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The Hepatitis C Core Curriculum provides an outline to IDSA members of the foundational knowledge points for treating hepatitis C virus (HCV). The core curriculum provides self-guided, structured learning by directing users to publically available educational resources. Upon completion of the Hepatitis C Core Curriculum, a clinician should be able to understand the pathogenesis of HCV, identify patients susceptible to HCV infection, perform critical pre-treatment evaluations to determine the most viable treatment option, and manage the complexities of patients undergoing treatment.
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This video lecture provides information on topics that include, but are not limited, to the following:• HCV genotypes• Progression of HCV • Treatment of HCV • HCV life cycle • HCV entry – a multistep process• RNA genome structure and organization • HCV RNA replication • Targets for antiviral drug development
This video provides information on topics that include, but are not limited, to the following: • HCV Genome• Composition of hepatitis c virus• HCV receptors/entry factors• HCV life cycle key features• HCV genotypes and quasispecies• Drugs to fight HCV infection• Targeting host cell functions required for HCV replication• Complementary and alternative medicine
The Center for the Study of Hepatitis C provides an interactive presentation on the sequence of biological events explaining how HCV enters a liver cell, makes copies of itself, and then exits to infect other cells. This process and the ensuing host immune response lead to cell damage that is the hallmark of liver disease.
The hepatitis C virus (HCV) is a major medical problem with at least 130 million infected individuals worldwide. Over the last decade multiple host factors required for HCV cell entry have been identified, but a detailed understanding of their mechanistic interplay remains elusive. Nonetheless, recent advances in defining species-specific barriers of HCV transmission have allowed the identification of a minimal set of entry factors that are required for HCV infection of rodent cells and has culminated in an animal model that recapitulates HCV entry in vivo. A detailed understanding of the viral uptake pathway is imperative to define new drug targets allowing for more effective intervention against this devastating disease.
The hepatitis C virus (HCV) is a remarkably successful pathogen, establishing persistent infection in more than two-thirds of those who contract it. Its success is related to its abilities to blunt innate antiviral pathways and to evade adaptive immune responses. These two themes may be related. We propose that HCV takes advantage of the impaired innate response to delay the organization of an effective adaptive immune attack. The tolerogenic liver environment may provide cover, prolonging this delay. HCV's error-prone replication strategy permits rapid evolution under immune pressure. Persistent high levels of viral antigens may contribute to immune exhaustion. Finally, the virus may benefit from the efficient enlistment of memory T and B cells in the pursuit of a moving target.
The Department of Veterans Affairs' topic review of Hepatitis C Genotypes and Quasispecies provides information on HCV genotypes, the clinical significance of hepatitis C genotypes, quasispecies and viral mutation, and clinical significance of quasispecies.
This video provides information on topics that include, but are not limited, to the following:• HCV pathogenesis• Emergence of HCV-related liver cancer• How HCV causes liver cancer• Role of c-Myc responsive genes in malignant conversion • Host factors in HCV replication and pathogenesis• NS5B regulation of pRb• HCV interactions with tumor suppressors and HCC
This video provides information on topics that include, but are not limited, to the following:• Spontaneous resolution of acute HCV• Differential host response gene expression in HCV infection• HCV: multiple interactions to antagonize interferon • Acute HCV and progression to chronic infection• HCV envelope proteins• Hepatic interactions of immune cells in HCV liver• CD4+ T cells determining outcome• HCV persistence associate with evolution of CTL epitopes
This video provides information on topics that include, but are not limited, to the following:• Determinants of the outcome of infection• Evidence for a role of the humoral immune response• Cellular immune response associated with recovery• CD4+ T-Lymphocytes • CD8+ T-Lymphocytes• HCV mutations
Hepatitis C virus (HCV) was discovered more than two decades ago, but progress towards a vaccine has been slow. HCV infection will spontaneously clear in about 25% of people. Studies of spontaneous HCV clearance in chimpanzees and human beings have identified host and viral factors that could be important in the control of HCV infection and the design of HCV vaccines. Although data from studies of chimpanzees suggest that protection against reinfection is possible after spontaneous clearance, HCV is a human disease. Results from studies of reinfection risk after spontaneous clearance in injecting drug users are conflicting, but some people seem to have protection against HCV persistence. To guide future vaccine development, we assess data from studies of HCV reinfection after spontaneous clearance, discuss flaws in the methods of previous human studies, and suggest essential components for future investigations of control of HCV infection.
HCV persistently infects the majority of patients exposed to it and can cause irreversible fibrosis, leading to the onerous clinical sequelae of cirrhosis. In this Review, we discuss the direct effects of HCV on hepatocytes and the role of the immune system in liver damage. HCV, like many viruses, has developed methods by which to subvert host innate and adaptive immune responses to infection. HCV proteins seem to modulate apoptosis and steatosis, ultimately leading to hepatic stellate cell activation, fibrosis and hepatocellular carcinoma. In addition, HCV manipulates the immune system, disrupting both innate and adaptive immunity to establish persistent infection. The immune system initially attempts to eradicate the virus, but, in the setting of chronic infection, probably promotes hepatocyte damage and fibrosis through direct cellular toxicity and the release of inflammatory cytokines. Multiple types of cytotoxic lymphocytes, comprising the unique immune hepatic microenvironment, are likely to be important in the pathogenesis of HCV-induced liver damage. The net liver damage from HCV infection depends on the balance between the host's antiviral mechanisms and the virus' ability to subvert them.
This chapter of the Caring Ambassadors Hepatitis C Choices book discusses immunological information and research conducted to better comprehend the aspects of the human immune system to naturally combat HCV infection.
The hepatitis C virus (HCV) persists in the majority of infected individuals and is a significant cause of human illness and death globally. Recent studies have yielded important insights into immunity to HCV, in particular revealing the central role of T cells in viral control and clearance. Other key features of adaptive immune responses remain obscure, including mechanisms by which T cells control HCV replication, the role of antibodies in conferring protection and how cellular and humoral immunity are subverted in persistent infection.
Since the identification of the hepatitis C virus (HCV) 20 years ago, much progress has been made in our understanding of its life cycle and interaction with the host immune system. Much has been learned from HCV itself, which, via decades of coevolution, gained an intricate knowledge of host innate and adaptive immune responses and developed sophisticated ways to preempt, subvert, and antagonize them. This review discusses the clinical, virological, and immunological features of acute and chronic hepatitis C and the role of the immune response in spontaneous and treatment-induced HCV clearance.
Dr. Andri Rauch discusses the findings of his manuscript "Genetic Variation in IL28B is Associated with Chronic Hepatitis C and Treatment Failure: A Genome-Wide Associate Study".
This slide presentation provides information topics that include, but are not limited, to the following:• Host genetics influence• Genomic overview of region determinant of response to treatment• Roche genome wide association study review• SVR rates with different genotypes• IL28B and triple therapy
Cell-type specific expression patterns of hepatic interferon-stimulated genes (ISGs) and single nucleotide polymorphisms (SNPs) near the IL28B gene are associated with response to interferon-based therapy in patients with chronic hepatitis C virus (HCV) infection. A study in the May issue of Gastroenterology finds that cell-type–specific expression pattern of ISGs varies among patients with different IL28B genotypes and is a strong predictor of response to interferon-based treatment. Dr. Kuemmerle discusses these findings with author Dr. Jordan Feld of the University of Toronto; Plus, a rundown of top stories from this month's issue of GI and Hepatology News.
The IL28B locus attracted the attention of HCV researchers after a series of genome-wide association studies independently identified a strong association between common IL28B polymorphisms and the outcome of PEG-IFN-α plus ribavirin combination therapy in patients chronically infected with HCV genotype 1. This association was subsequently replicated for other HCV genotypes and has been linked to spontaneous eradication of HCV, development of steatosis and biochemical changes (such as altered levels of γ-glutamyl transpeptidase and LDL). Despite the introduction of direct-acting antiviral drugs, IL28B genetics are likely to play a part in patient selection and treatment decisions—moving towards a personalized approach to therapy. In HCV-infected patients with the so-called favourable IL28B genotype (rs12979860 CC; associated with better treatment response), hepatic expression levels of IL28B and interferon-stimulated genes seem to be reduced at baseline, but are induced more strongly after IFN-α administration, perhaps resulting in more effective elimination of the virus. Clarification of the mechanisms underlying these biological phenomena will lead to improved understanding of the antiviral effects of IFN-λ and, ideally, to the development of better therapies against HCV infection. This Review summarizes current understanding of the role of IL28B in HCV infection and response to therapy.
It has been understood for some time that the treatment outcome of hepatitis C virus (HCV) infection is influenced by host genetic factors. Three independent genome-wide association studies have recently identified that a genetic variation in the IL28B gene [interferon-λ3 (IFN-λ3)] determines the outcome of IFN-α-based therapy in patients with genotype 1 chronic hepatitis C infection. This genetic polymorphism is also strongly associated with a higher likelihood of spontaneous clearance following acute hepatitis C infection. These results confirm the importance of specific host genetic markers in predicting outcome and treatment response. They also provide the framework and potential for a clinically relevant and meaningful pharmacogenomic approach to personalizing anti-HCV treatment.
Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America1. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-α-2b (PegIFN-α-2b) or -α-2a (PegIFN-α-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-λ-3 (IFN-λ-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 × 10-25) and African-Americans (P = 2.06 × 10-3). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.
Genome-wide association studies of chronic hepatitis C patients have identified common variants associated with the clearance of HCV and RBV-related hemolysis. IL28B genotype predicts spontaneous clearance of HCV and the outcomes of pegIFN and RBV treatment of genotype 1/4 HCV.
Developed by a collection of experts from the CDC and other federal agencies, professional associations, community-based organizations, and medical associations, MMWR recommends the one-time screening of persons born during 1945-1965.
In the United States, hepatitis C virus (HCV) infection is most prevalent among adults born from 1945 through 1965, and approximately 50% to 75% of infected adults are unaware of their infection. This article estimates the cost-effectiveness of birth-cohort screening in the primary care setting.
The USPSTF recommends screening for HCV infection in persons at high risk for infection. The USPSTF also recommends offering 1-time screening for HCV infection to adults born between 1945 and 1965. (B recommendation).Clinical Summary of U.S. Preventive Services Task Force Recommedation (PDF)Evidence Report for Screening for HCV Infection in Adults (PDF)
This module is intended for any clinician who may encounter persons with hepatitis C virus (HCV) infection who would like to establish core competence in screening, testing, and counseling patients regarding their initial testing results. Medical providers intended for this module include Primary care physicians, Advanced Registered Nurse Practitioners, Physician Assistants, Hospitalists, Infectious Diseases Specials, Gastroenterologists, and Hepatologists.
Dr. Joseph Yao provides information on the diagnosis and monitoring of patients with HCV along with the different screening tests available for detection and confirmation.
The AASLD Practice Guidelines provides recommendations for preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. Sections of interest are Testing and Counseling, and Laboratory Testing.
Testing for anti-HCV should include use of an antibody screening assay, and for screening test-positive results, a more specific supplemental assay. Verifying the presence of anti-HCV minimizes unnecessary medical visits and psychological harm for persons who test falsely positive by screening assays and ensures that counseling, medical referral, and evaluation are targeted for patients serologically confirmed as having been infected with HCV. However, substantial variation in reflex supplemental testing practices exists among laboratories, and an anti-HCV--positive laboratory report does not uniformly represent a confirmed positive result. These guidelines expand recommendations for anti-HCV testing to include an option for reflex supplemental testing based on screening-test--positive signal-to-cut--off (s/co) ratios. Use of s/co ratios minimizes the amount of supplemental testing that needs to be performed while improving the reliability of reported test results. These guidelines were developed on the basis of available knowledge of CDC staff in consultation with representatives from the Food and Drug Administration and public health, hospital, and independent laboratories. Adoption of these guidelines by all public and private laboratories that perform in vitro diagnostic anti-HCV testing will improve the accuracy and utility of reported anti-HCV test results for counseling and medical evaluation of patients by health-care professionals and for surveillance by public health departments.
The Department of Veterans Affairs provides information on serologic assays, assessment of HCV viremia, notes on methods of standardization for quantitative HCV RNA assays, genotype assays, and references.
This manual is intended to provide guidelines to human immunodeficiency virus (HIV) testing sites in non-health care settings such as community-based organizations (CBOs), and to HIV test counselors performing the OraQuick1 hepatitis C virus (HCV) rapid test. The manual outlines recommendations for conducting OraQuick HCV rapid testing, including provision of HCV testing services and referrals.
Molecular biology techniques are routinely used to diagnose and monitor treatment of patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. These tools can detect and quantify viral genomes and analyze their sequence to determine their genotype or subtype and to identify nucleotide or amino acid substitutions associated with resistance to antiviral drugs. They include real-time target amplification methods, which have been standardized and are widely used in clinical practice to diagnose and monitor HBV and HCV infections, and next-generation sequencing techniques, which are still restricted to research laboratories. In addition, new enzyme immunoassays can quantify hepatitis B surface and hepatitis C core antigens, and point-of-care tests and alternatives to biologic tests that require whole blood samples obtained by venipuncture have been developed. We review these new virologic methods and their clinical and research applications to HBV and HCV infections.
Deaths from hepatitis C virus (HCV)–related disease are increasing, now exceeding those from human immunodeficiency virus. Up to 7 million Americans (2.3%) may be infected with HCV, and more than half are undiagnosed. Proposed expansion of hepatitis C screening to include all persons born between 1945 and 1965 will lead to many new diagnoses, and infectious diseases physicians have a unique opportunity to be part of managing these patients. Apart from a liver-focused history and examination, the initial evaluation includes determination of the liver function via serum tests and assessment of liver fibrosis and necroinflammation through biopsy or noninvasive means. Patients with cirrhosis require screening for esophageal varices and for liver cancer. Nonimmune patients need vaccinations against hepatitis A and B, and alcohol abstinence is critical. Initial counseling on therapy emphasizes viral cure rates of currently 70%–80% as well as expected side effects. New treatments with fewer side effects and potentially higher cure rates are currently in development.
• HCV Diagnostic Tests• Testing Approach and Interpretation of Test Results• Communicating Test Results• Follow-up if HCV-Seropositive and HCV RNA Negative• Linkage to Care
Recent analyses suggest that of the estimated 3.2 million people infected with hepatitis C virus, only about half have been tested and know their status, about a third have been referred for HCV care, and only 5 to 6% have been successfully treated.
Dr. Chong-Gee Teo, Laboratory Branch Chief in the Division of Viral Hepatitis at CDC, discusses CDC's updated guidance for clinicians and laboratorians for testing for hepatitis C virus (HCV) infection. Testing for hepatitis C should be initiated with a test for antibody to HCV, and all reactive results should be followed by a test for HCV RNA. The bottom line - HCV testing must ensure the identification of persons with current HCV infection.
The Department of Veterans Affairs' topic review of Liver Biopsy provides information on risks, the procedure, histopathology, references, and suggested readings.
Dr. Andrew Muir provides a complete overview of Hepatitis C that includes the topics of epidemiology, natural history, diagnosis, and treatment.
The Department of Veterans Affairs provides information on symptoms and clinical manifestations, extrahepatic manifestations, factors associated with liver disease progression, and cirrhosis associated with HCV.
Dr. Susanna Naggie provides information concerning HBV vaccination in co-infected persons as well as the role of biopsy, medication interactions, and side effects.
The Advisory Committee on Immunization Practices (ACIP) develops recommendations on how to use vaccines to control diseases in the United States. The 2013 ACIP recommendations include updated vaccine practices regarding Hepatitis A and B.
The Department of Veterans Affairs has developed a pocketcard and poster intended to educate health care providers on how to vaccinate against hepatitis A and/or B.
Dr. Keyur Patel discusses reasons for liver biopsy, limitations of liver biopsy, serum markers, diagnostic imaging methods, non-invasive algorithm, and additional information concerning assessment of liver fibrosis.
The Department of Veterans Affairs' topic review of Hepatitis C and Alcohol provides information on Alcohol and Liver Disease in Patients with HCV, Alcohol and HCV Therapy, Alcohol and Hepatocellular Cancer in Patients with HCV, and References.
The Department of Veterans Affairs' topic review of Hepatitis C and Alcohol: A Clinician's Perspective provides answers for the following questions: Should I tell my patient with chronic hepatitis C that he/she shouldn't drink alcohol? What should I advise my patient who only drinks alcohol once per week or less? and Should I wait until my actively drinking patient has been abstinent for 6 months or more before performing a liver biopsy or initiating anti-HCV therapies?
The Department of Veterans Affairs provides a toolkit of materials to help providers discuss the reduction of alcohol consumption with patients infected with hepatitis C. A teaching guide for health care providers, audit-c score cards, OARS/FLO card, and interactive resources are available.
The objective of this study was to compare the safety and immunogenicity of 4 intramuscular double-dose and 4 intradermal low-dose regimens vs the standard hepatitis B vaccine regimen. The study concluded that in adults with HIV-1, both the 4 intramuscular double-dose regimen and the 4 intradermal low-dose regimen improved serological response compared with the standard HBV vaccine regimen.
Worldwide, an estimated 130-170 million people have HCV infection. HCV prevalence is highest in Egypt at >10% of the general population and China has the most people with HCV (29.8 million). Differences in past HCV incidence and current HCV prevalence, together with the generally protracted nature of HCV disease progression, has led to considerable diversity in the burden of advanced liver disease in different countries. Countries with a high incidence of HCV or peak incidence in the recent past will have further escalations in HCV-related cirrhosis and hepatocellular carcinoma (HCC) over the next two decades. Acute HCV infection is difficult to detect because of the generally asymptomatic nature of the disease and the marginalization of at-risk populations. Around 25% of patients with acute HCV infection undergo spontaneous clearance, with increased rates among those with favourable IL28B genotypes, acute symptoms and in women. The remaining 75% of patients progress to chronic HCV infection and are subsequently at risk of progression to hepatic fibrosis, cirrhosis and HCC. Chronic hepatitis C generally progresses slowly in the initial two decades, but can be accelerated during this time as a result of advancing age and co-factors such as heavy alcohol intake and HIV co-infection.
The Department of Veterans Affairs makes available 27 patient brochures designed to educate persons infected with hepatitis C in addition to prevention information to those at risk for contracting the disease. Patient brochure topics include HAV, HBV, diet and nutrition, co-infection, treatment side effects, liver biopsy, and more.
The Department of Veterans Affairs makes available multiple patient education resources offered in different formats such as videos, posters, wallet cards, and handouts.
• MELD and Child-Turcotte-Pugh• Compensated versus Decompensated Cirrhosis• Non-Invasive Measures of Liver Fibrosis (includes lab studies and imaging)• Performing and Interpreting Liver Biopsy
• OTC and Prescription Medications• Alcohol and Cannabis• Diet and Modifying Obesity• Complementary and Alternative Medicines
This module is intended for clinicians who play a substantial role in the long-term management of patients with chronic hepatitis C virus (HCV) infection, including Primary Care Physicians, Advanced Registered Nurse Practitioners, Physician Assistants, Infectious Diseases Specialists, Gastroenterologists, and Hepatologists. This module emphasizes the initial evaluation of a patient diagnosed with hepatitis C virus infection, understanding the natural history of hepatitis C, assessment for the degree of liver fibrosis, counseling patients on how to prevent further insults to their liver, evaluation of patients with cirrhosis, surveillance for hepatocellular carcinoma, and recognition of HCV-related extrahepatic manifestations.
Hepatitis C Virus is associated with a wide series of extrahepatic manifestations. Based on available data the link between the virus and some of these extrahepatic diseases is only suggested and needs further confirmation. Hepatitis C Virus-related lymphoproliferative disorders, whose prototype is mixed cryoglobulinaemia, represent the most closely related extrahepatic manifestations of Hepatitis C Virus. Other Hepatitis C Virus-associated disorders include nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, porphyria cutanea tarda, lichen planus, diabetes, chronic polyarthritis, cardiopathy and atherosclerosis. A pathogenetic link between Hepatitis C Virus and some extrahepatic manifestations was confirmed by their responsiveness to antiviral therapy, which is now deemed the first therapeutic option to consider. By contrast, there are diseases where treatment with interferon was ineffective or dangerous. The aim of the present paper is to outline the most recent evidence concerning extrahepatic disorders that are possibly associated with Hepatitis C Virus infection. Special emphasis will be given to discussion of the most appropriate clinical approaches to be adopted in order to diagnose, treat (possibly prevent) and follow-up extrahepathic diseases in patients with Hepatitis C Virus infection.
Hepatitis C virus may cause hepatic and extrahepatic diseases. Extrahepatic manifestations range from disorders for which a significant association with viral infection is supported by epidemiologic and pathogenetic data, to anecdotal observations without clear proof of causality. This article describes the diagnosis and treatment of these diseases.
The hepatitis C virus mainly affects the liver, but there are many other conditions that are associated with hepatitis C. Extrahepatic manifestation means diseases or conditions that affect organs other than the liver. Extrahepatic manifestations of hepatitis C can be found in the skin, eyes, joints, immune system, nervous system and kidneys. Some of these conditions – cryoglobulinemia, for example – are somewhat more common and well-documented, while others are infrequent or their association with hepatitis C has not yet been proven.
The Alcoholic Live Disease practice guidelines include information regarding the prevalence and natural history of alcoholic liver disease, the disease spectrum, risk factors, diagnosis, prognostic factors, therapy, long term management, and liver transplantation.
The Management of Acute Liver Failure position paper provides guidelines for clinical practice of diagnosing, treating, and managing a patient affected by acute liver failure.
Dr. Alexander Kuo discusses the following topics:• Burden of HCV disease• Fibrosis progression and models for scoring• Differences of compensated and decompensated cirrhosis • Main complications of cirrhosis • Role and timing of liver transplantation
Identification and treatment of advanced hepatitis C virus (HCV) infection is often challenging. Accurate fibrosis staging can be performed only by liver biopsy. For patients with advanced fibrosis (Metavir score, F3 or F4), progression to decompensated liver disease occurs at a rate of approximately 5% per year and progression to hepatocellular carcinoma occurs at a rate of 1% to 2% per year. Liver decompensation primarily results from altered hepatic blood flow caused by liver scarring and is characterized by ascites and its complications (hepatorenal syndrome, hepatic hydrothorax, and spontaneous bacterial peritonitis), hepatic encephalopathy, bleeding varices, and coagulopathy. Patients with advanced fibrosis need to be regularly monitored for evidence of decompensated disease, and complications need to be aggressively managed. This article summarizes a presentation by Kenneth E. Sherman, MD, at the IAS–USA live continuing medical education course, Management of Hepatitis C Virus in the New Era, held in New York City in April 2011.
The Department of Veterans Affairs' topic review of Hepatitis C and Hepatocellular Carcinoma provides information on risk factors, screening modalities, diagnosis, prognosis, treatment modalities, prevention of HCC, secondary prevention, and references.
The Management of Hepatocellular Carcinoma practice guidelines provide information on the key points, surveillance, diagnosis, staging, treatment, and references relating to HCC.
The Hepatocellular Carcinoma Quicknotes provide bottom-line current recommendations regarding the workup of liver masses uncovered during screening as well as guidelines regarding the diagnosis and management of HCC, including guidance regarding referral for liver transplantation.
The Department of Veterans Affairs' has developed an interactive treatment algorithm for the diagnosis and treatment of hepatocellular carcinoma. The recommendations are based on a critical review of the available data and expert consensus.
The Management and Treatment of Patients with Cirrhosis and Portal Hypertension practice guidelines provides information on the management of compensated and decompensated cirrhosis and the screening, diagnosis, and management of hepatocellular carcinoma.
The Cirrhosis Quicknotes provide bottom-line current recommendations regarding management of compensated and decompensated cirrhosis, including guidelines for screening and management of varices and hepatocellular carcinoma (HCC) and guidelines for the management of ascites, encephalopathy, variceal hemorrhage, and spontaneous bacterial peritonitis, including dosages of recommended medications and goals of therapy. They also provide guidance regarding referral for liver transplantation.
Human immunodeficiency virus (HIV) infection accelerates liver disease progression in patients with hepatitis C virus (HCV) and could shorten survival of those awaiting liver transplants. The Model for End-Stage Liver Disease (MELD) score predicts mortality in HIV-negative transplant candidates, but its reliability has not been established in HIV-positive candidates.
The Management of Ascites practice guidelines include information regarding evaluation and diagnosis, ascitic fluid analysis, differential diagnosis, treatment of ascites, refractory ascites, spontaneous bacterial peritonitis, prevention of spontaneous bacterial peritonitis, hepatorenal syndrome, additional considerations, and hepatic hydrothorax.
The Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage practice guidelines include information regarding the pathophysiology of portal hypertension in cirrhosis, evaluation of portal hypertension, natural history of varices, gastric varices, diagnosis of varices and variceal hemorrhage, and management recommendations
The TIPS practice guidelines include information regarding the procedure, pre-tips evaluation and contraindications, mortality, complications, indications, primary prevention of variceal bleeding, acutely bleeding esophageal varices refractory to medical treatment, esophageal variceal rebleeding, bleeding from gastric varices, prevention of bleeding from portal hypertensive gastropathy and gastric antral vascular ectasia, cirrhotic ascites, refractory hepatic hydrothorax, hepatorenal syndrome, veno-occlusive disease or sinusoidal obstruction syndrome, and hepatopulmonary syndrome.
• Diagnostic Paracentesis• Analysis of Ascitic Fluid• Basic Management of Ascites• Management of Refractory Ascites
• Indications for Spontaneous Bacterial Peritonitis Prophylaxis• Regimens for Spontaneous Bacterial Peritonitis Prophylaxis • Diagnosis of Spontaneous Bacterial Peritonitis• Management of Spontaneous Bacterial Peritonitis
• Pathophysiology and Portal Dynamics• Indications and Methods for Variceal Screening• Pre-primary Prophylaxis of Variceal Bleeding• Primary Prophylaxis of Variceal Bleeding
• Clinical Features• Laboratory Abnormalities• Correction of Precipitating Causes• Medical Therapy
This webcast provides viewers with information on how to: • Describe the relationship between hepatic anatomy and liver disease • Identify what constitutes hepatic decompensation and how to measure it• Recognize key management issues in advanced liver disease• Recognize when a patient needs to be eferred to a hepatologist
The Department of Veterans Affairs provides guidelines, clinician tools, case studies, journal articles, patient education material, and web resources relating to liver transplantation.
Information about infections unrelated to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus (HIV)–infected liver recipients is scarce. The aims of this study were to describe the prevalence, clinical characteristics, time of onset, and outcomes of bacterial, viral, and fungal infections in HIV/hepatitis C virus (HCV)–coinfected orthotopic liver transplant recipients and to identify risk factors for developing severe infections. We studied 84 consecutive HIV/HCV-coinfected patients who underwent liver transplantation at 17 sites in Spain between 2002 and 2006 and were followed until December 2009. In conclusion, the rates of severe and opportunistic infections are high in HIV/HCV-coinfected liver recipients and especially in those with a history of AIDS, a high MELD score, or non–tacrolimus-based immunosuppression.
Intended for use by physicians and health care providers working with adult recipients of liver transplantation (LT), these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventiveaspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case.
HRSA makes available a MELD Calculator that utilizes a formula approved by the Organ Procurement and Transplantation Network (OPTN) Board of Directors. The MELD score is on based on a patient's risk of dying while waiting for a liver transplant, and are based on objective and verifiable medical data.
There is a growing need for kidney and liver transplants in persons living with HIV. Fortunately, with the significant advances in antiretroviral therapy and management of opportunistic infections, HIV infection is no longer an absolute contraindication for solid organ transplantation. Data from several large prospective multi-center cohort studies have shown that solid organ transplantation in carefully selected HIV-infected individuals is safe. However, significant challenges have been identified including prevention of acute rejection, management of drug-drug interactions and treatment of recurrent viral hepatitis. This article reviews the selection criteria, outcomes, and special management considerations for HIV-infected patients undergoing liver or kidney transplantation.
Monday, March 4, 2013 (Bottom of Webpage)Dr. Dave Thomas presents at the 20th Conference on Retroviruses and Opportunistic Infections on the progress of hepatitis C treatments, the current state of treatment, cure with interferon-free therapy, the tools necessary to achieve cure, and the biologic context that makes it possible.
• Treatment-naïve Patients with Genotype 1• Treatment-naïve Patients with Genotype 2 or 3• Treatment-experienced Patients with Genotype 1• Treatment-experienced Patients with Genotype 2 or 3• Patients with Genotypes 4, 5, or 6• Patients with Acute Hepatitis C
Since 2007, the annual age-adjusted mortality rate in hepatitis C virus (HCV) infection in the United States has been greater than that in HIV disease, reflecting the continuing decline in HIV-related mortality and the continuing increase in HCV-related mortality. The approval of 2 new direct-acting antivirals within the past year, as well as the promise offered by numerous other direct-acting agents in development, provides hope that we will be able to markedly improve our ability to cure HCV disease. The addition of a protease inhibitor (PI) to what has been the standard HCV therapy of peginterferon alfa and ribavirin dramatically improves sustained virologic response rates in treatment-naive patients with genotype 1 infection. Similar results have been observed in some treatment-experienced patients in whom prior peginterferon alfa/ribavirin therapy has failed. The use of these new agents has also permitted response-guided therapy, wherein early sustained virologic response to treatment allows for a shortened treatment duration. However, these new PIs add cost and adverse effects to HCV therapy. Boceprevir is associated with increased risk of anemia and dysgeusia, and telaprevir is associated with increased risk of anemia and skin and gastrointestinal adverse effects. Early studies indicate that the addition of PIs results in high response rates in patients with HCV/HIV coinfection. Other studies suggest that combinations of PIs and other direct-acting antivirals may ultimately permit cure when used in interferon-sparing regimens. This article summarizes a presentation by David L. Thomas, MD, MPH, at the IAS–USA live continuing medical education course held in New York City in October 2011.
Dr. Robert T. Schooley discusses the treatment paradigm shift for Hepatitis C Virus and the similarities between HIV treatment.
The standard treatment for hepatitis C virus (HCV) infection is interferon, which is administered subcutaneously and can have troublesome side effects. We evaluated sofosbuvir, an oral nucleotide inhibitor of HCV polymerase, in interferon-sparing and interferon-free regimens for the treatment of HCV infection.
There is a need for interferon-free treatment regimens for hepatitis C virus (HCV) infection. The goal of this study was to evaluate ABT-450, a potent HCV NS3 protease inhibitor, combined with low-dose ritonavir (ABT-450/r), in addition to ABT-333, a nonnucleoside NS5B polymerase inhibitor, and ribavirin, for the treatment of HCV infection.
Only 20 years after the discovery of the hepatitis C virus, a cure is now likely for most people with chronic infection. This review considers current therapy and the present landscape of drug development for hepatitis C.
Recent advances in the treatment of hepatitis C virus infection (HCV) have led to high rates of viral cure. However, the use of newly approved protease inhibitors with activity against HCV still requires careful patient selection, counseling, and decision making before initiation of treatment. Laboratory work-up, staging of liver disease, and careful review of comorbid conditions is mandatory. Patients with cirrhosis may require treatment regimens that differ from those without cirrhosis. Because pegylated interferon alfa and ribavirin remain a key part of the treatment regimen, absolute and relative contraindications to their use must be considered. Management of common adverse events including anemia and rash must be embraced by the healthcare provider.
Dr. Andrew Muir discusses the complex issues around preparing patients for treatment and provides practical guidance.
• Adherence and the Risk of Viral Resistance and Treatment Failure• Factors Negatively Influencing Adherence• Methods to Enhance Adherence
The Department of Veterans Affairs provides information on pretreatment considerations, deciding to embark on therapy, therapy, after therapy, and supporting references.
The Department of Veterans Affairs provides guidelines, topic reviews, provider education material, clinician tools, case studies, and journal articles relating to the clinical management of HCV.
The Pretreatment Assessments section of the guidelines provides information on laboratory testing, liver disease staging, psychiatric assessment, assessments for substance use disorders, adherence, evaluation for HIV co-infection, pregnancy, testing for IL28B genotype, and concomitant medical conditions.
The Department of Veterans Affairs provides an Audit-C Test and Scoring Cards to help identify patients who are hazardous drinkers or have active alcohol use disorders.
The Department of Veterans Affairs' topic review of Hepatitis C and Alcohol provides information on alcohol and liver disease in patients with HCV, alcohol and HCV therapy, alcohol and hepatocellular cancer in patients with HCV, and references.
The current standard of care (SOC) for patients with chronic HCV genotype 1 is a combination of either boceprevir or telaprevir with peginterferon (PEG-IFN) and ribavirin (RBV). Although it is effective in a high percentage of patients, this treatment is associated with significant adverse events (AEs). The next generation of protease inhibitors, simeprevir and faldaprevir, will also be used with PEG-IFN/RBV. Interferon-free therapy with sofosbuvir appears promising and on the horizon for patients with genotypes 2 and 3, but may still be many years away for patients with HCV genotype 1. The factors which should be considered when deciding whether to treat a patient with HCV and mild fibrosis with the current SOC now, or to delay treatment until less toxic and/or more effective therapy is available is discussed.
This study assesses the validity of self-reported medication adherence provided by individuals in treatment for hepatitis C virus (HCV) infection with a regimen of peginterferon and ribavirin.
This article discusses the importance of treatment adherence to increase the likelihood of achieving a sustained virologic response with boceprevir and telaprevir therapies.
Chronic hepatitis C (HCV) infected patients with coexisting mental health and/or substance abuse issues face significant barriers to treatment and are often deferred. This paper sought to highlight critical pre-treatment strategies and provide tangible resources for HCV clinicians to facilitate preparation and successful treatment of these patients.
Hepatitis C virus (HCV) infection is a major health concern in the US as well as in other countries worldwide. Treatment issues and disease management strategies are complicated by the extremely high rate of psychiatric and substance use disorders in those who have HCV. The majority of new and existing cases of HCV are related to injection drug use and, in this population, the prevalence of psychiatric comorbidity is high. Optimally, all patients with HCV should be screened for psychiatric and substance use disorders before initiation of antiviral therapy. If a patient screens positive, he or she should be referred to a mental healthcare provider or addiction specialist, assessed for the presence of a psychiatric or substance use disorder, and appropriately treated prior to initiation of antiviral (i.e. interferon) therapy. Although interferon-based therapies can lead to severe neuropsychiatric adverse effects, including in rare instances suicide, evidence suggests that many patients with comorbid psychiatric and substance use diagnoses can be treated safely and effectively using comanagement strategies. However, most patients with HCV are not treated with antiviral therapy. Therefore, we must expand our definition of HCV 'treatment' to include treatment of the comorbid psychiatric and substance use disorders that accompany HCV infection and precede antiviral therapy. This paper reviews the epidemiology and management of psychiatric and substance use disorders in patients with HCV, the issue of psychiatric and substance use disorders as contraindications for antiviral therapy, and current treatment strategies for HCV patients with these comorbid conditions.
• MELD and Child-Turcotte-Pugh• Compensated versus Decompensated Cirrhosis • Non-invasive Measures of Liver Fibrosis (includes lab studies and imaging)• Performing and Interpreting Liver Biopsy
The Update on the Management and Treatment of Hepatitis C guidelines provides the best practices for staging liver disease in a patient being assessed prior to receiving triple therapy.
The AASLD diagnosis, management, and treatment practice guidelines provide information to clinicians with evidence-based approaches to the prevention, diagnosis, and management of HCV infection.
The prognosis and management of patients with chronic viral hepatitis B and C depend on the amount and progression of liver fibrosis and the risk for cirrhosis. Liver biopsy, traditionally considered to be the reference standard for staging of fibrosis, has been challenged over the past decade by the development of noninvasive methodologies. These methods rely on distinct but complementary approaches: a biologic approach, which quantifies serum levels of biomarkers of fibrosis, and a physical approach, which measures liver stiffness by ultrasound or magnetic resonance elastography. Noninvasive methods were initially studied and validated in patients with chronic hepatitis C but are now used increasingly for patients with hepatitis B, reducing the need for liver biopsy analysis. We review the advantages and limitations of the noninvasive methods used to manage patients with chronic viral hepatitis B or C infection.
The accurate diagnosis of hepatitis C virus (HCV)-related fibrosis is crucial for prognostication and treatment decisions. Due to the limitations of biopsy, noninvasive alternatives including FibroTest and FibroScan have been developed. Our objective was to systematically review studies describing the accuracy of these tests for predicting HCV-related fibrosis.
Accurately staging hepatitis C virus (HCV)-related fibrosis is crucial for treatment decisions and prognostication. Our objective was to systematically review studies describing the accuracy of serum marker panels for predicting fibrosis in HIV/HCV-coinfected patients.
The aspartate aminotransferase-to-platelet ratio index (APRI), a tool with limited expense and widespread availability, is a promising noninvasive alternative to liver biopsy for detecting hepatic fibrosis. The objective of this study was to update the 2007 meta-analysis to systematically assess the accuracy of APRI in predicting significant fibrosis, severe fibrosis, and cirrhosis stage in hepatitis C virus (HCV) monoinfected and HCV / human immunodeficiency virus (HIV) coinfected individuals. Studies comparing APRI versus biopsy in HCV patients were identified via a thorough literature search. Areas under summary receiver operating characteristic curves (AUROC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were used to examine the APRI accuracy for the diagnosis of significant fibrosis, severe fibrosis, and cirrhosis. Heterogeneity was explored using meta-regression. Twenty-one additional studies were eligible for the update and, in total, 40 studies were included in this review (n = 8,739). The summary AUROC of the APRI for the diagnosis of significant fibrosis, severe fibrosis, and cirrhosis were 0.77, 0.80, and 0.83, respectively. For significant fibrosis, an APRI threshold of 0.7 was 77% sensitive and 72% specific. For severe fibrosis, a threshold of 1.0 was 61% sensitive and 64% specific. For cirrhosis, a threshold of 1.0 was 76% sensitive and 72% specific. Moreover, we found that the APRI was less accurate for the identification of significant fibrosis, severe fibrosis, and cirrhosis in HIV/HCV coinfected patients. CONCLUSION: Our large meta-analysis suggests that APRI can identify hepatitis C-related fibrosis with a moderate degree of accuracy. Application of this index may decrease the need for staging liver biopsy specimens among chronic hepatitis C patients.
• MELD and Child-Turcotte-Pugh • Compensated versus Decompensated Cirrhosis • Non-Invasive Measures of Liver Fibrosis (includes lab studies and imaging)• Performing and Interpreting Liver Biopsy
The Department of Veterans Affairs' topic review of Liver Biopsy provides information on Risks, the Procedure, Histopathology, References, and Suggested Readings.
The purpose of this practice guideline is to summarize the current practice of liver biopsy and make recommendations about its performance. This guideline deals exclusively with liver biopsy as it relates to adult liver disease.
Dr. Susanna Naggie provides information on topics that include, but are not limited, to the following:• HCV Epidemiology• HCV Genome and Drug Targets• Viral Kinetics• Prior Standard of Care• Pharmacogenomic discoveries• What SVR really means?
Dr. David Wyles provides information on topics that include, but are not limited, to the following:• HCV: the virus• HCV Epidemiology• Acute HCV• Stopping/Futility Rules• Genetic Variations• Sustain Virologic Response
• Markers of virologic response• Monitoring HCV RNA during and after therapy• Categorizing responses• Response guided therapy• Stopping rules
• Overview of HCV• Life Cycle• Peginterferon• Ribavirin• Telaprevir• Boceprevir
This presentation provides information on topics that include, but are not limited, to the following: • Target of Direct Antiviral Agents• HCV Treatment Decisions for Protease Inhibitors• Candidates for DAA Triple Therapy• Treatment Initiation and Patient Education• Stopping Rules• Telaprevir and boceprevir adverse events• Treatment Adherence Strategies
The Update on the Management and Treatment of Hepatitis C Virus Infection practice guideline provides the current best practice in the management of hepatitis C that include the use of peginterferon, ribavirin, boceprevir, and telaprevir containing therapy regimens.
The updated AASLD practice guidelines include information regarding the changes for the optimal treatment regimen of genotype 1 chronic HCV patients, the development of direct-acting antiviral agents, and the identification of several single-nucleotide polymorphisms associated with spontaneous and treatment-induced clearance of HCV infection.
This article provides an overview of hepatitis C virus (HCV) disease, including characteristics of the virus, targets for direct-acting antiviral (DAA) drugs, characteristics of virologic response to treatment, background on peginterferon alfa and ribavirin therapy, lessons from the phase II studies of the DAAs telaprevir and boceprevir, and recent pharmacogenetic discoveries.
Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. The purpose of this study is to compare the two regimens, which have not been adequately compared previously.
Hepatitis C virus (HCV) treatment is frequently complicated by anemia from ribavirin (RBV)-related hemolysis and peginterferon-alfa (PEG-IFN)-related bone marrow suppression. We investigated the relationships among treatment outcomes, anemia, and their management with RBV dose reduction and/or erythropoiesis-stimulating agents (ESAs).
Until recently, the standard of care (SOC) for patients with chronic hepatitis C virus (HCV) infection has consisted of a combination of pegylated interferon-α [corrected] plus ribavirin, administered for 24- to 48-weeks depending on the HCV genotype. The sustained virologic response rate for this SOC has been only about 50% in patients infected with genotype 1 HCV, the most prevalent genotype in Europe and North America. HCV therapy has been revolutionised recently by the approval of two direct-acting antiviral agents (DAA) against the NS3/4A serine protease for use in genotype 1 HCV, the ketoamide inhibitors boceprevir and telaprevir. The novel SOC marks the beginning of an extraordinary new era in HCV therapy. We review this new SOC with an emphasis on practical issues related to protease inhibitors, e.g. prescribing guidelines, futility rules and management of adverse events. We also give a perspective on what to expect in the coming years. Newer DAA with simplified dosing regimens and/or minimal toxicity which, when used in combination, will lead to viral eradication in most if not all CHC patients who undergo treatment. The novel agents in clinical development are paving the way for future interferon-sparing regimens.
Recently developed drugs and innovative strategies for the treatment of chronic infection with genotype 1 hepatitis C virus (HCV) have become the standard of care. The protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) are the first direct-acting antiviral (DAA) agents approved, and many more are being developed. These drugs substantially increased rates of sustained virologic response in treatment-naïve and -experienced patients, in conjunction with peginterferon and ribavirin (triple therapy), in phase 3 trials. The efficacy of triple therapy depends on appropriate selection of patients, although the population of patients that receive triple therapy could be expanded as the risk/benefit ratio improves. Attention to details that reflect the standard of care, such as appropriate dosing, anticipation of adverse effects, and strict adherence to stopping rules, will insure the success of these drugs and lead the way for new combination therapies.
• Markers of Virologic Response (eRVR, RVR, EVR, ETR, SVR12, SVR24) • Monitoring HCV RNA During and After Therapy • Categorizing Responses (complete, partial, relapse, nonresponse) • Response Guided Therapy• Stopping Rules
This presentation provides information on topics that include, but are not limited, to the following: • Difference of Treatment Algorithms for telaprevir and boceprevir• Review of treatment-naïve patients: rapid responder, slow responder, poor IFN responsiveness• Stopping rules for telaprevir and boceprevir • Key treatment differences
The Department of Veterans Affairs provides information on the definitions of response associated with HCV treatment and the patterns of virologic response related to treatment.
The Department of Veterans Affairs makes available a treatment guidance table for monitoring patients on a pegylated interferon+ribavirin+protease inhibitor treatment regimen.
Molecular biology techniques are routinely used to diagnose and monitor treatment of patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. These tools can detect and quantify viral genomes, and analyze their sequence, in order to determine their genotype or subtype and to identify nucleotide or amino acid substitutions associated with resistance to antiviral drugs. They include real-time target amplification methods, which have been standardized and are widely used in clinical practice to diagnose and monitor HBV and HCV infections, and next-generation sequencing techniques, which are still restricted to research laboratories. In addition, new enzyme immunoassays can quantify hepatitis B surface and hepatitis C core antigens, and point-of-care tests and alternatives to biologic tests that require whole-blood samples obtained by venipuncture have been developed. We review these new virologic methods and their clinical and research applications to HBV and HCV infections.
• Treatment for genotype 1, 2, 3, 4, 5, 6• Treatment for acute hepatitis C• Treatment for Patients with compensated cirrhosis
Dr. Susanna Naggie discusses the characteristics of the Boceprevir and Telaprevir trials and how the data can be applied on the patient level.
The updated AASLD practice uidelines include information regarding the changes for the optimal treatment regimen of genotype 1 chronic HCV patients, the development of direct-acting antiviral agents, and the identification of several single-nucleotide polymorphisms associated with spontaneous and treatment-induced clearance of HCV infection.
In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients.
In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment.
Peginterferon–ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.
Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin.
In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon.
This case-study presentation provides information on topics that include, but are not limited, to the following: • Virologic responses• Effect of SVR on mortality• REALIZE Study: Telaprevir • Management of Telaprevir
• Characterizing prior treatment failure• Retreatment of genotype 1 with prior partial response or relapse• Retreatment of genotype 1 with prior nonresponse• Retreatment of genotype 2 or 3• Retreatment of genotype 4, 5, or 6
This presentation provides information on topics that include, but are not limited, to the following: • Considerations for treatment-experienced patients in 2012• Definitions of prior response• Factors to consider for retreatment• Key phase III clinical trial data for protease inhibitors• Stopping rules
Approximately 60% of patients who are infected with hepatitis C virus (HCV) genotype 1 are not cured by 48 weeks of peginterferon alfa combined with ribavirin. Such patients fall into one of three categories: those who have no response to therapy, which is defined as a reduction of less than 2 log10 in HCV RNA levels after 12 weeks of therapy; those who have a partial response, which is defined as a reduction of at least 2 log10 in a patient who has always had detectable serum HCV RNA during therapy; and those who have a relapse, which is defined as undetectable serum HCV RNA at the end of treatment but with subsequent virologic relapse.In two recent phase 2 trials, telaprevir, an orally bioavailable inhibitor of the nonstructural 3/4A HCV protease, substantially enhanced rates of sustained virologic response when it was combined with peginterferon plus ribavirin in patients who had received previous therapy. In this randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of the addition of telaprevir to a regimen of peginterferon plus ribavirin in patients with chronic HCV genotype 1 infection who did not have a sustained virologic response to previous treatment.
More than 170 million people are chronically infected with hepatitis C virus (HCV) worldwide.1 The standard treatment is combination therapy with peginterferon and ribavirin. Of the six HCV genotypes, genotype 1 is the least responsive to currently approved therapies, with rates of sustained virologic response of less than 50%. Thus, there is a large population of patients with few therapeutic options, and direct-acting antiviral therapy has become the focus of investigations regarding treatment for HCV infection.Boceprevir is a structurally novel peptidomimetic ketoamide protease inhibitor that binds reversibly to the HCV nonstructural (NS3) active site. Boceprevir has demonstrated antiviral activity in phase 2 studies of both patients infected with HCV genotype 1 who have not received prior treatment and those who have received prior treatment. The primary objective of this phase 3 study of patients with previously treated HCV genotype 1 infection was to compare the safety and efficacy of two therapeutic regimens of boceprevir in combination with peginterferon and ribavirin to therapy with peginterferon and ribavirin alone. The safety and efficacy of boceprevir in previously untreated patients are described in the article by Poordad and colleagues in this issue of the Journal.
Acute hepatitis C virus infection is associated with high rates of spontaneous clearance and variable rates of treatment-induced clearance. The benefit of early treatment versus awaiting spontaneous clearance is unknown, as is the optimal timing of treatment.We performed a MEDLINE and EMBASE search for the time period 1950 to October 2008. All English language abstracts using the search terms acute hepatitis C, hepatitis C and acute and hepatitis C and acute disease or acute infection were reviewed. Bibliographies were reviewed.Twenty-two studies including 1075 patients met the inclusion criteria. The sustained virologic response (SVR) rate for treated patients was 78%, significantly higher than 55.1% in untreated patients (OR = 3.08, 95% CI: 1.8-4.8 P value <0.0001). Mean time from diagnosis to spontaneous clearance was 9.7 weeks (SD 6.5). SVR rates varied inversely with time from acute HCV diagnosis. SVR rates for treatment within 12 weeks was 82.5% (95% CI: 75.6-89.3), significantly better than the clearance rates in untreated patients (P < 0.001). Response rates fell to 66.9% for treatment between 12 and 24 weeks, and decreased further to 62.5% for treatment beyond 24 weeks. Rates of viral clearance in treated patients with acute hepatitis C virus infection were significantly higher than that in untreated patients. Treatment rates were highest when treatment was initiated within 12 weeks of diagnosis. Based on these findings, we would advocate a 12 week period of observation for spontaneous clearance before treatment initiation. If no clearance has occurred by 12 weeks, treatment should be initiated.
• Monitoring for side effects and treatment-related toxicity• Management of peginterferon and ribavirin-related toxicity• Management of boceprevir-related toxicity• Management of telaprevir-related toxicity
This case-study presentation provides information on topics that include, but are not limited, to the following: • Common HCV management techniques• Treatment discontinuation• Psychiatric issues• Depression• Telaprevir dose reduction• Thrombocytopenia• Dermatologic issues• Dermatologic management considerations• Weight loss
This presentation provides information on topics that include, but are not limited, to the following: • The basics: telaprevir and boceprevir adverse events• Historical perspective on anemia in HCV• Boceprevir anemia summary• Telaprevir anemia summary• Occurrence of rash and management strategies• Managing drug-drug interactions
The Department of Veterans Affairs provide a topic review of the side effects of interferon and ribavirin treatment. The review contains sections on the management of side effects, constitutional, gastrointestinal, psychiatric side effects, dermatological, laboratory, other side effects, and references.
Chronic hepatitis C is one of the leading causes for chronic liver disease globally. The past two decades have seen many advances in hepatitis C treatment. Despite these advances, side effects of treatment are common. Haematological complications of treatment can result in treatment cessation and suboptimal results. Recent data have suggested a role for epoetin/granulocyte colony stimulating factor (G-CSF) in optimizing sustained virological response (SVR). This study investigates the nature, frequency and management of haematological side effects in the treatment of chronic hepatitis C infection.
Anemia is a common side effect that begins soon after the initiation of peginterferon/ribavirin in the treatment of hepatitis C virus (HCV) infection. It can cause symptoms that negatively impact quality of life (QOL) and is the most common reason for reducing the dose and temporarily or permanently discontinuing ribavirin. Such dose modifications have been shown to reduce the efficacy of treatment. Administering erythropoietin can improve anemia caused by peginterferon and ribavirin therapy and is more effective than dose reduction at improving QOL during treatment. However, erythropoietin, which is not approved by the U.S. Food and Drug Administration (FDA) for use in patients with HCV infection, adds another parenteral drug to the patient's treatment regimen, and is associated with additional costs, inconvenience, and potential side effects. A new ribavirin analog, viramidine, is expected to be associated with a lower incidence of anemia and, if proven effective, may eventually be substituted for ribavirin in combination with peginterferon to treat chronic hepatitis C. In the meantime, physicians must make the best possible use of the available options for managing anemia, especially in select patient groups who are most at risk for anemia and its complications.
• Overview of protease inhibitor resistance• Resistance testing• Potential impact of resistance on future therapy
This presentation provides information on topics that include, but are not limited, to the following: • Consequences of resistance• Mechanisms of resistance• Viral resistance• Viral resistance patterns• Outcomes with resistant variants• Viral resistance testing• Strategies to avoid resistance• Stopping rules
The International Antiviral Society-USA has developed a chart that presents mutations in hepatitis C virus that impact susceptibility to HCV drugs approved by the US FDA and to investigational drugs.
The addition of the hepatitis C virus (HCV) protease inhibitors telaprevir andboceprevir to peginterferon alfa with ribavirin therapy has increased cure rates in HCV infection. Numerous other direct-acting antivirals (DAAs) are in advanced stages of development, including next-generation protease inhibitors, nonstructural protein (NS) 5A inhibitors, and nonnucleoside and nucleos(t)ide NS5B polymerase inhibitors. The classes have different potencies, different resistance mutation profiles, and different barriers to the emergence of resistance. A comprehensive table of resistance mutations for classes of DAAs is presented. Numerous combinations of DAAs with or without ribavirin have been evaluated in early studies of interferon alfafree regimens, with results indicating that cure is indeed possible with such therapy and suggesting that identification of regimens that could produce cure in the majority of patients may occur within the foreseeable future. This article summarizes a presentation by David L. Wyles, MD, at the IAS-USA live continuing medical education activity held in New York in June 2012.
The onset of the acquired immune deficiency syndrome epidemic in the early 1980s led to successful antiviral drug discovery programs, which brought to the market a large number of antiretroviral drugs with different targets and mechanisms of action. However, it soon became apparent that human immunodeficiency virus (HIV) resistance to these drugs would be a problem in long-term antiretroviral therapy. A combination of drugs with different viral targets and no cross-resistance (highly active antiretroviral therapy [HAART]) was shown to be a valuable option to prevent HIV resistance in the long-term. Nevertheless, multidrug-resistant viruses emerge in some patients on HAART therapy, generally those who have been on treatment for many years and have received a number of different drugs during their life. These viruses escape the antiviral effect of all available drugs and their outgrowth is responsible for treatment failure, disease progression, and death.Based on this experience, hepatitis B virus (HBV) and hepatitis C virus (HCV) resistance to direct-acting antiviral (DAA) drugs often is seen as a dreadful threat. The reality is, however, different.
Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins of the hepatitis C virus (HCV) life cycle. These drugs, collectively termed directly acting antivirals (DAA) against HCV, include a range of non-structural (NS) 3/NS4A protease, NS5B polymerase, and NS5A inhibitors at various stages of clinical development. The rapid replication rate of HCV, along with the low fidelity of its polymerase, gives rise to generations of mutations throughout the viral genome resulting in remarkable sequence variation in the HCV population, known as a quasispecies. The efficacy of DAAs is limited by the presence of those mutations that give rise to amino-acid substitutions within the targeted protein, and that affect the viral sensitivity to these compounds. Thus, due to the high genetic variability of HCV, variants with reduced susceptibility to DAA can occur naturally even before treatment begins, but usually at low levels. Not surprisingly then, these changes are selected in patients either breaking through or not responding to potent DAA treatment. In vitro or in vivo, six major position mutations in the NS3 HCV protease (36, 54, 155, 156, 168, and 170) have now been reported associated with different levels of resistance. The amino acid composition at several of the drug resistance sites can vary between the HCV genotypes/subtypes, resulting in different consensus amino acids leading to a reduction in replicative fitness as well as reduced DAA sensitivity. Different amino acid diversity profiles for HCV genotypes/subtypes suggest differences in the position/type of immune escape and drug resistance mutations. Also, different pathways of resistance profiles based on the chemical scaffold (linear or macrocyclic) of the protease inhibitors have been described. This review first describes how resistance to a protease inhibitor can develop and then provides an overview of the mechanism of how particular mutations confer varying levels of resistance to protease inhibitor, which have been identified and characterized using both genotypic and phenotypic tools. Future potential therapeutic strategies to assist patients who do develop resistance to protease inhibitors are also outlined. The challenge developing new HCV protease inhibitors should take into consideration not only the antiviral potency of the drugs, the occurrence and importance of side effects, the frequency of oral administration, but also the resistance profiles of these agents.
• Overview of inhibition and induction• Key drug-drug interactions
This presentation provides information on the following topics:
• Compare and contrast the clinical pharmacology of BOC and TVR• Identify therapeutic classes of drugs with the potential for drug interactions with BOC and TVR• Discuss management of interactions with BOC and TVR• Examine pharmacology and interaction potential of next "batch" of Hepatitis C agents
This case-based presentation provides information on topics that include, but are not limited, to the following: • BOC, TVR and drug interactions • Effect of BOC and TVR on other CYP3A and/or Pgp substrates• Telaprevir effect on ortho-OH-atorvastatin• Impact of Ritonavir on TVR,BOC pharamcokinetics• HIV protease inhibitors interactions with TVR,BOC
Hep-druginteractions.org provides evidence-based drug-drug interaction resources available as HCV drug interaction charts, current articles, webcasts, video presentations, and links.
This Cases on the Web activity describes a case and presents various clinical decision points, each about a patient with hepatitis C virus (HCV) infection who may be experiencing complications resulting from an interaction between the drugs in his HCV regimen and other coadministered drugs.
Boceprevir and telaprevir, when added to pegylated interferon and ribavirin for the treatment of chronic hepatitis C virus infection, increase the rates of sustained virologic response in treatment naïve persons to approximately 70%. While these agents represent an important advance in the treatment of chronic hepatitis C virus, they present new treatment challenges to the Hepatology community. Boceprevir and telaprevir are both substrates and inhibitors of the hepatic enzyme cytochrome P450 3A and the drug transporter, P-glycoprotein, which predisposes these agents to many drug interactions. Identification and appropriate management of potential drug interactions with telaprevir and boceprevir is critical for optimizing therapeutic outcomes during hepatitis C treatment. This review highlights the pharmacologic characteristics and drug interaction potential of boceprevir and telaprevir and provides guidance on the management of drug interactions with these agents.
This presentation provides information on topics that include, but are not limited, to the following: • Treatment-Emergent substitutions• Drug class unique features• ATOMIC Trial• Combination therapy for null responders• ELECTRON Study• Quad Therapy
Although TVR- and BOC-based regimens represent the first generation of oral DAA agents that have significantly improved SVR rates in HCV genotype 1-infected individuals, PegIFN and RBV are still required, treatment regimens are complex, adverse effects are significant, and treatment has limited efficacy in certain subgroups (e.g., nonresponders to PegIFN/RBV). Future therapies against HCV will likely yield higher SVR, lower pill burden with once or twice daily dosing, shorter treatment duration, less viral resistance, more favorable safety profiles, and broader genotype coverage
The American Association for the Study of Liver Diseases (AASLD) held its annual meeting from November 9, 2012, through November 13, 2012, in Boston, Massachusetts. Hepatitis C virus (HCV) was prominently featured in the meeting, reflecting the rapid pace at which new developments in the field of HCV treatment are being introduced. HCV was the topic of an estimated 451 of the 2051 submitted abstracts (22%), with 148 abstracts (7.2%) focused on investigational drugs; it was also the topic of 1 presidential plenary session (top oral abstracts), 1 symposium, 10 of 37 parallel sessions (oral abstracts), and 1 debriefing session at the close of the meeting. This article will summarize some of the major findings presented at the meeting.
Development of robust cell culture models for hepatitis C viral infection has greatly increased our understanding of this virus and its life cycle. This knowledge has led to the development of many drugs that target specific elements of viral replication, including viral proteins and host factors required for replication. The NS3/4A serine protease inhibitors were the first of these to be used in the clinic, and reagents that target other elements of the viral lifecycle are in advanced stages of clinical development. These include new NS3/4A protease inhibitors, NS5B RNA-dependent RNA polymerase inhibitors, NS5A inhibitors, and host-directed antivirals, such as cyclophilin inhibitors. Alternative interferons with possibly improved tolerability, specifically interferon-λ1 (interleukin-29), are also under development. These new reagents against hepatitis C virus should lead to highly effective, well-tolerated, and likely interferon-sparing therapies in the next several years.
Daclatasvir is a first-in-class, highly selective HCV NS5A replication complex inhibitor with picomolar potency in vitro. Asunaprevir is a highly active HCV NS3 protease inhibitor. Both daclatasvir and asunaprevir produce robust declines in HCV RNA levels in patients with HCV genotype 1 infection, and administration of the two drugs in combination did not produce a clinically meaningful pharmacokinetic interaction. In this study, daclatasvir and asunaprevir were administered in combination, with or without peginterferon alfa-2a and ribavirin, for 24 weeks in patients with HCV genotype 1 infection who had not had a response to previous treatment with peginterferon and ribavirin. We report preliminary data from the exploratory cohort, including the percentages of patients with sustained virologic response at 12, 24, and 48 weeks after the end of the treatment period.
Many promising small molecule inhibitors directed against hepatitis C virus (HCV) proteins (direct-acting antiviral [DAA] agents) and compounds targeting host cell factors (host-targeting agents [HTAs]) are currently in the drug development and clinical trial pipeline, whereas contraindications and adverse effects limit the clinical applicability of peginterferon (Peg-IFN)-based therapies. The increasing number of alternative treatment options is driving the investigation of interferon-sparing regimens and paving the way for the question on the future place for interferon in HCV therapy.
The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV.
Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1-3 HCV infection.
• High Burden of HCV Disease in Corrections• Timing of Treatment
Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) both emerged in the second half of the 20th century, and chronic infection with these agents is among the greatest challenges facing health care in the United States and worldwide. Despite tremendous advances in treatment and management of HIV and HCV, individuals with HIV/HCV coinfection experience a more complicated disease course and treatment. Recognition of the important role that host factors, such as IL28B genotype, have in response to HCV therapy and the emergence of new effective therapies for HCV are actively reshaping the standard of care. These advances may translate into more effective treatment and management of patients with chronic HCV and HIV coinfection in the years ahead.
This Cases on the Web activity describes 3 cases and presents various clinical decision points, each focusing on use of hepatitis C virus protease inhibitors (HCV PIs) in treating a patient who has HIV and HCV coinfection.
This Cases on the Web activity consists of 2 cases and various clinical decision points, each focusing on providing care for HIV-infected patients with ongoing liver disease.
With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among patients with both infections (coinfection). In addition to the high prevalence of chronic HCV, particularly among HIV-infected injection drug users, the rate of incident HIV infections is increasing among HIV-infected men who have sex with men, leading to recommendations for education and screening for HCV in this population. Liver disease is the second leading and, in some cases, a preventable cause of death among coinfected patients. Those at risk for liver disease progression are usually treated with a combination of interferon (IFN) and ribavirin (RBV), which is not highly effective; it has low rates of sustained virologic response (SVR), especially for coinfected patients with HCV genotype 1 and those of African descent. Direct-acting antivirals might overcome factors such as immunodeficiency that can reduce the efficacy of IFN. However, for now it remains challenging to treat coinfected patients due to interactions among drugs, additive drug toxicities, and the continued need for combination therapies that include pegylated IFN. Recently developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with pegylated IFN and RBV, could increase the rate of SVR with manageable toxicity and drug interactions. We review the latest developments and obstacles to treating coinfected patients.
This presentation provides information on the following topics: • HCV standard of care treatment in HIV• Use of TVR and BOC - lessons from monoinfection• Genotype 1 treatment algorithms (monoinfected)• TVR and BOC HIV/HCV study data• Future treatment strategies• Individualized decision - treat vs. wait?
The goal of hcvinfo.org is to provide resources to providers, patients, and patient supporters to help with the care of patients with hepatitis C. Through the clinics at Duke, HCVinfo.org content providers have gained tremendous experience in this field, and hope to share their resources and tools.
The Department of Veterans Affairs makes available information concerning Hepatitis A, B, C, getting tested, diagnosis, treatment, liver complications, living with hepatitis C, and community resources.
Dr. Dawd Siraj discusses the benefits of sustained virologic response (SVR) longevity, the durability of SVR, SVR follow-up, and literature references for a better understanding of management after SVR is achieved.
Sustained virologic response (SVR) is defined as aviremia 24 weeks after completion of antiviral therapy for chronic hepatitis C virus (HCV) infection. In analyses of SVR durability, the incidence of late relapse is extremely low (<1%). Histologic regression of both necroinflammation and fibrosis has been demonstrated in paired liver biopsy samples in SVR-achieving patients. More noteworthy is the sustained responder's favorable prognosis even with baseline cirrhosis; despite mostly retrospective analyses, relative to nonresponders or to those untreated, patients with SVR have significantly fewer liver-related complications, less hepatocellular carcinoma, and fewer liver-related deaths. Although HCV is associated with insulin resistance, successful eradication of HCV appears to reduce the risk of impaired fasting glucose and diabetes development. In summary, chronic HCV infection is curable with SVR attainment, and with cure comes improved liver histology and more favorable clinical outcomes, in comparison with patients who do not achieve the same therapeutic milestone.
The Brody School of Medicine, East Carolina University HCV Management Manual provides information on staff education and roles, clinic hours of operation, procedures, resources, and clinic organization that is necessary to provide comprehensive care to HCV patients receiving treatment.
The Brody School of Medicine, East Carolina University HCV Management Manual was developed from information referenced from Projects in Knowledge® eHandbook HCV & Guidance: Chapter 1: Getting Ready for Direct-Acting Antiviral (DAA) Therapy (Free Registration Required).
Clinical Care Options' interactive programs inform practitioners about hepatitis treatments, guidelines, and management strategies, and provides conference coverage.
Offers free online sessions on management and treatment strategies of hepatitis C and HIV.
Projects In Knowledge provides physicians and other clinical professionals ACCME accredited educational resources on a variety of topics.
AASLD Curriculum & Training (ACT) is a initiative that will provide strategies and mentoring for managing HCV and is designed to increase the confidence and competence of healthcare professionals new to providing care for patients with HCV. ACT on HCV Curriculum includes the following components: five online interactive CME/CE-certified modules; an experiential component which includes logging direct clinical experiences, mentoring from "Expert Resources", and participation in case-based discussions via the ACT on HCV community teleconference/web-based programming; an online final examination, and a Certificate of Curriculum Completion for successful trainees.
Average 5 out of 5
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A pair in Henderson County were arrested after an alleged meth lab was found Thursday afternoon.
According to the Henderson County Sheriff's office, deputies attempted to serve an arrest warrant at a residence on Mill Street in Smith Mills. The husband, 44 year old Timothy A Vanover met deputies at the front door while 35 year old Jamie R Vanover allegedly bolted out the back.A brief foot pursuit led to the apprehension of Mrs. Vanover.
Deputies later found a large amount of alleged items used to manufacture meth, along with a loaded, high powered rifle, marijuana and drug paraphernalia.
Both Vanovers were arrested and lodged in the Henderson County Detention Center under a no bond.

subset: commoncrawl


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Mechanical Drafting Mechanical Drafting This course is designed to provide instructional Mechanical Drafters Specialist training. Students gain a general overview of Mechanical Drafting employing Computer Aided Drafting techniques, software, and basic procedures needed when designing /Architectural Drafting. This course also provides a skill development in typing with an emphasis on alphabet, numbers, and symbols with speed and accuracy. *Duration: 900 Course Hours +*Program Cost: $6,000 |


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Military radar indicates that the missing Boeing 777 jet may have turned back, Malaysia's air force chief said.
Benghazi (Libya) (AFP) - Libya threatened to bomb a North Korean-flagged tanker at an oil terminal held by militants in the restive east, saying it was being loaded illegally. Separatists blockading Al-Sidra facility attempted to load crude aboard the Morning Glory in the latest challenge to central government control. "The attorney general has given the order for the ship to be stopped," Prime Minister Ali Zeidan told a news conference. The self-proclaimed government of Cyrenaica in the east, the political wing of the separatists, said oil exports from Al-Sidra had now begun.


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Survivor Story: Jenifer Middleton
I am a four-and-a-half-year survivor of pancreatic cancer. At the time of my diagnosis in September of 2006, my life changed drastically when I was diagnosed with a 4.5 cm tumor – an adenocarcinoma – on the tail of my pancreas. I learned about it in a very unusual way and I realize now that there were many "little miracles" that helped me along the way.
At the time, I was going about my life raising three children and a niece, working as a registered nurse and under treatment with a rheumatologist for what we thought was polymyalgia rheumatica. He had been treating my vague back pain for four months when I decided to go to a gynecologist for a checkup.
This was my first miracle: scheduling an appointment with a new gynecologist and then seeing him just a few hours later. Something in his gut told him to draw blood and check my CA19-9 level (a tumor marker blood test); this was my second miracle. My CA 19-9 level was elevated to an abnormally high 3,500. I saw my primary care physician that same day, had a CT scan, and got the results within a few hours.
I saw an oncologist the next day and was informed that I could be a surgical candidate if my tumor would shrink through chemotherapy. I began four months of an aggressive chemotherapy regimen. I was then able to have a modified surgery to remove the tail and mid-body of my pancreas, left kidney, adrenal gland and spleen. Recovery was long, lasting five months. After that, I began chemoradiation.
After the chemoradiation, I went back on the original chemotherapy regimen for five more months until my CA19-9 level jumped from 12 to 12,800 in January of 2008 and a PET scan showed a liver metastasis. Then, I had three treatments of radiosurgery, which annihilated that tumor. After that, I started a new chemotherapy regimen. I was on that one for a few months and then started taking a targeted therapy drug until December of 2009, when a PET scan showed a small lung metastasis which was also treated with radiosurgery.
I have not been on any treatment since January of 2010 and today my CA19-9 level is 8. A recent PET scan also showed no sign of cancer!
When I was diagnosed, my family and friends gathered around and everyone was assigned a role. This got me through those first three years when I was undergoing aggressive treatment. Residual effects remain from all the aggressive treatments, and each has to be dealt with, but these are really just inconveniences in the grand scheme of things.
I have a fabulous support system and a positive attitude which is very important. I just knew I couldn't die at that time because I wasn't finished raising my children yet. I have been able to celebrate graduations, holidays and birthdays that not many people thought I would live to see. When people ask me if I wonder, "Why me?," I answer "Why NOT me?"
Living after a diagnosis of pancreatic cancer means that one's "normal" has changed, but the gift given is the ability to give back for all that you have received. I am very thankful to my family, friends and doctors for their continued love and support. I hope to continue to survive and serve as the voice for the many who have already been lost to this vicious disease.
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