pleconaril susceptibility was determined in cytopathic effect-inhibitory, plaque reduction or virus yield assays. Sequence analysis of the genome region coding for VP1 and/or subsequent alignment of amino acids lining the hydrophobic pocket of five CVB3 laboratory strains and 20 clinical isolates were carried out. Virus chimeras and computational analysis were used to prove the role of amino acid 1092. Results and conclusions Despite high conservation of pocket amino acids, polymorphism was detected at positions 1092, 1094 and 1180. Neither Pro-1094-->Thr nor Val-1180-->Ile altered efficacy of pleconaril treatment. But the amino acid at position 1092 was strongly associated with susceptibility of CVB3 to the capsid inhibitor. Whereas leucine was involved in resistance, isoleucine and valine were detected in pleconaril-susceptible CVB3. Results from antiviral assays with hybrid viruses demonstrate the crucial role of amino acid 1092 in pleconaril susceptibility. A resistant cDNA-generated CVB3 became pleconaril-susceptible after accepting parts from the genome region encoding Ile-1092 into its capsid. Computational analysis suggests that conformational changes in the hydrophobic pocket occur when leucine is substituted for isoleucine or valine and that this change leads to susceptibility to pleconaril.

As epidemiological data concerning varicella in Germany were not available, a retrospective study was conducted to investigate the impact of the disease, focusing also on economic aspects. A representative German-wide sample of 1334 unvaccinated varicella cases was obtained in 1999 from randomly selected paediatric (P) and general, as well as internal, mainly adult (A), practices. Following representative weighting, the median age was 5 years, with 90% of cases aged < 12 years. The highest incidence was in children aged 5–6 years. Varicella-related complications occurred in 5.7% of patients, and accounted for 0.1 hospital days/case on average. Certificates of sick leave were issued for 1.3 sick days/case, with 0.6 days paid by health insurance funds to parents caring for their sick child, and 0.7 days paid by the employer. With an annual incidence of 760 000 diagnosed cases in Germany for the year 1999, this amounts to an annual cost of c.150 million Euro, with c. 50 million Euro paid by the statutory health insurance system. It was concluded that universal varicella vaccination in Germany would provide essential clinical improvements for patients and prevent hospital admissions. In addition, significant economic benefits can be expected, mainly because of the high level of indirect health costs in Germany.

Varicella (chickenpox) has traditionally been regarded as a benign, inevitable disease of childhood. In Germany information on the clinical and economic impact of varicella is limited. This study assessed the health risks and economic burden of varicella with a special focus on the relevance of complications as a cost driver. We used an age-structured, dynamic infectious disease model for the spread of infection in the German population combined with a module modeling the course of disease and medical management in the case of infection. Model input data were derived mainly from a retrospective epidemiological survey of 1,334 varicella cases in Germany. This survey included detailed information on outpatient care, complications, inpatient treatment, and sick leave. In the base case analysis the model predicted approx. 740,000 varicella cases per year. Some 40,000 experienced complications, of which 5,700 required inpatient care. Total annual costs for payers, i.e., sickness funds, was 78 million euro, the largest portion of which was due to the significant coverage of work loss costs incurred by parents caring for their sick children ("Kinderpflegekrankengeld"). For the society total annual costs were 187.5 million euro, 82% of which was indirect. Complications account for disproportionate 32% (25%) of cost from the payers' (societal) perspective. However, the vast majority of costs are due to uncomplicated cases. The burden of varicella in Germany is thus significant, not only in terms of morbidity but also from an economic viewpoint. Vaccination strategies targeting groups with high risk of complications might fail to reduce the considerable burden of varicella substantially. Routine vaccination against varicella would be a meaningful measure to reduce the burden of VZV infection in Germany.

The amino acid substitution of aspartic acid to glycine in hemagglutinin (HA) in position 222 (HA-D222G) as well as HA-222D/G polymorphism of pandemic (H1N1) 2009 influenza viruses (A(H1N1)pdm09) were frequently reported in severe influenza in humans and mice. Their impact on viral pathogenicity and the course of influenza has been discussed controversially and the underlying mechanism remained unclarified. In the present study, BALB/c mice, infected with the once mouse lung- and cell-passaged A(H1N1)pdm09 isolate A/Jena/5258/09 (mpJena/5258), developed severe pneumonia. From day 2 to 3 or 4 post infection (p.i.) symptoms (body weight loss and clinical score) continuously worsened. After a short disease stagnation or even recovery phase in most mice, severity of disease further increased on days 6 and 7 p.i. Thereafter, surviving mice recovered. A 45 times higher virus titer maximum in the lung than in the trachea on day 2 p.i. and significantly higher tracheal virus titers compared to lung on day 6 p.i. indicated changes in the organ tropism during infection. Sequence analysis revealed an HA-222D/G polymorphism. HA-D222 and HA-G222 variants co-circulated in lung and trachea. Whereas, HA-D222 variant predominated in the lung, HA-G222 became the major variant in the trachea after day 4 p.i. This was accompanied by lower neutralizing antibody titers and broader receptor recognition including terminal sialic acid α-2,3-linked galactose, which is abundant on mouse trachea epithelial cells. Plaque-purified HA-G222-mpJena/5258 virus induced severe influenza with maximum symptom on day 6 p.i. These results demonstrated for the first time that HA-222D/G quasispecies of A(H1N1)pdm09 caused severe biphasic influenza because of fast viral intra-host evolution, which enabled partial antibody escape and minor changes in receptor binding.

The antiviral activity of 17 polyhydroxycarboxylates derived from phenolic compounds was evaluated against herpesviruses and HIV. When present during virus adsorption several of the polymers exhibited potent activity against herpes simplex virus type 1 (HSV-1), HSV-2, thymidine kinase deficient HSV-1, human cytomegalovirus (HCMV) and HIV-1 and HIV-2 at concentrations that were not toxic to the host cells. A close correlation was found between the 50% inhibitory concentrations of the polyhydroxycarboxylates against HCMV-induced cytopathicity, their inhibitory effect on the expression of HCMV-specific immediate early antigens and their inhibitory effects on HCMV adsorption to the cells. The antiviral activity of the phenolic polymers was dependent on the presence of a sufficient number of carboxylic groups. The mechanism of antiviral action of the polyhydroxycarboxylates can thus be ascribed to inhibition of virus adsorption. This type of compound may have potential in a vaginal gel to prevent sexual transmission of HSV and HIV.

Herpes simplex virus (HSV) infections can be treated efficiently by the application of antiviral compounds. Several drugs on the basis of acyclovir (ACV), penciclovir (PCV) and foscarnet (FOS) have been approved. Resistant viral isolates can be observed especially in immunocompromised patients, who are treated with antivirals for long time intervals. That is why methods for analysis of HSV resistance to antiviral drugs have to be available in virological laboratories. We analyzed HSV type 1 (HSV-1) and type 2 (HSV-2) isolates resistant to ACV for correlation between phenotypic and genotypic drug resistance using tetrazolium reduction assay as well as sequencing of thymidine kinase (TK) and DNA polymerase (pol) genes. All strains were characterized as cross-resistant to PCV, brivudin and susceptible to cidofovir. In addition, three sequential isolates were resistant to FOS. Genotypic analysis revealed high polymorphism of TK among HSV-1 isolates and high polymorphism of DNA pol among both HSV-1- and 2 isolates. In nearly half of ACV-resistant strains, nucleotide insertions and deletions, responsible for a frameshift and the synthesis of a non-functional TK could be related to resistance. In the remaining strains, there were non-synonymous nucleotide substitutions which were not known as part of gene polymorphism. In conclusion, for reliable interpretation of genotypic resistance, a database of non-synonymous mutations has to be established.

Maternal varicella during the first two trimesters of pregnancy may cause the congenital varicella syndrome (CVS). After infection in the first 20 weeks' gestation, the incidence is estimated to be about 2%. To date, nearly 100 infants born with signs of CVS have been reported in the literature, more than three quarters of them during the last two decades. The characteristic symptoms consist of skin lesions in dermatomal distribution (76%), neurologic defects (60%), eye diseases (51%), and skeletal anomalies (49%). About 30% of infants born with these lesions died in the first months of life. The diagnosis of CVS should be established by the appearance of maternal varicella, the presence of typical clinical symptoms as well as the laboratory evidence of in utero varicella-zoster virus (VZV) infection. In the reviewed infants, intrauterine VZV-infection has been proved in about 60%. Passive immunization may reduce the risk of fetal infection but there is no evidence to prevent fetal viremia. Up to now, there are no controlled studies concerning antiviral chemotherapy in preventing CVS.

The anti-Epstein–Barr virus (EBV) activity of different classes of compounds was assessed by means of an EBV DNA hybridization assay using a digoxigenin-labelled probe specific for the BamHI W fragment of the EBV genome, as well as by measuring viral capsid antigen (VCA) expression after a 7 day incubation period of P3HR-1 producer cells with the test substances. Acyclovir, ganciclovir, cidofovir and zidovudine were included as reference compounds. Several compounds proved to be potent and selective inhibitors of EBV DNA synthesis and VCA expression. Of the new compounds that were evaluated for their anti-EBV activity, the highest efficacy (lowest EC50) and highest selectivity index (SI) were shown by the purine nucleoside analogue 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242) (EC50 0.6 ng/ml; SI 600), the acyclic nucleoside phosphonate analogues 9-(2-phosphonomethoxyethyl)-6-dimethylaminopurine (EC50 1.1 μg/ml; SI 91), 9-(2-phosphonomethoxyethyl)-2-amino-6-benzhydrylaminopurine (EC501.3 μg/ml; SI 29), 7-(2-phosphonomethoxyethyl)-6-dimethylaminopurine (EC50 0.8 μg/ml; SI 56), 9-( R)-(2-phosphonomethoxypropyl)-6-(2-dimethylaminoethyl)-aminopurine (EC50 0.5 μg/ml; SI 42), the 2′,3′-dideoxythymidine derivative 3′-oximino-2′,3′-dideoxythymidine (EC501.5 μg/ml; SI 65), and 1-(2,3-dideoxy-3- N-hydroxyamino-β-d-threo-pentafuran yl)pentafuranosyl)thymine (EC50 4.1 μg/ml; SI >24).

The main target groups for influenza vaccination are the elderly, the chronically ill, infants, and toddlers. Influenza vaccines are needed that suit the immunological particularities of each of these age and risk groups. Recent years have seen the approval of influenza vaccines that are more immunogenic than before, but whose use in Germany is limited by the restriction of reimbursement to a small number of vaccines.The Medline database was selectively searched for pertinent literature.The suboptimal immunogenicity of conventional influenza vaccines that contain inactivated viral cleavage products and subunits can be markedly improved by the use of squalene-based adjuvant systems, by the integration of viral antigens in virosomal particles, or by intradermal administration. The vaccination of elderly persons with a vaccine containing the adjuvant MF59 was found to lower the risk of hospitalization for influenza or pneumonia by 25% compared to vaccination with a trivalent inactivated vaccine (TIV). On the other hand, the adjuvant ASO3 was found to be associated with an up to 17-fold increase in the frequency of narcolepsy among 4- to 18-year-olds. In a prospective study, a virosomal vaccine lowered the frequency of laboratory-confirmed influenza in vaccinated children by 88% compared to unvaccinated children (2 versus 18 cases per 1000 individuals). A live, attenuated influenza vaccine lowered the rate of disease in children up to age 7 by 48% compared to a TIV (4.2% versus 8.1%).The newer vaccines possess improved efficacy when used for primary and booster immunization in certain age and risk groups, and they are superior in this respect to conventional vaccines based on viral cleavage products and subunits. The risk/benefit profiles of all currently available vaccines vary depending on the age group or risk group in which they are used.

Background: Routine annual influenza vaccination is primarily recommended for all persons aged 60 and above and for people with underlying chronic conditions in Germany. Other countries have already adopted additional childhood influenza immunisation programmes. The objective of this study is to determine the potential epidemiological impact of implementing paediatric influenza vaccination using intranasally administered live-attenuated influenza vaccine (LAIV) in Germany. Methods: A deterministic age-structured model is used to simulate the population-level impact of different vaccination strategies on the transmission dynamics of seasonal influenza in Germany. In our base-case analysis, we estimate the effects of adding a LAIV-based immunisation programme targeting children 2 to 17 years of age to the existing influenza vaccination policy. The data used in the model is based on published evidence complemented by expert opinion. Results: In our model, additional vaccination of children 2 to 17 years of age with LAIV leads to the prevention of 23.9 million influenza infections and nearly 16 million symptomatic influenza cases within 10 years. This reduction in burden of disease is not restricted to children. About one third of all adult cases can indirectly be prevented by LAIV immunisation of children. Conclusions: Our results demonstrate that vaccinating children 2-17 years of age is likely associated with a significant reduction in the burden of paediatric influenza. Furthermore, annual routine childhood vaccination against seasonal influenza is expected to decrease the incidence of influenza among adults and older people due to indirect effects of herd protection. In summary, our model provides data supporting the introduction of a paediatric influenza immunisation programme in Germany.

Neoplasias associated with anogenital human papilloma viruses (HPV) are characterised by high patient morbidity and mortality and by appreciable limitations in the patientʼs quality of life. Each year 530,000 women worldwide and 4800 women in Germany develop cervical cancer 1, 2. Biomolecular and epidemiological studies carried out in the past 25 years have demonstrated causal link between persisting infections with HPV 16 and HPV 18 and at least 11 other so-called high-risk HPVs (HR-HPVs) and the development of cervical cancer and its precursor lesions (so-called dysplasias or, respectively, cervical intraepithelial neoplasias – CIN). HPV 16, HPV 18 and other HR-HPVs are also the causes of other cancers and their precursors, for example, vulvar, vaginal, penile and anal cancers as well as tonsillar and throat cancers and certain forms of skin cancer. So-called low-risk HPVs (LR-HPVs) such as HPV 6 and HPV 11 are responsible for over 90 % of anogenital condylomata acuminata (anogenital warts). Condylomata acuminata are the most common viral sexually transmitted disease (STD) worldwide 3. It is estimated that around 1 % of European and German populations (aged 15–49 years) have these benign but often very unpleasant tumours. The development of a prophylactic quadrivalent vaccine (HPV 6, 11, 16, 18) and a bivalent vaccine (HPV 16, 18) has made it possible to prevent infections of the cervical epithelium and other squamous epithelia and the development of precancerous lesions. In the case of the quadrivalent vaccine (HPV 6, 11, 16, 18), the development of condylomata acuminata can also be prevented. The Standing Committee on Immunisation of the Robert Koch Institute (STIKO) has published a recommendation on HPV vaccination. Based on data from studies on the efficacy of HPV vaccines for the prevention of precancerous lesions of the cervix, vagina, and vulva, the STIKO recommends immunisation for girls aged between 12 and 17 years. The current guidelines do not contradict this recommendation but rather provide a more comprehensive supplement. The S3 guidelines focus on prophylactic vaccination against HPV-16 and HPV-18 or, respectively, HPV-6 and HPV-11 infections and thus on the prevention of cervical, vulvar, vaginal, anal and penile cancer and their precursors as well as on the primary prevention of condylomata acuminata and laryngeal papillomas. This S3 guideline thus clearly differs from other guidelines such as the S1 guideline “Condylomata acuminata and other HPV-associated clinical entities of the genitals, anus and urethra” (Guideline of the German STI Society in cooperation with the German Dermatological Society and the Paul-Ehrlich Society) and the S2 guideline of the German Society for Gynaecology and Obstetrics “Prevention, diagnostics and therapy for HPV infections and HPV-associated pre-invasive lesions in gynaecology and obstetrics”. After the debate on HPV immunisation has been concluded, the S3 guideline for the prevention of cervical cancer issued by the German Society for Gynaecology and Obstetrics will follow the recommendations in the current guideline, which will be updated. The development process and most important contents of the guideline are briefly described below. The long version of the guideline gives a more detailed account (www.awmf.org).

Phenolic polymers of the humic acid (HA) type, like other polyanionic substances, are inhibitors of herpes simplex virus type 1 (HSV-1) replication. The antiviral potency of the low molecular weight (MW) phenolic starting compounds has not been investigated systematically up to now. To reveal possible relationships between the chemical structure of o-diphenolic starting compounds and the anti-HSV-1 activity of HA-like polymers, nine polymers were synthesized by oxidation of the corresponding o-dihydroxybenzene derivatives. They were characterized by MW distribution, Fourier transform infra-red spectra and functional group analysis. Using an XTT-based tetrazolium reduction assay, both the low MW starting compounds and the synthesized polymers were examined for their antiviral and cytotoxic activities in HSV-1-infected Vera cells. The results demonstrate that most of the starting compounds failed to inhibit herpesvirus replication. The polymeric oxidation products (OP), however, developed detectable anti-HSV-1 activity with IC50 values in the range 2.3 [the OP of 3,4 dihydroxycinnamic acid (caffeic acid); KOP] to 42.1 μg mL−1 (3,4-dihydroxy-toluene OP). The CC50 of polymers varied between 40.8 (3,4-dihydroxybenzaldehyde OP) and >128 μg mL−1 (most polymers). Functional group analysis revealed that the presence of carboxylic groups in the starting compounds enhanced the antiviral activity and reduced the cytotoxicity of polymers. The introduction of a C=C double bond into the side chain [i.e. caffeic acid; 3-O-(3,4-dihydroxycinnamoyl)-d-chinic acid (chlorogenic acid; CH)] yielded the most effective polymers (KOP, CHOP). These may be considered as leader substances for HSV-1 inhibitors of the HA type.