THE GORDON WILSON LECTURE: THE HEPATITIS C VIRUS: FROM HIPPOCRATES TO CURE.

The modern age of viral hepatitis began in the early 1960s with the serendipitous discovery of the Australia antigen, a protein that was later shown to represent the envelope of the hepatitis B virus leading to its designation as the hepatitis B surface antigen. This was the first marker for any hepatitis virus and became not only a diagnostic assay, but also a mandatory blood donor screening test and the basis for the first generation hepatitis B vaccine. Prospective studies of transfusion recipients then showed that hepatitis B virus accounted for only 25% of cases of post-transfusion hepatitis (PTH). Discovery of the hepatitis A virus in 1975 revealed that none of the non-B PTH cases were due to hepatitis A virus infection resulting in the designation of this predominant form of PTH as non-A, non-B hepatitis. Using pedigreed patient samples and the chimp model, it was shown even before the advent of molecular biology that the non-A, non-B agent was small and lipid enveloped suggesting it might be a flavivirus. This was confirmed when the agent was cloned by Houghton and colleagues at the Chiron Corporation in 1987 and renamed the hepatitis C virus (HCV). In 1990 a donor screening assay for HCV was introduced nationwide and by 1997 PTH had virtually disappeared with rates now mathematically estimated to be one case per 2 million transfusions, compared to a 30% incidence before 1970. Clinical and molecular studies of HCV have shown that it results in persistent infection in 75% to 85% of cases due to its high replication rate, its existence as a quasispecies with a high mutation rate and the ability of HCV proteins to blunt and ultimately exhaust the HCV immune response. Although HCV infection is clinically and histologically mild in most patients, it can lead to progressive fibrosis over the course of decades in 30% to 40% and culminate in cirrhosis and end-stage liver disease. HCV can also cause hepatocellular carcinoma, generally on the background of cirrhosis with an incidence of 1% to 3% per year in this setting. After 2 decades of difficult and prolonged treatments with interferon-based regimens that resulted in cure rates of less than 50%, successive generations of HCV specific direct-acting antivirals were introduced that now result in cure rates of 95% to 100% across all genotypes after only 8 to 12 weeks of nontoxic oral therapy. This unprecedented efficacy has led to speculation that HCV infection might be eradicated even in the absence of a vaccine, but there are many impediments to global eradication including ascertainment of silent carriers, access to medication, and high drug cost. Nonetheless, we are in a new era of HCV control and optimism abounds.

Viral safety of coagulation factor concentrates: memoirs from an insider.

The purpose of this essay is to recall the actions taken globally to improve the viral safety of coagulation factor concentrates, mainly in the years 1985-1990, at a time of confusing and often contradictory information on bloodborne viral infections in multitransfused patients with hemophilia (PWHs). I shall first recall the problem of the transmission and control of the hepatitis viruses, and then that of HIV: not only for temporal reasons, but also because understanding the progress of knowledge on hepatitis and the poor success of the early measures taken to tackle this problem in PWHs is essential to understand how the problem of HIV transmission was ultimately dealt with successfully.

The life, times, and health care of Harry L Hopkins: Presidential advisor and perpetual patient.

Harry Hopkins was the most important nontitled allied leader in World War II. He was the advisor to President Roosevelt who managed the diplomacy between Roosevelt, Churchill, and Stalin from 1941 to 1946. Throughout these times, Hopkins was ill and required transfusions, admissions to the hospital, and nutritional supplementation to keep him well enough to travel the world and manage the allied war diplomacy. There has been no unifying theory to account for all his symptoms and his reported pathologic and autopsy findings. In this paper, we will review his political and medical history and a differential diagnosis of his illness.

History and Global Burden of Viral Hepatitis.

Between 1963 and 1989, 5 hepatotropic viruses have been discovered that are the major causes of viral hepatitides worldwide: hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus and hepatitis E virus. Their epidemiology and pathogenesis have been studied in great detail. Furthermore, the structure and genetic organization of their DNA or RNA genome including the viral life cycle have been elucidated and have been successfully translated into important clinical applications, such as the specific diagnosis, therapy and prevention of the associated liver diseases, including liver cirrhosis and hepatocellular carcinoma (HCC). The prevalence of acute and chronic viral hepatitis A-E shows distinct geographic differences. The global burden of disease (prevalence, incidence, death, disability-adjusted life years) has been analyzed in seminal studies that show that the worldwide prevalence of hepatitis A-E has significantly decreased between 1990 and 2013. During the same time, the incidence of HBV-related liver cirrhosis and HCC, respectively, also decreased or increased slightly, the incidence of the HCV-related liver cirrhosis remained stable and the incidence of HCV-related HCC showed a major increase. During the coming years, we expect to improve our ability to prevent and effectively treat viral hepatitis A-E, resulting in the control of these global infections and the elimination of their associated morbidities and mortalities.

Viral hepatitis: past and future of HBV and HDV.

Viral hepatitis is a significant disease afflicting hundreds of millions of people. Hepatitis-causing viruses initiate significant morbidity and mortality by establishing both acute and chronic infections, and several of these viruses are specifically associated with the development of hepatocellular carcinoma (HCC). Consequently, intense research efforts are focused on increasing our understanding of virus biology and on improving antiviral therapy. Even though viral hepatitis can be caused by several viruses from a range of virus families, the discovery of components of the hepatitis B virus (HBV) became a catalyst for the development of diagnostic assays that differentiate between these viruses as well as strategies for novel methods of vaccine development. Improvements in both the treatment and prevention of viral hepatitis are advancing rapidly. However, HBV, along with the associated infection by the hepatitis D virus, is still among the most common pathogens afflicting humans.

[The infectious diseases experiments conducted on human guinea pigs by Nazis in concentration camps]. / Gli esperimenti di infezioni su cavie umane compiuti dai nazisti nei campi di concentramento.

The author systematically examined all available publications and web documents, with regard to scientifically documented experiments carried out by Nazi physicians in their concentration camps during World War II. This research focused on human experiments dealing with: malaria, tuberculosis, petechial typhus, viral hepatitis, and those regarding sulphonamides as antimicrobial agents. The concentration camps involved by experimental programmes on human guinea pigs were: Natzweiler Struthof, Dachau, Mauthausen, Buchenwald, Neuengamme, Ravensbrück, Sachsenhausen and Auschwitz. Overall, around 7,200 deported prisoners went to their deaths during or because of these experiments (also considering human trials other than previously quoted ones). At the end of the war several physicians were charged with war crimes in two trials (Nuremberg and Dachau), and those found guilty were sentenced to death, or years of imprisonment. Some of them, including the notorious Josef Mengele, succeeded in escaping capture and being brought to justice. Thanks to these trials, partial light has been shed on these crimes, which not infrequently had children as designated victims, selected with excruciating cruelty in special segregation sections. The SS was the key structure which ensured maximum efficiency for these experimental programmes, from both logistic planning through to an operative control system carried out in concentration camps, and thanks to an autonomous, dedicated medical structure, which included a rigid hierarchy of physicians directly dependent on the head of SS forces (Reichsführer), i.e. Dr. Heinrich Himmler. Moreover, it is worth noting that also physicians who were not part of the SS corps collaborated in the above experiments on human guinea pigs: these included military personnel belonging to the Wehrmacht, academic physicians from German universities, and researchers who worked in some German pharmaceutical industries, such as IG Farben, Bayer and Boehring.

From hepatic diseases and jaundice to viral hepatitis: the configuration of a kaleidoscope.

Viral hepatitis A, B, C, D and E--systemic hepatotropic viral infections--present as acute hepatitis that, depending on the etiological agent, viral load and host conditions, may evolve into chronic hepatitis, cirrhosis, liver cancer and acute fulminant disease. The ecological versatility of these viruses, their spectrum of transmission in time and space, potentialized by the sub-clinical course of a large proportion of infections, comprise an epidemiological challenge. This essay describes scenarios and tendencies in the socioepidemiologic profile, based on the history of these infections, and indicates the need to overcome patterns, models, and protocols and instead investigate each particular situation. In other words, it highlights the need to explore singularities in order to be able to develop new proposals for general actions tailored to local specificities.

Das hepatopatias e icterícias às hepatites virais: configuração de um caleidoscópio / From hepatic diseases and jaundice to viral hepatitis: the configuration of a kaleidoscope / De las hepatopatías e ictericias a las hepatitis virales: configuración de un caleidoscopio

As hepatites virais A, B, C, D e E - viroses sistêmicas hepatotrópicas - produzem quadros de hepatite aguda. Dependendo do agente etiológico, da carga viral e de condições do hospedeiro, podem evoluir para hepatite crônica, cirrose, câncer de fígado e formas agudas fulminantes. A versatilidade ecológica desses vírus configura uma natureza espectral e cambiante de transmissão no tempo e no espaço; potencializada pelo curso subclínico por vezes prolongado de grande parte das infecções, constitui-se em desafio epidemiológico. Com base no curso histórico dessas infecções foram descritos cenários e tendências relativas ao seu comportamento socioepidemiológico, apontando para a necessidade de superar modelos, padrões, protocolos e retornar à investigação de cada situação de saúde/doença. Ou seja, assinala para a imprescindível exploração das singularidades no sentido de desenvolver ações gerais modeladas pelas especificidades locais.

Viral hepatitis A, B, C, D and E - systemic hepatotropic viral infections - present as acute hepatitis that, depending on the etiological agent, viral load and host conditions, may evolve into chronic hepatitis, cirrhosis, liver cancer and acute fulminant disease. The ecological versatility of these viruses, their spectrum of transmission in time and space, potentialized by the sub-clinical course of a large proportion of infections, comprise an epidemiological challenge. This essay describes scenarios and tendencies in the socioepidemiologic profile, based on the history of these infections, and indicates the need to overcome patterns, models, and protocols and instead investigate each particular situation. In other words, it highlights the need to explore singularities in order to be able to develop new proposals for general actions tailored to local specificities.

Las hepatitis virales A, B, C, D y E - virosis sistémicas hepatotrópicas - producen cuadros de hepatitis aguda. Dependiendo del agente etiológico, de la carga viral y de las condiciones del hospedador, pueden evolucionar hacia hepatitis crónica, cirrosis, cáncer del hígado y formas agudas fulminantes. La versatilidad ecológica de estos virus, configura una naturaleza espectral y cambiante de transmisión en el tiempo y espacio; potencializada por el curso subclínico, a veces prolongado, constituye un desafío epidemiológico en gran parte de las infecciones. Con base en el curso histórico de estas infecciones se han descrito escenarios y tendencias relativas a su comportamiento socioepidemiológico, apuntando hacia la necesidad de superar modelos, patrones, protocolos, y retornar a la investigación de cada situación de salud/enfermedad. Es decir, señala la imprescindible exploración de las singularidades en el sentido de desarrollar acciones generales modeladas por las especificidades locales.

Mortality and morbidity among military personnel and civilians during the 1930s and World War II from transmission of hepatitis during yellow fever vaccination: systematic review.

During World War II, nearly all US and Allied troops received yellow fever vaccine. Until May 1942, it was both grown and suspended in human serum. In April 1942, major epidemics of hepatitis occurred in US and Allied troops who had received yellow fever vaccine. A rapid and thorough investigation by the US surgeon general followed, and a directive was issued discontinuing the use of human serum in vaccine production. The large number of cases of hepatitis caused by the administration of this vaccine could have been avoided. Had authorities undertaken a thorough review of the literature, they would have discovered published reports, as early as 1885, of postvaccination epidemics of hepatitis in both men and horses. It would take 4 additional decades of experiments and epidemiological research before viruses of hepatitis A, B, C, D, and E were identified, their modes of transmission understood, and their genomes sequenced.

[Hepatitis: a longstanding companion in human history]. / L'epatite: un compagno di lungo corso della storia umana.

Hepatitis has gone along with human history since its origins, due to its prompt identifiability linked to jaundice as a symptom. Written evidence of outbreaks of epidemic jaundice can be tracked back a few millenniums before Christ. Unavoidable confusion arises due to the overlap of different sources possibly linked to different aetiologies, identified over time as epidemic jaundice (HAV or HEV hepatitis?) and serum hepatitis (HBV or HCV hepatitis?). The journey that brought to recognize viruses as the main cause of jaundice was long and started midway during the last century, when the infectious hypothesis, which had taken place step by step, was finally confirmed by epidemiological investigations of an outbreak occurring in the US army in 1942, after a yellow fever immunization campaign. Further research identified two clinically different types of hepatitis, called for the first time hepatitis A and hepatitis B.

Does pediatrics need its own bioethics?

Pediatric bioethics raises unique issues because children are constantly growing, developing, and changing. The ethical issues that arise for newborns are different from those that arise for seven-year-olds or 17-year-olds. Furthermore, children do not develop cognitive capacities or moral reasoning skills at the same rate. Thus, it is difficult to generalize about what is appropriate or inappropriate for children in either the clinical or the research setting. This article responds to some of the issues raised by a new volume of essays about pediatric bioethics. It puts these issues into historical context by examining the implications of Saul Krugman's famous studies on the etiology and prevention of hepatitis at New York's Willowbrook State School.

[History of viral hepatitis]. / Histórico das hepatites virais.

INTRODUCTION: The history of viral hepatitis goes back thousands of years and is a fascinating one. When humans were first infected by such agents, a natural repetitive cycle began, with the capacity to infect billions of humans, thus decimating the population and causing sequelae in thousands of lives. METHODS: This article reviews the available scientific information on the history of viral hepatitis. All the information was obtained through extensive bibliographic review, including original and review articles and consultations on the internet. RESULTS: There are reports on outbreaks of jaundice epidemics in China 5,000 years ago and in Babylon more than 2,500 years ago. The catastrophic history of great jaundice epidemics and pandemics is well known and generally associated with major wars. In the American Civil War, 40,000 cases occurred among Union troops. In 1885, an outbreak of catarrhal jaundice affected 191 workers at the Bremen shipyard (Germany) after vaccination against smallpox. In 1942, 28,585 soldiers became infected with hepatitis after inoculation with the yellow fever vaccine. The number of cases of hepatitis during the Second World War was estimated to be 16 million. Only in the twentieth century were the main agents causing viral hepatitis identified. The hepatitis B virus was the first to be discovered. CONCLUSIONS: In this paper, through reviewing the history of major epidemics caused by hepatitis viruses and the history of discovery of these agents, singular peculiarities were revealed. Examples of this include the accidental or chance discovery of the hepatitis B and D viruses.

Histórico das hepatites virais / History of viral hepatitis

INTRODUÇÃO: A história das hepatites virais remonta milhares de anos e é fascinante. Quando o ser humano sofreu pela primeira vez a invasão do seu organismo por tais agentes, iniciou-se um ciclo natural e repetitivo capaz de infectar bilhões de seres humanos, dizimar e sequelar milhares de vida. MÉTODOS: Este artigo rever informações científicas disponíveis sobre o histórico das hepatites virais. Todas as informações foram obtidas através de extensa revisão bibliográfica, compreendendo artigos originais e de revisão e consultas na rede internet. RESULTADOS: Existem relatos de surtos de icterícia epidêmica na China há mais de 5.000 anos e na Babilônia, há mais de 2.500 anos. A história catastrófica das grandes epidemias ou pandemias ictéricas são conhecidas e geralmente estão associadas às grandes guerras. Na guerra da Secessão Americana, 40 mil casos ocorreram entre militares da União. Em 1885, um surto de icterícia catarral acometeu 191 trabalhadores do estaleiro de Bremen (Alemanha) após vacinação contra varíola. Em 1942, 28.585 soldados contraíram hepatite após inoculação da vacina contra a febre amarela. O número de casos de hepatite durante a Segunda Grande Guerra foi estimado em 16 milhões. Somente no século XX, foram identificados os principais agentes causadores das hepatites virais. O vírus da hepatite B foi o primeiro a ser descoberto. CONCLUSÕES: Neste artigo, a revisão da história das grandes epidemias ocasionadas pelos vírus das hepatites e a descoberta desses agentes revelam singulares peculiaridades, citando como exemplo, a descoberta acidental ou por acaso dos vírus da hepatite B e D.

INTRODUCTION: The history of viral hepatitis goes back thousands of years and is a fascinating one. When humans were first infected by such agents, a natural repetitive cycle began, with the capacity to infect billions of humans, thus decimating the population and causing sequelae in thousands of lives. METHODS: This article reviews the available scientific information on the history of viral hepatitis. All the information was obtained through extensive bibliographic review, including original and review articles and consultations on the internet. RESULTS: There are reports on outbreaks of jaundice epidemics in China 5,000 years ago and in Babylon more than 2,500 years ago. The catastrophic history of great jaundice epidemics and pandemics is well known and generally associated with major wars. In the American Civil War, 40,000 cases occurred among Union troops. In 1885, an outbreak of catarrhal jaundice affected 191 workers at the Bremen shipyard (Germany) after vaccination against smallpox. In 1942, 28,585 soldiers became infected with hepatitis after inoculation with the yellow fever vaccine. The number of cases of hepatitis during the Second World War was estimated to be 16 million. Only in the twentieth century were the main agents causing viral hepatitis identified. The hepatitis B virus was the first to be discovered. CONCLUSIONS: In this paper, through reviewing the history of major epidemics caused by hepatitis viruses and the history of discovery of these agents, singular peculiarities were revealed. Examples of this include the accidental or chance discovery of the hepatitis B and D viruses.

Advances in viral hepatitis: 50 years of Australian gastroenterology.

Viral hepatitis classification, treatments and pathogenesis has been increasingly defined over the past 50 years. Australian researchers have made significant contributions in the areas of viral hepatitis A vaccine development, treatment outcomes for chronic hepatitis B and C, the role of liver transplantation and the pathogenesis of injury and disease progression. This review outlines some of these contributions.