Potencial uso terapéutico del ARN de interferencia contra la COVID-19 / Potential therapeutic use of RNA interference against COVID-19

Introducción: El SARS-CoV-2 es el agente causal de la COVID-19, enfermedad respiratoria que ha causado miles de víctimas fatales a escala global, y para la cual no existe ninguna terapia curativa efectiva. Objetivo: Reflejar la relevancia potencial de la tecnología de ARN de interferencia (ARNi), como alternativa terapéutica contra la COVID-19. Material y métodos: Se consultaron las bases de datos especializadas en busca de artículos publicados hasta abril de 2020. Se emplearon descriptores específicos y operadores booleanos. Se empleó la estrategia de búsqueda avanzada para la selección de los artículos, teniendo en cuenta la calidad metodológica o validez de los estudios. Desarrollo: Fueron identificadas evidencias de aplicación a nivel experimental de la tecnología de ARNi contra el SARS-CoV. Se han diseñado y evaluado varios ARNs pequeños interferentes y ARNs pequeños con estructura en lazo, orientados al silenciamiento de genes esenciales del SARS-CoV, incluyendo aquellos que codifican las proteínas S, RdRp, M, E, N, 3a/3b y 7a/7b. Se comprobó la efectividad de los ARNi en el silenciamiento de sus genes diana. Aunque la mayoría de estas investigaciones se han realizado en sistemas in vitro, también se ha comprobado la utilidad terapéutica de la administración intranasal de ARNi en un modelo de SARS-CoV in vivo. Conclusiones: La tecnología de ARNi ha mostrado potencialidades como estrategia terapéutica contra el SARS-CoV en modelos celulares y animales. Dadas las similitudes a nivel genómico y en cuanto al proceso patogénico entre SARS-CoV y SARS-CoV-2, esta tecnología es potencialmente aplicable el tratamiento de la COVID-19(AU)

Introduction: SARS-CoV-2 is the causal agent of COVID-19, a respiratory disease that has caused thousands of deaths globally for which there is no effective curative therapy. Objective: To demonstrate the potential relevance of RNA interference (RNAi) technology as a therapeutic alternative in the treatment of COVID-19. Materials and methods: Specialized biomedical databases were searched looking for studies published until April 2020. The search was carried out using descriptors and Boolean operators. Advanced search strategy was used for the selection of articles, taking into account the methodological quality and validity of the studies. Results: Evidence of experimental application of RNAi technology against SARS-CoV was identified. Several small interfering RNAs and small loop-structured RNAs oriented to the silencing of essential SARS-CoV genes including those encoding the S, RdRp, M, E, N, 3a/3b and 7a/7b proteins have been designed and evaluated. The effectiveness of RNAi for silencing its target genes was proven. Although most of these research studies have been conducted in in vitro systems, the therapeutic effectiveness of the intranasal administration of small RNA interference has also been proven in an in vivo SARS-CoV model. Conclusions: RNAi technology has demonstrated to be a potential therapeutic strategy against SARS-CoV in cellular and animal models. Given the similarities at the genomic level and in terms of the pathogenic process between SARS-CoV and SARS-CoV-2, this technology has a potential applicability for the treatment of COVID-19(AU)

Manejo de las infecciones por citomegalovirus y virus herpes simple en gestantes y recién nacidos / Management of Cytomegalovirus Infections and Herpes Simplex Virus in Pregnant Women and Newborns

Existe un grupo de infecciones que pueden producir defectos congénitos graves cuando se adquieren durante la gestación. Estas inciden en la morbilidad y mortalidad infantil, especialmente si la infección ocurre antes de las 20 semanas de embarazo. Entre ellas se encuentran las producidas por el citomegalovirus y el virus del herpes simple que con frecuencia se asocian con infección congénita y daño al recién nacido. El citomegalovirus humano está mundialmente distribuido entre las poblaciones humanas, desde los países desarrollados hasta las comunidades aborígenes. En países en vías de desarrollo y en los estratos socioeconómicos bajos de los países desarrollados, la prevalencia es mayor (más de 90 por ciento) y el virus se adquiere en edades más tempranas de la vida. Es la infección viral congénita más frecuente, ocurre de 0,3 a 2 por ciento de los nacimientos y en el 40 por ciento la transmisión es vertical. La distribución del virus del herpes simple es amplia y la seroprevalencia en el adulto es entre 60 y 75 por ciento para virus del herpes simple -1 y de 11-30 por ciento para virus del herpes simple -2. El objetivo de la presente revisión es describir estas dos entidades al abordar las características más comunes de estas afecciones, la epidemiología, el diagnóstico, la clínica y la terapéutica. Es necesario que el médico de asistencia las conozca a profundidad para realizar un correcto manejo de estas(AU)

There is a group of infections, which can cause serious birth defects when acquired during pregnancy. They affect infant morbidity and mortality, especially if the infection occurs before 20 weekspregnant. These include those caused by cytomegalovirus and herpes simplex virus that are often associated with congenital infection and damage to the newborn.Human cytomegalovirus (HCMV)is globally distributed among human populations from developed countries to Aboriginal communities. In developing and low socioeconomic strata of the developed countries, the prevalence is higher (over 90 percent) and the virus is acquired in earlier stages of life. It is the most common congenital viral infection. It occurs 0.3 to 2 percent of births and 40 percent transmission is vertical. The distribution of herpes simplex virus is broad and seroprevalence in adults is between 60 and 75 percent for herpes simplex 1 virus and 11-30 percent for herpes simplex virus -2. The aim of this review is to describe these two entities in addressing the most common features of these conditions as epidemiology, diagnosis, clinical and therapeutic. A profound knowledge is necessary for the attending physician to the proper handling of them(AU)

Rebrote virológico en el tratamiento de hepatitis B con entecavir: ¿resistencia? / Virological breakthrough in treating hepatitis B with entecavir: It means resistance?

Paciente varón de 45 años natural de Lima, casado con antecedentes de , múltiples parejas sexuales y operado de fimosis, que debuta con eritema nodoso y diagnosticado de hepatitis B crónica en Agosto del 2008, en controles por consultorio se realiza diagnóstico de cirrosis hepática child A y hepatocarcinoma. Inicia tratamiento para la hepatitis B con Entecavir 0,5mg y luego se realiza hepatectomía del segmento V, En Febrero 2009 en controles de imágenes se evidencia recidiva de hepatocarcinoma en el segmento VI (lesión de 14mm) con AFP de 68 ng/dl, se realiza etanolización, con evolución final favorable. Durante el seguimiento no se observa evidencia de recidiva de HCC, continua con Entecavir 0,5 mg /d y en abril 2010, luego de 72 semanas de tratamiento con adecuada adherencia al tratamiento presenta rebrote virológico (carga viral positiva de 646 UI/dl), y se decide agregar a la terapia Tenofovir. Actualmente paciente con buena evolución con última carga viral de Abril del 2012 negativa recibiendo terapia doble para VHB. Reportamos el caso por ser uno de los primeros en nuestro país de resistencia probable a Entecavir y donde se pone de manifiesto la necesidad de examenes complementarios que confirmen dicha sospecha.

A 45 year- old - married man, with several sexual partners, initiated symptoms with nodosum erythema and in August 2008, is diagnosed of chronic hepatitis due to hepatitis B virus (HBV). Later he was diagnosed of Child A cirrhosis and hepatocarcinoma. He began HBV treatment with Entecavir 0,5 mg; then he underwent a V segment hepatectomy. In February 2009 he presented a relapse with a tumor of 14 mm on VI segment with AFP values of 68 ng/dl, so he underwent an ethanolization with good evolution. During the follow up, he has not presented evidence of relapse of hepatocarcinoma and continued with Entecavir 0,5 mg/d. In April 2010, after 72 weeks of therapy with good compliance, the patient presented a virological breakthrough (viral load 646 UI/dl) and Tenofovir was added to his therapy. Nowadays the patient is receiving double therapy for HBV and his last viral load, April 2012, was negative. This could be the first case in our country of a probable resistance to Entecavir; complementary tests are needed in order to rule out this suspicion.

Manejo de la hepatitis B aguda grave y fulminante / Management of acute fulminant hepatitis B

Fulminant hepatitis B virus infection occurs in less than 1percent of acutely infected patients. Acute hepatitis Baccounts for 2-42 percent of the total of fulminant hepatitis cases depending on the geographic area. This infection is associated with 65-93 percent of mortality, without liver transplantation. Its pathogenesis is related to a severe immune response to infected hepatocytes, causing massive cytolysis and liver failure. During the last 3 decades its prognosis has improved due to better medical support in intensive care units, the use of liver transplantation and an improvement in the prevention and management of its complications. More recently the use of liver support devices (MARS, Prometheus, and BAL) has been considered in this situation as a bridge to liver transplantation. Recurrent hepatitis B virus reinfection of the graft was a major issue in the past, but currently with the use of hepatitis B immunoglobulin (HBIg) and oral antiviral therapy, the prognosis has improved, leading to excellent graft and patient outcomes after liver transplantation. There is controversial data on the use of oral antiviral therapy among fulminant hepatitis patients. While some authors have shown beneficial effects, other communications have failed to demonstrate any benefits. Nevertheless, many experts currently recommend the use of oral antiviral therapy in this setting due to their relative safety and potential benefits. This paper reviews the current view on management issues in reference to the patient with fulminant hepatic failure due to acute hepatitis B.

La hepatitis fulminante por virus de hepatitis B ocurre en menos del 1 por ciento de los casos de hepatitis B aguda. Del total de hepatitis fulminantes, entre el 2-42 por ciento son causadas por hepatitis B aguda, dependiendo del lugar geográfico donde se estudia. Se asocia a elevada mortalidad, entre 65-93 por ciento, sin el uso de trasplante hepático. Su patogenia se relaciona a una significativa respuesta inmune a hepatocitos infectados, determinando citolisis masiva y falla hepática. En las últimas 3 décadas el pronóstico de esta patología ha mejorado gracias al soporte médico en unidades de tratamiento intensivo, a la implementación del trasplante hepático, y a la mejoría en la prevención y manejo de sus complicaciones. Más recientemente se ha usado dispositivos de soporte hepático (MARS, Prometheus, BAL), como un puente al trasplante hepático. La reinfección del injerto con hepatitis B era una consideración importante en el pasado, pero con el uso de gamaglobulina específica para hepatitis B y el tratamiento antiviral oral, su pronóstico ha mejorado, determinando un excelente pronóstico del injerto y del paciente a largo plazo post trasplante hepático. Existen datos controversiales referentes al uso de antivirales orales durante una hepatitis fulminante, pues algunos autores muestran beneficios en esta condición, pero otros no han demostrado un beneficio real. Sin embargo, muchos expertos actualmente recomiendan su uso en este escenario, pues son seguros y pueden tener un potencial beneficio. Este artículo revisa el manejo actual del paciente con hepatitis fulminante por hepatitis B aguda.

Actualización en manejo de la Hepatitis B / Update on hepatitis B management

La infección por virus de la Hepatitis B (VHB) constituye un grave problema de salud. Aproximadamente un cuarto de la población mundial presenta evidencia serológica de infección pasada o presente por VHB y 350 millones de personas presentan la infección en forma crónica. La infección por VHB se asocia con 500.000 muertes al año causadas por hepatitis, cirrosis y carcinoma hepatocelular. Chile es considerado un país con baja prevalencia de infección por VHB (menor que 1 por ciento) en que la mayoría de los casos se adquieren en la adultez, contrariamente a lo que ocurre en países de Asia y África, donde la infección crónica por VHB es muy común (5-18 por ciento) y donde esta enfermedad es adquirida generalmente en el período perinatal o durante la infancia. La historia natural de la infección crónica por VHB es variable y fluctúa desde estado de portadores inactivos de HBs Ag a una hepatitis crónica menos progresiva, que potencialmente puede evolucionar a cirrosis y hepatocarcinoma. Programas efectivos de vacunación contra la infección por VHB disminuirán la incidencia de nuevas infecciones por VHB y la carga de enfermedad en las próximas décadas. Los pacientes con infección crónica por VHB deben ser correctamente evaluados para decidir si requerirán o no terapia antiviral. Pacientes adultos con infección crónica por VHB con una carga viral de, mayor 104 copias/ml (mayor que 2.000 UI/mL), con niveles anormales de alanina aminotransferasa (ALT) y evidencia de actividad necroinflamatoria en la biopsia hepática son candidatos para tratamiento antiviral. Actualmente se encuentran disponibles siete drogas para el tratamiento de la hepatitis B crónica: interferón-α convencional, lamivudina, adefovir dipivoxil, interferón pegilado α 2a y 2b, entecavir, telbivudina y tenofovir. Los análogos de nucleósidos/nucleótidos orales actualmente disponibles son muy potentes y pueden producir altas tasas de respuesta virológica, con una alta barrera genética a...

Hepatitis B virus (HBV) infection constitutes a serious health problem, with approximately one-fourth of the world population having serological evidence of past or present infection by HBV and 350 million people being chronically infected. HBV infection is associated to 500,000 deaths per year caused by hepatitis, cirrhosis, and hepatocellular carcinoma. Chile is considered a country with a low prevalence of HVB infection (less than 1 percent) where most cases are acquired in adulthood, as opposed to countries in Asia and Africa, where chronic HBV infection is very common (5-18 percent) and where this disease is usually acquired perinatally or during childhood. The natural history of HBV chronic infection is variable, ranging from an inactive HBsAg carrier state to a more or less progressive chronic hepatitis, potentially evolving to cirrhosis and hepatocarcinoma. Effective vaccination programs against HBV infection will decrease the incidence of new HVB infections and the burden of disease in the next few decades. Patients with chronic HVB infection need to be correctly evaluated to decide whether or not they will require antiviral therapy. Adult patients with chronic HVB infection with a viral load of more than 104 copies/ml (more than 2,000 IU/mL), with abnormal ALT levels and evidence of necroinfl ammatory activity on liver biopsy are candidates for antiviral treatment. Seven drugs are currently available for the treatment of chronic hepatitis B (CHB): conventional interferon-α, lamivudine, adefovir dipivoxil, pegylated interferon α-2a and 2b, entecavir, telbivudine and tenofovir. Currently available oral nucleotide analogues are very potent and can induce high rates of virological response, with a high genetic barrier to resistance in the majority of patients (entecavir and tenofovir).

Influência dos genótipos no tratamento da hepatite B: [revisão] / Influence on its genotypes of the treatment for type B hepatitis: [review]

A hepatite B pode ser classificada em oito diferentes genótipos (A-H). Esses genótipos diferem na sua distribuição geográfica mundial. No Brasil, os genótipos mais freqüentemente encontrados são o A, D e F. Algumas alterações na estrutura genética desses genótipos podem resultar em diferentes níveis de patogenicidade, sendo relacionadas com maior ou menor risco de desenvolvimento de hepatocarcinoma ou cirrose no fígado. Além das diferenças citadas, a heterogeneidade dos genótipos da hepatite B parece estar relacionada com diferenças na evolução clínica da infecção e na resposta ao tratamento antiviral. Alguns genótipos demonstraram responder melhor ao tratamento com interferon ou nucleotídeos análogos do que outros. O objetivo desta revisão foi demonstrar a importância do tratamento da hepatite B baseado nos seus diferentes genótipos. Foram revisados artigos da literatura, selecionando aqueles que abordavam questões relacionadas aos genótipos da hepatite B e sua relação com o tratamento desta infecção. Nos artigos revisados, o tratamento da hepatite B baseada em genótipos apresentou diferenças significativas. Os genótipos A e B parecem ter uma melhor resposta ao tratamento antiviral com interferon alfa e/ou lamivudina; porém, mais estudos são necessários para a consistência dessa afirmação. No entanto, através dos presentes dados, já é possível demonstrar forte associação entre genótipos e resposta antiviral. Deste modo, adaptar o tratamento aos genótipos pode promover uma melhor resposta do interferon e dos nucleotídeos na terapêutica da infecção pelo vírus da hepatite B.

Type B hepatitis can be classified according to eight different genotypes (A-H). These genotypes are different in terms of worldwide geographical distribution. In Brazil the most frequent genotypes are A, D and F. Some changes in the genetic structure of these genotypes can cause different levels of pathogenesis, being related to lower or higher risk of developing hepatocellular carcinoma or liver cirrhosis. In addition to the above mentioned differences, heterogeneity of hepatitis B genotypes seems to be related to the differences in clinical evolution of the infection and response to antiviral treatment. Some genotypes proved to have a better response to the treatment using interferon or similar nucleotides than others. This review aimed at showing the importance of treatment of type B hepatitis based on its different genotypes. Different articles from the specific medical literature were reviewed and those including genotypes for type B hepatitis and their association with the treatment of this infection were selected. In the reviewed articles genotypebased treatment of hepatitis B showed significant differences. Genotypes A and B seem to have a better response to the antiviral treatment with alpha interferon and/or lamivudine; however, more studies are necessary to confirm this assertion. Nevertheless, using the present data it is already possible to prove a strong connection between genotypes and antiviral response. Therefore, adjusting treatment to genotypes can cause a better therapeutic response from interferon and nucleotides in type B hepatitis therapy.

Correlação entre uso de quimioterápicos antiinfecciosos e mortalidade / Correlation between antimicrobial chemotherapy and mortality

Objetivo: Correlacionar o consumo de quimioterápicos antiinfecciosos com mortes. Delineamento: Vigilância epidemiológica. População: Foram registradas todas as drogas quimioterápicas antiinfecciosas prescritas para tratar doenças infecciosas em um hospital. Os pacientes que as usaram foram seguidos desde a admissão até a alta ou o óbito hospitalar. Resultados: Foram estudados 4.968 pacientes que internaram 6.043 vezes. Das 2.305 internações nas quais os pacientes usaram quimioterápicos antiinfecciosos, 2.206 (95,7%) das vezes eles sobreviveram e 99 (4,29%) morreram. Os que sobreviveram usaram em média 1,55 (DP 1,09) quimioterápicos antiinfecciosos e os que morreram usaram em média 2,78 (DP 2,44) quimioterápicos antiinfecciosos, p<0.001. A correlação foi linear entre o número de quimioterápicos antiinfecciosos usados e a mortalidade. Os coeficientes obtidos foram: de correlação, 0.869 (p<0.001) e de determinação de Pearson de 0.755. O consumo de quimioterápicos antiinfecciosos por pacientes obteve correlação linear positiva de Spearman's rho de 0.905 (p=0.002). As relações entre as idades e a mortalidade obtiveram o coeficiente de correlação de Sperman's rho de 0.936, p<0.00. Conclusão: A quantidade de quimioterápicos antiinfecciosos usados para tratar pacientes se correlacionou positivamente com a morte e não parece ser uma boa estratégia para prevenila. Os autores sugerem desenvolver-se o conceito epidemiológico de suficiência de tratamento, considerando a cura e a morte como desfechos, como um índice de uso racional de quimioterápicos antiinfecciosos. Acredita-se que essa estratégia possa obter resultados de impacto no combate a crescente resistência antimicrobiana e na diminuição de gastos desnecessários em quimioterápicos antiinfecciosos (AU)

Aim: To correlate the consumption of antimicrobial chemotherapeutic agents with death figures. Research design: Epidemiological surveillance. Population: All antimicrobial chemotherapeutic agents prescribed to treat infectious diseases in a given hospital were registered. Patients were followed since admission until discharge or fatal outcome at the hospital. Results: Charts from 4968 patients, whose admissions totaled 6043 occasions, were analyzed. From a total of 2305 admissions in which patients were prescribed antimicrobial chemotherapeutic agents, in 2206 (95,7%) of the occasions patients survived, whereas in 99 occasions (4,29%) they died. Those who survived used in average 1,55 (SD 1,09) antimicrobial chemotherapeutic agents, while those who died used in average 2,78 (SD 2,44) antimicrobial chemotherapeutic agents (p<0.001). The observed correlation was linear between the number of antimicrobial chemotherapeutic agents prescribed and mortality. Two coefficients endorsed the observed correlation: a correlation coefficient of 0.869 (p<0.001) and a Pearson of 0.755. The consumption of antimicrobial chemotherapeutic displayed a linear and positive Spearman's correlation of 0.905 (p=0.002). The correlations between age and mortality yelled a Sperman's ρ of 0.936 (p<0.00). Conclusion: The quantity of prescribed antimicrobial chemotherapeutic was positively correlated with death. The development of a concept of epidemiological sufficiency of treatment is recommend by the authors. This concept, which considers cure and death as possible outcomes, would constitute a index of rational use of antimicrobial chemotherapeutic agents. It is believed that this strategy might help to curb the bacterial resistance to antimicrobial chemotherapeutic agents as well as to reduce dispensable expenditures with these pharmacological tools (AU)