RESUMEN
Reproductive toxicity is one of the major concerns in drug development. Thus, we have developed its screening system using Caenorhabditis elegans, which has a life cycle of three days and similar coding genes as humans. Antiviral nucleoside analogs used for acute infections are known to cause reproductive toxicity, contraindicated for pregnant women, and are used for comparing their reproductive toxicity in C. elegans and experimental animals. None of the drug treatments affected the number of offspring and the concentrations without toxicity to nematodes were consistent with no cytotoxicity or toxicity in experimental animals or humans. Favipiravir, ribavirin, molnupiravir (NHC), acyclovir, ganciclovir, zidovudine, and thalidomide significantly increased the incidence of arrested embryos but amenamevir, letermovir, and guanosine did not. RNA-dependent RNA polymerase (RdRp) inhibitors, in the order of favipiravir, ribavirin, and NHC increased the incidence of arrested embryos, possibly due to the specificity of favipiravir for RdRp and less cytotoxicity. RdRp inhibitors would impair RNA interference through RdRp expressed by telomerase reverse transcriptase during embryogenesis and cause embryo-fetal toxicity. The incidence of arrested embryos may be affected by differences in the substrate specificity of DNA polymerases and metabolism between C. elegans, animals, and humans. The concordance between the results of the screening system for reproductive toxicity of antivirals in C. elegans and those in experimental animals based on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, reproductive toxicology confirms its appropriateness as a screening system for reproductive toxicity. Favipiravir and zidovudine were the least toxic to C. e legans among the antiviral drugs examined.
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Although neonates are commonly exposed to vaginal herpes simplex virus (HSV)-2, neonatal herpes is rare. Therefore, we analyzed paired infant and maternal HSV-2 isolates from two cases of mother-to-infant transmission to identify viral factors contributing to vertical transmission. Sixteen infant isolates with neonatal herpes and 27 genital isolates in their third trimester were included. The infant isolates were significantly more temperature-independent than the maternal isolates. Sequence comparison revealed viral UL13 protein kinase (UL13-PK) mutation in the infant isolates in both cases. In the expanded cohort, infant isolates (5/18) had significantly more UL13-PK mutations than genital isolates (1/29). Isolates within 8 days post-birth (3/4) had a significantly higher frequency of UL13-PK mutation than those after 9 days (2/14), suggesting a close association between UL13-PK mutations and vertical transmission. Elongation factor 1-delta was identified as a target of UL13-PK by proteomic analysis of UL13-PK-positive and -negative HepG2 cells. The mixed infant isolates with the intact and mutated UL13-PK conferred altered cell tropism, temperature independence adapting to fetal temperature, and better growth properties in Vero and hepatoblastoma HepG2 cells than in HSV-2 with intact and mutated UL13-PK alone, indicating that viral UL13-PK mutation is essential for vertical HSV-2 transmission.
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Herpes Simple , Complicaciones Infecciosas del Embarazo , Embarazo , Femenino , Recién Nacido , Humanos , Herpesvirus Humano 2/genética , Madres , Proteómica , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Proteínas Virales/genética , Mutación , Tropismo , Transmisión Vertical de Enfermedad InfecciosaRESUMEN
BK polyomavirus (BKPyV) infection causes various diseases in immunocompromised patients. Cells from human lung and kidney were infected with BKPyV and treated with commercially available intravenous immunoglobulin G (IVIG). Its effects on BKPyV replication and spread of infection were investigated, focusing on administration timing. IVIG treatment 3 hours after infection suppressed BKPyV replication assessed by real-time PCR and expression of the viral capsid protein 1 and large T-antigen. IVIG effectively reduced the number of BKPyV-infected cells 2 weeks after infection in an antibody titer-dependent manner. Virus release in the culture supernatants was not influenced by IVIG treatment 6-80 hours and 3-9 days after infection. Collectively, IVIG did not affect viral release from infected cells but inhibited the spread of infection by neutralizing the released virus and blocking the new infected cell formation, indicating greater efficacy in early localized infection. BKPyV replication resumed in IVIG-treated cultures at 7 days after IVIG removal. Early prophylactic administration of IVIG is expected to reduce the growth and spread of BKPyV infection, resulting in the reduction of infected cell lesions and prevention of BKPyV-associated diseases.
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BK polyomavirus-associated nephropathy is one of serious complications in transplant recipients. Everolimus-a mammalian target of rapamycin inhibitor-has been shown to reduce the incidence of BK polyomavirus infection in transplant recipients. In this study, the effects of everolimus were examined on viral replication and the spread of infection in BK polyomavirus-infected cultures. BK polyomavirus replicated in renal and pulmonary cells, contrary to that in hepatocytes, and spread as diffusely scattered patterns of infected cells, unlike plaque formation through the cell-to-cell mode. BK polyomavirus is stable to heat up to 65 °C with a particle per infectivity ratio of 5000, and the replication cycle was for approximately 34 h. Everolimus administration remarkably reduced the viral replication to 20% in cells treated with 0.1-10 ng/mL, the concentration at which everolimus reached the serum of transplant recipients. In addition, it reduced the amount of viral capsid protein 1 at 5 ng/mL without reducing the ratio of viral capsid protein 1 versus ß-actin, and it also retained the pattern of viral capsid protein 1 localization in the nuclei. Everolimus suppressed the number of infected cells to 32.8% during a 14-day treatment, indicating the reduction of BK polyomavirus-infected cell mass to 18.8% of untreated cultures by modifying cellular functions. The reduction in the total number of BK polyomavirus infected cells by everolimus indicates that everolimus alleviates BK polyomavirus infection, including nephropathy in transplant recipients.
Asunto(s)
Virus BK , Trasplante de Riñón , Infecciones por Polyomavirus , Infecciones Tumorales por Virus , Humanos , Everolimus/farmacología , Proteínas de la Cápside , Infecciones por Polyomavirus/tratamiento farmacológico , Infecciones Tumorales por Virus/tratamiento farmacológicoRESUMEN
Favipiravir, a broad-spectrum RNA-dependent RNA polymerase inhibitor, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at significantly lower concentrations than the plasma trough levels achieved by the dosage adopted for influenza treatment and exhibits efficacy against coronavirus disease 2019 (COVID-19) pneumonia. Although high doses of favipiravir are required due to the molecule being a purine analog, its conversion into the active form in infected cells with active viral RNA synthesis enhances the antiviral specificity and selectivity as a chain terminator with lethal mutagenesis. Another characteristic feature is the lack of generation of favipiravir-resistant virus. COVID-19 pneumonia is caused by strong cell-mediated immunity against virus-infected cells, and the inflammatory response induced by adaptive immunity continues to peak for 3 to 5 days despite antiviral treatment. This has also been observed in herpes zoster (HZ) and cytomegalovirus (CMV) pneumonia. Inflammation due to an immune response may mask the effectiveness of favipiravir against COVID-19 pneumonia. Favipiravir significantly shortened the recovery time in patients with mild COVID-19 pneumonia by 3 days with the start of treatment by the 5th day of symptom onset. Since both CMV and COVID-19 pneumonia are caused by adaptive immunity and prevention of cytomegalovirus pneumonia is the standard treatment due to difficulties in treating refractory CMV pneumonia, COVID-19 pneumonia should be prevented with early treatment as well. In the present study, we have comprehensively reviewed the optimal antiviral therapy for COVID-19 based on clinical trials of favipiravir for the treatment of COVID-19 pneumonia and the concurrently established therapies for other viral infections, particularly HZ and CMV pneumonia. Optimally, antivirals should be administered immediately after COVID-19 diagnosis, similar to that after influenza diagnosis, to prevent COVID-19 pneumonia and complications resulting from microangiopathy.
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Tratamiento Farmacológico de COVID-19 , Infecciones por Citomegalovirus , Gripe Humana , Amidas/uso terapéutico , Antivirales/farmacología , Antivirales/uso terapéutico , Prueba de COVID-19 , Infecciones por Citomegalovirus/tratamiento farmacológico , Humanos , Gripe Humana/tratamiento farmacológico , Pirazinas , SARS-CoV-2RESUMEN
In this study, we investigated the effects of fosphenytoin (fPHT), a water-soluble prodrug of phenytoin, on the pain responses of a mouse herpes zoster (HZ) pain model. Transdermal herpes simplex virus type 1 (HSV-1) inoculation induced mechanical allodynia and hyperalgesia of the hind paw and spontaneous pain-like behaviors, such as licking the affected skin. Intravenous injection of fPHT (15 and 30 mg/kg) alleviated HSV-1-induced provoked pain (allodynia and hyperalgesia). The suppressive effects of fPHT on provoked pain were weaker than those of diclofenac and pregabalin which were used as positive controls. fPHT, diclofenac, and pregabalin significantly suppressed HSV-1-induced spontaneous pain-like behaviors. Among them, high-dose fPHT (30 mg/kg) showed the strongest suppression. Intravenous fPHT may become a viable option for an acute HZ pain, especially for spontaneous pain.
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Herpes Simple , Herpesvirus Humano 1 , Animales , Herpes Simple/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Ratones , Dolor/tratamiento farmacológico , Fenitoína/análogos & derivados , Fenitoína/farmacología , Fenitoína/uso terapéuticoRESUMEN
BACKGROUND: Since 2014, universal varicella vaccination has reduced the varicella and herpes zoster (HZ) incidence in vaccine recipients and increased the incidence in the child-rearing generation until 2017. OBJECTIVE: This study aimed to understand the future epidemiologic trends of HZ after the disappearance of varicella epidemics and during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: The Miyazaki Dermatologist Society has been monitoring and analyzing the incidence of HZ patients after universal vaccination since 1997. RESULTS: The HZ incidence in Oka varicella vaccine recipients aged 0-4 years decreased with the reduction in chickenpox incidence. The HZ incidence among those aged 5-9 years increased between 2015 and 2017 and decreased thereafter. From 2014-2020, the HZ incidence continued to increase to 36.6%, 51.3%, 70.2%, 56.7%, and 27.3% among those aged 10-19, 20-29, 30-39, 40-49, and 50-59 years, respectively. The HZ incidence in patients aged ≥ 60 years increased by 2.3% annually from 2014 to 2020, corresponding to an annual 2% increase since 1997, and was unaffected by varicella epidemics. COVID-19 infection control measures, lifestyle changes and the resulting stress did not affect the HZ incidence in 2020. CONCLUSION: Universal varicella vaccination eliminated varicella epidemics, and HZ was reduced in vaccine recipients. The HZ incidence for those aged 10-59 years increased from 2014 to 2020, in contrast to those aged ≥ 60 years, which is attributable to booster immunity expiration due to varicella contact in this age group.
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COVID-19/epidemiología , Vacuna contra la Varicela/uso terapéutico , Herpes Zóster/epidemiología , Herpes Zóster/prevención & control , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Varicela/prevención & control , Niño , Preescolar , Dermatología/tendencias , Femenino , Conductas Relacionadas con la Salud , Humanos , Programas de Inmunización , Incidencia , Estilo de Vida , Masculino , Persona de Mediana Edad , Pandemias , Vacunación , Adulto JovenRESUMEN
Acyclovir, valacyclovir, and famciclovir are used for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Helicase-primase inhibitors (HPIs) inhibit replication fork progression that separates double DNA strands into two single strands during DNA synthesis. The HPIs amenamevir and pritelivir have novel mechanisms of anti-herpetic action, and their once-daily administration has clinical efficacy for genital herpes. Among HPIs, amenamevir has anti-VZV activity. The concentrations of HSV-1 and VZV required for the 50% plaque reduction of amenamevir were 0.036 and 0.047 µM, respectively. We characterized the features of amenamevir regarding its mechanism, resistance, and synergism with acyclovir. Its antiviral activity was not influenced by the viral replication cycle, in contrast to acyclovir. A clinical trial of amenamevir for herpes zoster demonstrated its non-inferiority to valacyclovir. To date, amenamevir has been successfully used in over 1,240,000 patients with herpes zoster in Japan. Post-marketing surveillance of amenamevir in Japan reported side effects with significant potential risk identified by the Japanese Risk Management Plan, including thrombocytopenia, gingival bleeding, and palpitations, although none of these were serious. The clinical efficacy and safety profiles of amenamevir were established in patients with herpes zoster. Therefore, amenamevir as an HPI opens a new era of anti-herpes therapy.
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Antivirales/uso terapéutico , ADN Helicasas/antagonistas & inhibidores , ADN Primasa/antagonistas & inhibidores , Herpes Zóster/tratamiento farmacológico , Herpesvirus Humano 1/efectos de los fármacos , Oxadiazoles/uso terapéutico , Animales , Ensayos Clínicos como Asunto , Herpes Genital/tratamiento farmacológico , Humanos , RatonesRESUMEN
Introduction: Acyclovir has led to the development of successful systemic therapy for herpes simplex virus and varicella-zoster virus (VZV) infection, and the use of valacyclovir and famciclovir has improved treatment. Additionally, the use of a helicase-primase (HP) inhibitor (HPI), amenamevir, is changing the treatment of herpes zoster (HZ).Area covered: VZV infection is prevented by vaccines and is treated with antiviral agents. Acyclovir and penciclovir are phosphorylated by viral thymidine kinase and work as chain terminators. Improvements in the management of immunocompromised patients have reduced severe and prolonged immunosuppression and chronic VZV infection with acyclovir-resistant mutants has become rarer. The HP is involved in the initial step of DNA synthesis and amenamevir has novel mechanisms of action, efficacy to acyclovir-resistant mutants, and pharmacokinetic characteristics. The literature search for PUBMED was conducted on 10 April 2020 and updated on 4 November 2020.Expert opinion: Amenamevir has been used to treat HZ in Japan. Although the number of patients with VZV infection will decrease owing to the use of vaccines, the addition of HPI will improve treatment and treatment options for resistant viruses. The clinical use of HPIs in addition to current nucleoside analogs opens a new era of antiherpes therapy.
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Aciclovir , Antivirales , Herpes Zóster , Herpesvirus Humano 3 , Aciclovir/farmacología , Aciclovir/uso terapéutico , Antivirales/farmacología , Antivirales/uso terapéutico , ADN Primasa , Herpes Zóster/tratamiento farmacológico , Herpes Zóster/epidemiología , Herpes Zóster/prevención & control , Herpesvirus Humano 3/efectos de los fármacos , Herpesvirus Humano 3/genética , HumanosRESUMEN
Varicella zoster virus (VZV) reactivates more frequently in immunocompromised patients than immunocompetent subjects and is a significant cause of morbidity and mortality. Acyclovir is frequently used for treatment against VZV reactivation. However, long-term use of acyclovir can result in the emergence of VZV strain resistant to acyclovir. Here, we report a 67-year-old man with adult T-cell leukemia who suffered from herpes zoster with acyclovir-resistant VZV after long-term prophylaxis. The isolated viruses from his skin lesions were a mixture of acyclovir-resistant and acyclovir-susceptible strains. Sequence analysis showed the presence of thymidine kinase (TK) mutations in the resistant clones. Interestingly, oral administration of famciclovir, a prodrug form of penciclovir, resulted in resolution of his herpes zoster, although most acyclovir-resistant strains of VZV were reported to be resistant to penciclovir. This implied that a certain amount of susceptible VZV with wild-type viral TK gene was present in vivo, and that famciclovir could be phosphorylated intracellularly by the intact viral kinases. As famciclovir is more potent and longer-acting than acyclovir, the susceptible strains might have suppressed the generation and proliferation of the resistant in vivo. Even when VZV is developing resistance to acyclovir, famciclovir might be effective at least in the early resistant phase.
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Herpes Zóster , Herpesvirus Humano 3 , Aciclovir/uso terapéutico , Anciano , Antivirales/uso terapéutico , Famciclovir/uso terapéutico , Herpes Zóster/tratamiento farmacológico , Humanos , MasculinoRESUMEN
Amenamevir is a helicase-primase inhibitor of herpes simplex virus (HSV) and varicella-zoster virus (VZV) and is used for the treatment of herpes zoster in Japan. The half maximal effective concentrations (EC50s) of acyclovir and sorivudine for VZV increased as the time of treatment was delayed from 6 to 18 h after infection, while those of amenamevir and foscarnet were not affected. Susceptibility of infected cells at 0 and 18 h after infection was examined with four anti-herpes drugs, and the fold increases in EC50 for acyclovir, sorivudine, amenamevir, and foscarnet were 13.1, 6.3, 1.3, and 1.0, respectively. The increase in the EC50s for acyclovir in the late phase of infection in VZV and HSV was abolished by hydroxyurea, a ribonucleotide reductase (RR) inhibitor. The common mechanism affecting antiviral activities of acyclovir to HSV and VZV was examined in HSV-infected cells. The amount of HSV DNA in cells treated with amenamevir at 10 x EC50 was similar at 0 and 12 h but less than that in cells treated with acyclovir at 10 x EC50. dGTP, produced through viral RR, peaked at 4 h and decreased thereafter as it was consumed by viral DNA synthesis. Because acyclovir and amenamevir inhibited viral DNA synthesis, thus making dGTP unnecessary, dGTP was significantly more abundant in the presence of acyclovir and amenamevir than in untreated, infected cells. Abundant dGTP supplied by RR may compete with acyclovir triphosphate and attenuate its antiviral activity. In contrast, abundant dGTP did not influence the inhibitory action of amenamevir on viral helicase-primase activity. ATP was significantly decreased at 12 h after infection and significantly more abundant in untreated infected cells compared to cells treated with acyclovir and amenamevir. The anti-herpetic activity of amenamevir was not affected by the replication cycle of VZV and HSV, indicating the suitability of amenamevir for the treatment of herpes zoster and suppressive therapy for genital herpes.
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Aciclovir/farmacología , Antivirales/farmacología , Herpesvirus Humano 3/efectos de los fármacos , Herpesvirus Humano 3/enzimología , Oxadiazoles/farmacología , Ribonucleótido Reductasas/metabolismo , Animales , Células Cultivadas , Chlorocebus aethiops , Nucleótidos de Desoxiguanina/metabolismo , Nucleótidos de Desoxiguanina/farmacología , Inhibidores Enzimáticos/farmacología , Humanos , Células Vero , Proteínas Virales/antagonistas & inhibidores , Replicación Viral/efectos de los fármacosRESUMEN
Favipiravir has been developed as an anti-influenza drug and licensed as an anti-influenza drug in Japan. Additionally, favipiravir is being stockpiled for 2 million people as a countermeasure for novel influenza strains. This drug functions as a chain terminator at the site of incorporation of the viral RNA and reduces the viral load. Favipiravir cures all mice in a lethal influenza infection model, while oseltamivir fails to cure the animals. Thus, favipiravir contributes to curing animals with lethal infection. In addition to influenza, favipiravir has a broad spectrum of anti-RNA virus activities in vitro and efficacies in animal models with lethal RNA viruses and has been used for treatment of human infection with life-threatening Ebola virus, Lassa virus, rabies, and severe fever with thrombocytopenia syndrome. The best feature of favipiravir as an antiviral agent is the apparent lack of generation of favipiravir-resistant viruses. Favipiravir alone maintains its therapeutic efficacy from the first to the last patient in an influenza pandemic or an epidemic lethal RNA virus infection. Favipiravir is expected to be an important therapeutic agent for severe influenza, the next pandemic influenza strain, and other severe RNA virus infections for which standard treatments are not available.
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Amidas/uso terapéutico , Antivirales/uso terapéutico , Gripe Humana/tratamiento farmacológico , Pirazinas/uso terapéutico , Infecciones por Virus ARN/tratamiento farmacológico , Animales , Humanos , Gripe Humana/genética , Gripe Humana/metabolismo , Infecciones por Virus ARN/genética , Infecciones por Virus ARN/metabolismoRESUMEN
Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and reduces the risk of cytomegalovirus (CMV) infection in transplant recipients. Everolimus inhibits mTOR complex 1, which regulates factors involved in several crucial cellular functions and is required for CMV replication. However, it is not clear how everolimus regulates CMV replication and prevents and alleviates CMV infection. Effects of everolimus on CMV infection, spread, and DNA synthesis and release from infected cells were assessed by plaque formation, infectious centre assay, real-time PCR of infected cells, and culture supernatant in CMV-infected cultures with and without everolimus. Everolimus enhanced plaque formation by 3.6 times, but the size of the plaques was reduced to 36.4% of untreated cultures in the absence of a pretreatment period. Everolimus reduced viral adsorption but enhanced the replication efficiency of inoculated virus, resulting in an increase in plaque number in the early phase of infection. Preinfection treatment of cells with everolimus efficiently exhibited its antiviral efficacy, and everolimus delayed and suppressed viral DNA synthesis and release from infected cells. Everolimus had suppressed the spread of infection and reduced the number of total infected cells to 40% of untreated cells on day 9, indicating reduction of the size of CMV lesions to one-sixth in 2-3 replication cycles. Preinfection treatment of the cells with everolimus augmented its suppressive effect on CMV infection and replication. Everolimus reduced the total number of infected cells and limited the CMV lesions, and this reduction in the spread of CMV infection would alleviate CMV infection in transplant recipients.
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Antivirales/farmacología , Infecciones por Citomegalovirus/tratamiento farmacológico , Citomegalovirus/efectos de los fármacos , Everolimus/farmacología , Replicación Viral/efectos de los fármacos , Células Cultivadas , Citomegalovirus/fisiología , ADN Viral/biosíntesis , Humanos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ensayo de Placa ViralRESUMEN
Resistant herpes simplex virus type 1 (HSV-1) infection is sometimes fatal for immunocompromised patients. Here, we report 10-year-old girl receiving hematopoietic stem cell transplantation developed refractory HSV-1 infection, which was persisted to intermittent acyclovir (ACV) or foscarnet (FOS) administrations but was improved by continuous ACV administration. The isolates from the lesion were identified with low susceptibilities to ACV and FOS by plaque reduction assay due to DNA pol gene mutation. Continuous ACV administration overcomes the efficacy of intermittent administration and could be the best option to treat severe HSV-1 infectious patients.
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Aciclovir/administración & dosificación , Antivirales/administración & dosificación , Farmacorresistencia Viral , Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 1/efectos de los fármacos , Leucemia Monocítica Aguda/tratamiento farmacológico , Aciclovir/uso terapéutico , Antivirales/uso terapéutico , Niño , Femenino , Foscarnet/administración & dosificación , Foscarnet/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Herpes Simple/complicaciones , Herpes Simple/diagnóstico , Herpes Simple/virología , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/aislamiento & purificación , Humanos , Infusiones Intravenosas , Leucemia Monocítica Aguda/complicaciones , Leucemia Monocítica Aguda/virología , Labio/patología , Labio/virología , MutaciónAsunto(s)
Vacuna contra el Herpes Zóster/administración & dosificación , Herpes Zóster/prevención & control , Programas de Inmunización , Vacunación , Distribución por Edad , Niño , Preescolar , Herpes Zóster/diagnóstico , Herpes Zóster/epidemiología , Herpes Zóster/virología , Humanos , Incidencia , Lactante , Japón/epidemiología , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Effects of universal varicella vaccination on the herpes zoster (HZ) incidence have not been elucidated. Universal varicella vaccination was introduced in Japan in October 2014. OBJECTIVE: We investigated the effects of universal varicella vaccination on HZ epidemiology. METHODS: Patients with HZ have been monitored by the Miyazaki Dermatologist Society since 1997, and the effects of universal vaccination on the HZ incidences have been analyzed to determine which generation is most affected. RESULTS: The number of HZ patients increased 1.54 times, and the gradual increase in the HZ incidence was observed in not only patients >60 years, but also other generations during the period from 1997 to 2017. The number of varicella patients was gradually reduced from 2010 to 2017 before introduction of universal varicella vaccination, and the HZ incidence in yearly change significantly increased from 2014 to 2016 in the total population associated with the significant decrease in varicella incidence. The HZ incidence significantly increased for individuals aged 20 to 49 years from 2014 to 2015 and most for individuals age 20-29 years (odds ratio [OR], 1.270; 95% confidence interval [CI], 1.071-1.505, P<0.001). We identified the child-rearing generation of age 20 to 49 years (OR, 1.270; 95% CI, 1.071-1.505, P<0.001) as the generation most influenced by universal varicella vaccination, when the HZ incidence increased gradually by approximately 2% per year. CONCLUSIONS: Universal vaccination increased the HZ incidence in the child-rearing generation among the generations, possibly by reduced chance of boosting their immunity by exposure to varicella.
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Vacuna contra la Varicela/administración & dosificación , Varicela/prevención & control , Herpes Zóster/epidemiología , Vacunación , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Varicela/epidemiología , Varicela/inmunología , Varicela/virología , Niño , Crianza del Niño , Preescolar , Femenino , Herpes Zóster/inmunología , Herpes Zóster/virología , Humanos , Incidencia , Lactante , Recién Nacido , Japón/epidemiología , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto JovenRESUMEN
The discovery of acyclovir and penciclovir has led to the development of a successful systemic therapy for treating herpes simplex virus infection and varicella-zoster virus infection, and the orally available prodrugs, valacyclovir and famciclovir, have improved antiviral treatment compliance. Acyclovir and penciclovir are phosphorylated by viral thymidine kinase and are incorporated into the DNA chain by viral DNA polymerase, resulting in chain termination. Helicase-primase plays an initial step in DNA synthesis to separate the double strand into two single strands (replication fork) and is a new target of antiviral therapy. The helicase-primase inhibitors (HPIs) pritelivir and amenamevir have novel mechanisms of action, drug resistance properties, pharmacokinetic characteristics, and clinical efficacy for treating genital herpes. The clinical study of amenamevir in herpes zoster has been completed, and amenamevir has been submitted for approval for treating herpes zoster in Japan. The clinical use of HPIs will be the beginning of a new era of anti-herpes therapy.
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Antivirales/administración & dosificación , Herpes Simple/tratamiento farmacológico , Herpes Zóster/tratamiento farmacológico , Aciclovir/administración & dosificación , Aciclovir/análogos & derivados , Animales , Ensayos Clínicos como Asunto , Guanina , Herpes Simple/virología , Herpes Zóster/virología , Herpesvirus Humano 3/efectos de los fármacos , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/fisiología , Humanos , Oxadiazoles/administración & dosificación , Simplexvirus/efectos de los fármacos , Simplexvirus/genética , Simplexvirus/fisiologíaRESUMEN
BACKGROUND: Varicella-zoster virus causes herpes zoster (HZ) along specific dermatomes, but the effects of age and sex on HZ distribution are unclear. OBJECTIVE: We investigated the age- and sex-dependent distribution characteristics of HZ. METHODS: Patients with HZ were monitored by members of the Miyazaki Dermatologist Society. Questionnaires containing information on age, sex, and dermatome distribution and lesion specimens from 2730 patients were collected, and 2508 PCR-diagnosed cases were analyzed. RESULTS: The ratio of lesions in the thoracic area to lesions in the whole body decreased with age, whereas those of other areas increased. HZ incidence increased with age to about four times that of the basic incidence in the dermatome areas at age 0-29 years; the incidence in the trigeminal area in both sexes increased 11-fold, and the incidence in the thoracic and lumbosacral areas increased in females more than in males. Furthermore, the fact that the highest incidence was found along the first branch of the trigeminal nerve suggests an association with long-term ultraviolet ray exposure. Segmental dermatomes comprising thoracic 10-lumbar 1/sacral 2-4 and thoracic 5-6 were significantly more frequently affected in female patients at age 50-59 years and are consistent with areas of obstetric anesthesia for childbirth and of breastfeeding, respectively. CONCLUSIONS: HZ incidence increased with age; moreover, exposure to ultraviolet rays, childbirth, and breastfeeding might increase the incidence at specific dermatomes in older individuals. This study provides important information on the etiology of HZ.
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Herpes Zóster/epidemiología , Herpesvirus Humano 3/aislamiento & purificación , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Anestesia Epidural/efectos adversos , Anestesia Obstétrica/efectos adversos , Niño , Preescolar , Monitoreo Epidemiológico , Femenino , Herpes Zóster/etiología , Herpes Zóster/patología , Humanos , Incidencia , Lactante , Recién Nacido , Japón/epidemiología , Región Lumbosacra , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Factores Sexuales , Piel/inervación , Piel/patología , Piel/virología , Torso , Nervio Trigémino , Adulto JovenRESUMEN
BACKGROUND: T-705 (favipiravir) is a potent inhibitor of RNA-dependent RNA polymerases of influenza viruses and no favipiravir-resistant virus has been isolated. Poliovirus RNA polymerase has been well characterized and isolation of resistant virus was examined in poliovirus. METHODS: Susceptibility variants of poliovirus I (Sabin strain) were isolated during passages in the presence of favipiravir and characterized for their susceptibility and the sequence of RNA polymerase. RESULTS: Five variants with 0.47-1.88 times the 50% inhibitory concentration for plaque formation of the parent poliovirus had amino acid variations in the 3D gene of the RNA polymerase. The distribution of amino acid variations was not related to ribavirin resistance, and two amino acid variation sites were found near the finger domain. CONCLUSION: Favipiravir as a chain terminator would not be incorporated and replicate to cause lethal mutagenesis as a mutagen like ribavirin, and resistant mutants were not isolated. A high replication level would generate mutations leading to favipiravir resistance as ribavirin resistance was generated, but generated mutations would be lethal to the RNA polymerase function.