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This page is for the disease. For the virus, see Hepatitis C virus. This page is for the virus For the disease see Hepatitis C. Hepatitis C virus ( HCV) is a small (50 nm in size
Hepatitis C
Classification and external resources
Electron Microscopy of HCV
ICD-10 B17.1, B18.2
ICD-9 070.4, 070.5
OMIM 609532
DiseasesDB 5783
MedlinePlus 000284
eMedicine med/993  ped/979
MeSH D006526

Hepatitis C is a blood-borne infectious disease that is caused by the Hepatitis C virus (HCV), affecting the liver. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings A00-A79 - Bacterial infections and other intestinal infectious diseases and STDs (A00-A09 Intestinal Infectious diseases ( A00-A79 - Bacterial infections and other intestinal infectious diseases and STDs (A00-A09 Intestinal Infectious diseases ( The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. MedlinePlus, with the MedlinePlus Medical Encyclopedia, is a website network containing Health information from the world's largest medical Library eMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely two medical doctors Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books A blood-borne disease is one that can be spread by contamination by Blood. This page is for the virus For the disease see Hepatitis C. Hepatitis C virus ( HCV) is a small (50 nm in size The liver is a vital organ in the human body and is present in Vertebrates and some other animals [1] The infection is often asymptomatic, but once established, chronic infection can cause inflammation of the liver (chronic hepatitis). Hepatitis (plural hepatitides) implies injury to the Liver characterized by the presence of Inflammatory cells in the tissue of This condition can progress to scarring of the liver (fibrosis), and advanced scarring (cirrhosis). Fibrosis is the formation or development of excess fibrous Connective tissue in an organ or tissue as a reparative or reactive process as opposed to a formation of Fibrous Cirrhosis is a consequence of chronic Liver Disease characterized by replacement of liver tissue by fibrous Scar tissue as well as regenerative In some cases, those with cirrhosis will go on to develop liver failure or other complications of cirrhosis, including liver cancer. Liver failure is the inability of the Liver to perform its normal synthetic and metabolic function as part of normal physiology Hepatocellular carcinoma (HCC also called hepatoma) is a primary malignancy (cancer of the Liver.

The hepatitis C virus (HCV) is spread by blood-to-blood contact. No vaccine against hepatitis C is available. The symptoms of infection can be medically managed, and a proportion of patients can be cleared of the virus by a course of anti-viral medicines. Although early medical intervention is helpful, people with HCV infection can experience mild symptoms, and consequently do not seek treatment. [1] An estimated 150-200 million people worldwide are infected with hepatitis C.

Hepatitis C (originally "non-A non-B hepatitis") is one of six known hepatitis viruses: A, B, C, D, E, G. Hepatitis A, (formerly known as infectious hepatitis) is an acute Infectious disease of the Liver caused by Hepatitis A virus which is Hepatitis D is a Disease caused by a small circular RNA virus ( Hepatitis delta virus or hepatitis D virus, HDV) Hepatitis E is a viral Hepatitis (liver inflammation caused by Infection with a Virus called hepatitis E virus ( HEV)

Contents

History

In the mid 1970s, Harvey J. Alter, Chief of the Infectious Disease Section in the Department of Transfusion Medicine at the National Institutes of Health, and his research team demonstrated that most post-transfusion hepatitis cases were not due to hepatitis A and B viruses. Harvey J Alter, chief of the Infectious disease section in the department of transfusion medicine at the National Institutes of Health (NIH was awarded the 2000 "NIH" redirects here For other meanings of NIH see NIH (disambiguation. Blood transfusion is the process of transferring Blood or blood-based products from one person into the Circulatory system of another Hepatitis A, (formerly known as infectious hepatitis) is an acute Infectious disease of the Liver caused by Hepatitis A virus which is Despite this discovery, international research effort to identify the virus, initially called non-A, non-B hepatitis (NANBH), failed for the next decade. In 1987, Michael Houghton, Qui-Lim Choo, and George Kuo at Chiron Corporation, collaborating with Dr. Year 1987 ( MCMLXXXVII) was a Common year starting on Thursday (link displays 1987 Gregorian calendar) Chiron Corporation was a Multinational biotechnology firm based in Emeryville California that was acquired by Novartis International AG on April 20 D. W. Bradley from CDC, utilized a novel molecular cloning approach to identify the unknown organism. Molecular cloning refers to the procedure of isolating a defined DNA sequence and obtaining multiple copies of it In vivo. [2] In 1988, the virus was confirmed by Alter by verifying its presence in a panel of NANBH specimens. Year 1988 ( MCMLXXXVIII) was a Leap year starting on Friday (link displays 1988 Gregorian calendar) In April of 1989, the discovery of the virus, re-named hepatitis C virus (HCV), was published in two articles in the journal Science. Year 1989 ( MCMLXXXIX) was a Common year starting on Sunday (link displays 1989 Gregorian calendar) [3][4]

Chiron filed for several patents on the virus and its diagnosis. [5] A competing patent application by the CDC was dropped in 1990 after Chiron paid $1. 9 million to the CDC and $337,500 to Bradley. In 1994 Bradley sued Chiron, seeking to invalidate the patent, have himself included as a co-inventor, and receive damages and royalty income. He dropped the suit in 1998 after losing before an appeals court. [6]

In 2000, Drs. Alter and Houghton were honored with the Lasker Award for Clinical Medical Research for "pioneering work leading to the discovery of the virus that causes hepatitis C and the development of screening methods that reduced the risk of blood transfusion-associated hepatitis in the U. The Albert Lasker Medical Research Awards have been awarded annually since 1946 to living persons who have made major contributions to Medical science. S. from 30% in 1970 to virtually zero in 2000. "[7]

In 2004 Chiron held 100 patents in 20 countries related to hepatitis C and had successfully sued many companies for infringement. Scientists and competitors have complained that the company hinders the fight against hepatitis C by demanding too much money for its technology. [6]

Signs and symptoms

Early studies of viral loads in eleven asymptomatic viral carriers indicated that asymptomatic viral loads in blood plasma varied between 100/mL and 50,000,000/mL. Viral load is a measure of the severity of a viral infection and can be calculated by estimating the amount of virus in an involved body fluid [8]

Cirrhosis of the liver and liver cancer may ensue from Hepatitis C.
Cirrhosis of the liver and liver cancer may ensue from Hepatitis C. Cirrhosis is a consequence of chronic Liver Disease characterized by replacement of liver tissue by fibrous Scar tissue as well as regenerative Hepatocellular carcinoma (HCC also called hepatoma) is a primary malignancy (cancer of the Liver.

Acute Hepatitis C

Acute hepatitis C refers to the first 6 months after infection with HCV. Between 60% to 70% of people infected develop no symptoms during the acute phase. In the minority of patients who experience acute phase symptoms, they are generally mild and nonspecific, and rarely lead to a specific diagnosis of hepatitis C. Symptoms of acute hepatitis C infection include decreased appetite, fatigue, abdominal pain, jaundice, itching, and flu-like symptoms. Abdominal pain can be one of the Symptoms associated with transient disorders or serious disease Jaundice, also known as icterus (attributive adjective "icteric" is yellowish discoloration of the Skin, sclerae (whites of the eyes Itch ( Latin: pruritus) is an unpleasant Sensation that evokes the desire or Reflex to scratch

The hepatitis C virus is usually detectable in the blood within one to three weeks after infection, and antibodies to the virus are generally detectable within 3 to 12 weeks. Approximately 15-40% of persons infected with HCV clear the virus from their bodies during the acute phase as shown by normalization in liver function tests (LFTs) such as alanine transaminase (ALT) & aspartate transaminase (AST) normalization, as well as plasma HCV-RNA clearance (this is known as spontaneous viral clearance). Liver function tests (LFTs or LFs which include liver enzymes, are groups of Clinical biochemistry laboratory blood assays designed to give information about the Alanine transaminase or ALT is a Transaminase Enzyme ( It is also called serum glutamic pyruvic transaminase (SGPT or alanine aminotransferase Aspartate Transaminase ( AST) also called serum glutamic oxaloacetic transaminase ( SGOT) or aspartate aminotransferase ( ASAT/AAT The remaining 60-85% of patients infected with HCV develop chronic hepatitis C, i. In Medicine, a chronic disease is a Disease that is long-lasting or recurrent e. , infection lasting more than 6 months. [9][10][11]

Previous practice was to not treat acute infections to see if the person would spontaneously clear; recent studies have shown that treatment during the acute phase of genotype 1 infections has a greater than 90% success rate with half the treatment time required for chronic infections, but that the majority of acute hepatitis C is cleared. The genotype is the genetic constitution of a cell an organism or an individual (i [12]

Chronic Hepatitis C

Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for more than six months. Clinically, it is often asymptomatic (without symptoms) and it is mostly discovered accidentally.

The natural course of chronic hepatitis C varies considerably from one person to another. Virtually all people infected with HCV have evidence of inflammation on liver biopsy, however, the rate of progression of liver scarring (fibrosis) shows significant variability among individuals. Recent data suggests that among untreated patients, roughly one-third progress to liver cirrhosis in less than 20 years. Another third progress to cirrhosis within 30 years. The remainder of patients appear to progress so slowly that they are unlikely to develop cirrhosis within their lifetimes. Factors that have been reported to influence the rate of HCV disease progression include age (increasing age associated with more rapid progression), gender (males have more rapid disease progression than females), alcohol consumption (associated with an increased rate of disease progression), HIV coinfection (associated with a markedly increased rate of disease progression), and fatty liver (the presence of fat in liver cells has been associated with an increased rate of disease progression).

Symptoms specifically suggestive of liver disease are typically absent until substantial scarring of the liver has occurred. However, hepatitis C is a systemic disease and patients may experience a wide spectrum of clinical manifestations ranging from an absence of symptoms to a more symptomatic illness prior to the development of advanced liver disease. Generalized signs and symptoms associated with chronic hepatitis C include fatigue, marked weight loss, flu-like symptoms, muscle pain, joint pain, intermittent low-grade fevers, itching, sleep disturbances, abdominal pain (especially in the right upper quadrant), appetite changes, nausea, diarrhea, dyspepsia, cognitive changes, depression, headaches, and mood swings.

Once chronic hepatitis C has progressed to cirrhosis, signs and symptoms may appear that are generally caused by either decreased liver function or increased pressure in the liver circulation, a condition known as portal hypertension. Cirrhosis is a consequence of chronic Liver Disease characterized by replacement of liver tissue by fibrous Scar tissue as well as regenerative Possible signs and symptoms of liver cirrhosis include ascites (accumulation of fluid in the abdomen), bruising and bleeding tendency, bone pain, varices (enlarged veins, especially in the stomach and esophagus), fatty stools (steatorrhea), jaundice, and a syndrome of cognitive impairment known as hepatic encephalopathy. In Medicine ( Gastroenterology) ascites (also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more Steatorrhea is the presence of excess fat in Feces. Stools may also float due to excess gas have an oily appearance and be foul smelling Jaundice, also known as icterus (attributive adjective "icteric" is yellowish discoloration of the Skin, sclerae (whites of the eyes Hepatic encephalopathy (sometimes hepatoencephalopathy) is a potentially-reversible Neuropsychiatric abnormality in the setting of Liver failure, whether

Liver function tests show variable elevation of ALAT, AST and GGTP and periodically they might show normal results. Alat or Rus Alatı (Алат Рус Алаты is a village ( selo) in Vysokogorsky District of the Republic of Tatarstan Gamma-glutamyl transferase ( GGT or GGTP, or Gamma-GT) ( is primarily a Liver Enzyme. Usually prothrombin and albumin results are normal. Thrombin (activated Factor II ') is a Coagulation protein that has many effects in the coagulation cascade. Serum albumin, often referred to simply as albumin, is the most abundant Plasma protein in humans and other Mammals Albumin is essential for maintaining The level of elevation of liver tests do not correlate well with the amount of liver injury on biopsy. Viral genotype and viral load also do not correlate with the amount of liver injury. Liver biopsy is the best test to determine the amount of scarring and inflammation. Radiographic studies such as ultrasound or CT scan do not show liver injury until it is fairly advanced.

Chronic hepatitis C, more than other forms of hepatitis, is diagnosed because of extrahepatic manifestations associated with the presence of HCV such as thyroiditis (inflammation of the thyroid) with hyperthyreosis or hypothyreosis, porphyria cutanea tarda, cryoglobulinemia (a form of vasculitis)[13] and glomerulonephritis (inflammation of the kidney), specifically membranoproliferative glomerulonephritis (MPGN). Thyroiditis is the inflammation of the thyroid gland The thyroid gland is located on the front of the neck below the Laryngeal prominence, and makes hormones that Porphyria cutanea tarda (PCT is the most common subtype of Porphyria. Cryoglobulins are proteins that become insoluble at reduced temperatures- less than 4 degrees Celsius Vasculitis (plural vasculitides) a group of diseases featuring Inflammation of the wall of Blood vessels including veins ( Phlebitis) arteries Glomerulonephritis, also known as glomerular nephritis, abbreviated GN, is a renal disease characterized by Inflammation of the glomeruli Membranoproliferative glomerulonephritis or MPGN is a type of Glomerulonephritis caused by deposits in the kidney glomerular mesangium and basement membrane ( GBM) [14] Hepatitis C is also associated with sicca syndrome, thrombocytopenia, lichen planus, diabetes mellitus and with B-cell lymphoproliferative disorders. Sjögren's syndrome is an autoimmune disorder in which Immune cells attack and destroy the Exocrine glands ref name="pmid18289371"> that Thrombocytopenia (or -paenia, or thrombopenia in short is the presence of relatively few Platelets in Blood. Lichen planus is an Inflammatory Disease that affects the Skin and the Oral mucosa, and presents itself in the form of Papules Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc Lymphoproliferative disorders (LPDs refer to several conditions in which Lymphocytes are produced in excessive quantities [15]

Virology

Main article: Hepatitis C virus

The Hepatitis C virus (HCV) is a small (50 nm in size), enveloped, single-stranded, positive sense RNA virus. This page is for the virus For the disease see Hepatitis C. Hepatitis C virus ( HCV) is a small (50 nm in size The metre or meter is a unit of Length. It is the basic unit of Length in the Metric system and in the International An RNA virus is a Virus that has RNA (ribonucleic acid as its Genetic material. It is the only known member of the hepacivirus genus in the family Flaviviridae. The Flaviviridae are a family of Viruses that are primarily spread through arthropod vectors (mainly ticks and mosquitoes There are six major genotypes of the hepatitis C virus, which are indicated numerically (e. g. , genotype 1, genotype 2, etc. ).

Diagnosis

The diagnosis of "hepatitis C" is rarely made during the acute phase of the disease because the majority of people infected experience no symptoms during this phase of the disease. Those who do experience acute phase symptoms are rarely ill enough to seek medical attention. The diagnosis of chronic phase hepatitis C is also challenging due to the absence or lack of specificity of symptoms until advanced liver disease develops, which may not occur until decades into the disease.

Chronic hepatitis C may be suspected on the basis of the medical history (particularly if there is any history of IV drug abuse or inhaled substance usage such as cocaine), a history of piercings or tattoos, unexplained symptoms, or abnormal liver enzymes or liver function tests found during routine blood testing. The medical history or Anamnesis of a Patient is information gained by a Physician or other healthcare professional by asking specific questions A tattoo is a permanent marking made by inserting ink into the layers of Skin to change the pigment for decorative or other reasons Occasionally, hepatitis C is diagnosed as a result of targeted screening such as blood donation (blood donors are screened for numerous blood-borne diseases including hepatitis C) or contact tracing. In Epidemiology, contact tracing is the identification and diagnosis of persons who may have come into contact with an infected person

Serologic profile of Hepatitis C infection
Serologic profile of Hepatitis C infection

Hepatitis C testing begins with serological blood tests used to detect antibodies to HCV. Serology is the scientific study of blood serum. In practice the term usually refers to the Diagnostic identification of antibodies in the serum Anti-HCV antibodies can be detected in 80% of patients within 15 weeks after exposure, in >90% within 5 months after exposure, and in >97% by 6 months after exposure. Overall, HCV antibody tests have a strong positive predictive value for exposure to the hepatitis C virus, but may miss patients who have not yet developed antibodies (seroconversion), or have an insufficient level of antibodies to detect. The positive predictive value, or precision rate, or post-test probability of disease, is the proportion of patients with positive test results who are correctly diagnosed Seroconversion is the development of detectable specific Antibodies to Microorganisms in the blood serum as a result of Infection or Immunization Rarely, people infected with HCV never develop antibodies to the virus and therefore, never test positive using HCV antibody screening. Because of this possibility, RNA testing (see nucleic acid testing methods below) should be considered when antibody testing is negative but suspicion of hepatitis C is high (e. g. because of elevated transaminases in someone with risk factors for hepatitis C). The presence of elevated transaminases, commonly the transaminases Alanine transaminase (ALT & Aspartate transaminase (AST, may be an indicator

Anti-HCV antibodies indicate exposure to the virus, but cannot determine if ongoing infection is present. All persons with positive anti-HCV antibody tests must undergo additional testing for the presence of the hepatitis C virus itself to determine whether current infection is present. The presence of the virus is tested for using molecular nucleic acid testing methods such as polymerase chain reaction (PCR), transcription mediated amplification (TMA), or branched DNA (b-DNA). All HCV nucleic acid molecular tests have the capacity to detect not only whether the virus is present, but also to measure the amount of virus present in the blood (the HCV viral load). The HCV viral load is an important factor in determining the probability of response to interferon-based therapy, but does not indicate disease severity nor the likelihood of disease progression.

In people with confirmed HCV infection, genotype testing is generally recommended. HCV genotype testing is used to determine the required length and potential response to interferon-based therapy.

Transmission

CDC figures for sources of infection in the US. Source
CDC figures for sources of infection in the US. Source

The hepatitis C virus (HCV) is transmitted by blood-to-blood contact. In developed countries, it is estimated that 90% of persons with chronic HCV infection were infected through transfusion of unscreened blood or blood products or via injecting drug use or by inhalational drug use. In developing countries, the primary sources of HCV infection are unsterilized injection equipment and infusion of inadequately screened blood and blood products.

Although injection drug use and receipt of infected blood/blood products are the most common routes of HCV infection, any practice, activity, or situation that involves blood-to-blood exposure can potentially be a source of HCV infection. The virus may be sexually transmitted, although this is rare, and usually only occurs when an STD (like HIV) is also present and makes blood contact more likely. A sexually transmitted disease ( STD) or venereal disease ( VD) is an illness that has a significant probability of transmission between Humans Human immunodeficiency virus ( HIV) is a Lentivirus (a member of the Retrovirus family that can lead to acquired immunodeficiency syndrome [16].

Methods of transmission

Several activities and practices have been identified as potential sources of exposure to the hepatitis C virus. Anyone who may have been exposed to HCV through one or more of these routes should be screened for hepatitis C.

Injection drug use

Those who currently use or have used drug injection as their delivery route for illicit drugs are at increased risk for getting hepatitis C because they may be sharing needles or other drug paraphernalia (includes cookers, cotton, spoons, water, etc. Injection of Recreational drugs is a method of the drug into the body with a hollow needle and a Syringe which is pierced through the skin into the body (usually Intravenous Drug paraphernalia is defined by the American Federal Drug Enforcement Administration as any equipment product or material that is modified for making using or concealing ), which may be contaminated with HCV-infected blood. An estimated 60% to 80% of all IV drug users in the United States have been infected with HCV. [17] Harm reduction strategies are encouraged in many countries to reduce the spread of hepatitis C, through education, provision of clean needles and syringes, and safer injecting techniques. Harm reduction is a Philosophy of Public health, intended to be a progressive alternative to the prohibition of certain potentially dangerous

Drug use by nasal inhalation (Drugs that are "snorted")

Researchers have suggested that the transmission of HCV may be possible through the nasal inhalation (insuffulation) of illegal drugs such as cocaine and crystal methamphetamine when straws (containing even trace amounts of mucus and blood) are shared among users. [18]

Blood products

Blood transfusion, blood products, or organ transplantation prior to implementation of HCV screening (in the U. Blood transfusion is the process of transferring Blood or blood-based products from one person into the Circulatory system of another S. , this would refer to procedures prior to 1992) is a decreasing risk factor for hepatitis C.

The virus was first isolated in 1989 and reliable tests to screen for the virus were not available until 1992. Therefore, those who received blood or blood products prior to the implementation of screening the blood supply for HCV may have been exposed to the virus. Blood products include clotting factors (taken by hemophiliacs), immunoglobulin, Rhogam, platelets, and plasma. Haemophilia (also spelled as hemophilia In 2001, the Centers for Disease Control and Prevention reported that the risk of HCV infection from a unit of transfused blood in the United States is less than one per million transfused units.

Iatrogenic medical or dental exposure

People can be exposed to HCV via inadequately or improperly sterilized medical or dental equipment. Equipment that may harbor contaminated blood if improperly sterilized includes needles or syringes, hemodialysis equipment, oral hygiene instruments, and jet air guns, etc. Oral hygiene is the practice of keeping the Mouth and Teeth clean in order to prevent dental problems and bad breath. Scrupulous use of appropriate sterilization techniques and proper disposal of used equipment can reduce the risk of iatrogenic exposure to HCV to virtually zero.

Occupational exposure to blood

Medical and dental personnel, first responders (e. g. , firefighters, paramedics, emergency medical technicians, law enforcement officers), and military combat personnel can be exposed to HCV through accidental exposure to blood through accidental needlesticks or blood spatter to the eyes or open wounds. Universal precautions to protect against such accidental exposures significantly reduce the risk of exposure to HCV.

Recreational exposure to blood

Contact sports and other activities, such as "slam dancing" that may result in accidental blood-to-blood exposure are potential sources of exposure to HCV. Many Sports involve a degree of player-to-player and/or player-to-object contact Moshing or slamming refers to the activity in which audience members at live music performances aggressively push or slam into each other [19]

Sexual exposure

Sexual transmission of HCV is considered to be rare. Studies show the risk of sexual transmission in heterosexual, monogamous relationships is extremely rare or even null. [20][21] The CDC does not recommend the use of condoms between long-term monogamous discordant couples (where one partner is positive and the other is negative). [22] However, because of the high prevalence of hepatitis C, this small risk may translate into a non-trivial number of cases transmitted by sexual routes. Vaginal penetrative sex is believed to have a lower risk of transmission than sexual practices that involve higher levels of trauma to anogenital mucosa (anal penetrative sex, fisting, use of sex toys). [23]

Body piercings and tattoos

Tattooing dyes, ink pots, stylets and piercing implements can transmit HCV-infected blood from one person to another if proper sterilization techniques are not followed. Tattoos or piercings performed before the mid 1980s, "underground," or non-professionally are of particular concern since sterile techniques in such settings may have been or be insufficient to prevent disease.

Shared personal care items

Personal care items such as razors, toothbrushes, cuticle scissors, and other manicuring or pedicuring equipment can easily be contaminated with blood. Sharing such items can potentially lead to exposure to HCV.

HCV is not spread through casual contact such as hugging, kissing, or sharing eating or cooking utensils.

Vertical transmission

Vertical transmission refers to the transmission of a communicable disease from an infected mother to her child during the birth process. Vertical transmission, also known as Mother-to-child transmission refers to transmission of an Infection, such as HIV, Hepatitis B, or Hepatitis Mother-to-child transmission of hepatitis C has been well described, but occurs relatively infrequently. Transmission occurs only among women who are HCV RNA positive at the time of delivery; the risk of transmission in this setting is approximately 6 out of 100. Among women who are both HCV and HIV positive at the time of delivery, the risk of HCV is increased to approximately 25 out of 100.

The risk of vertical transmission of HCV does not appear to be associated with method of delivery or breast feeding.

Epidemiology

Hepatitis C infects an estimated 170 million people worldwide and 4 million in the United States. There are about 35,000 to 185,000 new cases a year in the United States, and hepatitis C is the leading cause of liver transplant in the USA. Co-infection with HIV is common and rates among HIV positive populations are higher. Human immunodeficiency virus ( HIV) is a Lentivirus (a member of the Retrovirus family that can lead to acquired immunodeficiency syndrome 10,000-20,000 deaths a year in the United States are from HCV; expectations are that this mortality rate will increase, as those who were infected by transfusion before HCV testing become apparent. A survey conducted in California showed prevalence of up to 34% among prison inmates;[24] 82% of subjects diagnosed with hepatitis C have previously been in jail,[25] and transmission while in prison is well described. [26]

Egypt has the highest seroprevalence for HCV, up to 20% in some areas. This article is about the country of Egypt For a topic outline on this subject see List of basic Egypt topics. There is a hypothesis that the high prevalence is linked to a now-discontinued mass-treatment campaign for schistosomiasis, which is endemic in that country. Schistosomiasis (also known as bilharzia, bilharziosis or snail fever) is a Parasitic disease caused by several species of fluke [27] Regardless of how the epidemic started, a high rate of HCV transmission continues in Egypt, both iatrogenically and within the community and household.

Co-infection with HIV

Approximately 350,000, or 35% of patients in the USA infected with HIV are also infected with the hepatitis C virus, mainly because both viruses are blood-borne and present in similar populations. In other countries co-infection is less common, and this is possibly related to differing drug policies. HCV is the leading cause of chronic liver disease in the USA. It has been demonstrated in clinical studies that HIV infection causes a more rapid progression of chronic hepatitis C to cirrhosis and liver failure. This is not to say treatment is not an option for those living with co-infection.

Treatment and prognosis

There is a very small chance of clearing the virus spontaneously in chronic HCV carriers (0. 5 to 0. 74% per year),[28],[29] however, the majority of patients with chronic hepatitis C will not clear it without treatment.

Current treatment is a combination of pegylated interferon alpha (brand names Pegasys and PEG-Intron) and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending on genotype. Ribavirin (Copegus Rebetol Ribasphere VilonaVirazole also generics from Sandoz Teva Warrick is an Anti-viral drug which is active against a number of DNA and Indications for treatment include patients with proven hepatitis C virus infection and persistent abnormal liver function tests. Sustained cure rates (sustained viral response) of 75% or better occur in people with genotypes HCV 2 and 3 in 24 weeks of treatment,[30] about 50% in those with genotype 1 with 48 weeks of treatment and 65% for those with genotype 4 in 48 weeks of treatment. About 80% of hepatitis C patients in the United States have genotype 1. Genotype 4 is more common in the Middle East and Africa. The Middle East is a Subcontinent with no clear boundaries often used as a synonym to Near East, in opposition to Far East. Should treatment with pegylated ribivirin-interferon not return a 2-log viral reduction or complete clearance of RNA (termed early virological response) after 12 weeks for genotype 1, the chance of treatment success is less than 1%. Early virological response is typically not tested for in non-genotype 1 patients, as the chances of attaining it are greater than 90%. The mechanism of action is not entirely clear, because even patients who appear to have had a sustained virological response still have actively replicating virus in their liver and peripheral blood mononuclear cells. [31]

Treatment during the acute infection phase has much higher success rates (greater than 90%) with a shorter duration of treatment; however, this must be balanced against the 15-40% chance of spontaneous clearance without treatment (see Acute Hepatitis C section above).

Those with low initial viral loads respond much better to treatment than those with higher viral loads (greater than 2 million virions/ml). Current combination therapy is usually supervised by physicians in the fields of gastroenterology, hepatology or infectious disease. Gastroenterology ( MeSH heading is the branch of Medicine whereby the Digestive system and its disorders are studied Hepatology is the branch of Medicine that incorporates study of Liver, Gallbladder, Biliary tree and Pancreas as well as management An infectious disease is a clinically evident Disease resulting from the presence of Pathogenic microbial agents including Pathogenic viruses Pathogenic

The treatment may be physically demanding, particularly those with a prior history of drug or alcohol abuse. It can qualify for temporary disability in some cases. A substantial proportion of patients will experience a panoply of side effects ranging from a 'flu-like' syndrome (the most common, experienced for a few days after the weekly injection of interferon) to severe adverse events including anemia, cardiovascular events and psychiatric problems such as suicide or suicidal ideation. Anemia ( AmE) or anæmia/anaemia ( BrE) (from the Ancient Greek grc-Latn anaîmia, meaning “without blood” is defined as a qualitative Cardiovascular disease or cardiovascular diseases refers to the class of diseases that involve the Heart or Blood vessels ( arteries and The latter are exacerbated by the general physiological stress experienced by the patient.

In addition to the standard treatment with interferon and ribavirin, some studies have shown higher success rates when the antiviral drug amantadine (Symmetrel) is added to the regimen. Amantadine is the Organic compound known formally as 1-aminoadamantane Sometimes called "triple therapy", it involves the addition of 100mg of amantadine twice a day. Studies indicate that this may be especially helpful for "nonresponders" - patients who have not been successful in previous treatments using interferon and ribavirin only. [32] Currently, amantadine is not approved for treatment of Hepatitis C, and studies are ongoing to determine when it is most likely to benefit the patient. Followup studies have shown no benefit to adding this drug and currently it is not commonly used by experienced hepatologists.

Current guidelines strongly recommend that hepatitis C patients be vaccinated for hepatitis A and B if they have not yet been exposed to these viruses, as this would radically worsen their liver disease.

Alcoholic beverage consumption accelerates HCV associated fibrosis and cirrhosis, and makes liver cancer more likely; insulin resistance and metabolic syndrome may similarly worsen the hepatic prognosis. Insulin resistance is the condition in which normal amounts of Insulin are inadequate to produce a normal Insulin response from Fat, Muscle Metabolic syndrome is a combination of medical disorders that increase the risk of developing Cardiovascular disease and diabetes. There is also evidence that smoking increases the fibrosis (scarring) rate.

During pregnancy and breastfeeding

If a pregnant woman has risk factors for hepatitis C, she should be tested for antibodies against HCV. Pregnancy ( Latin graviditas) is the carrying of one or more offspring known as a Fetus or Embryo, inside the Uterus of a Female About four out of every hundred infants born to HCV infected women become infected. The virus is spread to the baby at the time of birth. There is no treatment that can prevent this from happening.

In a mother that also has HIV, the rate of transmission can be as high as 19%. There are currently no data to determine whether antiviral therapy reduces perinatal transmission. Vertical transmission, also known as Mother-to-child transmission refers to transmission of an Infection, such as HIV, Hepatitis B, or Hepatitis Ribavirin and interferons are contraindicated during pregnancy. Ribavirin (Copegus Rebetol Ribasphere VilonaVirazole also generics from Sandoz Teva Warrick is an Anti-viral drug which is active against a number of DNA and Interferons ( IFN s are natural Proteins produced by the cells of the Immune system of most Vertebrates in response to challenges by foreign agents However, avoiding fetal scalp monitoring and prolonged labor after rupture of membranes may reduce the risk of transmission to the infant. (ROM is a term used during Pregnancy to describe a rupture of the Amniotic sac at the onset of or during labor.

HCV antibodies from the mother may persist in infants until 15 months of age. If an early diagnosis is desired, testing for HCV RNA can be performed between the ages of 2 and 6 months, with a repeat test done independent of the first test result. Diagnosis is the identification by Process of elimination, of the nature of anything If a later diagnosis is preferred, an anti-HCV test can performed after 15 months of age. Most infants infected with HCV at the time of birth have no symptoms and do well during childhood. A symptom' (from Greek σύμπτωμα, "accident misfortune that which befalls" from συμπίπτω, "I befall" from There is no evidence that breast-feeding spreads HCV. Breastfeeding is the feeding of an Infant or young Child with Breast milk directly from human Breasts, not from a Baby bottle or other To be cautious, an infected mother should avoid breastfeeding if her nipples are cracked and bleeding. [33]

Alternative therapies

Several alternative therapies purport to reduce the liver's duties, rather than treat the virus itself, thereby slowing the course of the disease or keeping the quality of life of the person. The term alternative medicine, as used in the modern western world encompasses any healing practice "that does not fall within the realm of conventional Medicine. As an example, extract of Silybum marianum and licorice are sold for their HCV related effects; the first is said to provide some generic help to hepatic functions, and the second to have a mild antiviral effect and to raise blood pressure. Blessed Milk Thistle ( Silybum marianum) is a Milk thistle, a plant of the Asteraceae family Liquorice (UK or licorice (US (see spelling differences;, or) is the root of Glycyrrhiza glabra, from which a sweet flavour can be extracted [34]

Experimental treatments

The drug viramidine, which is a prodrug of ribavirin that has better targeting for the liver, and therefore may be more effective against hepatitis C for a given tolerated dose, is in phase III experimental trials against hepatitis C. Taribavirin ( rINN; also known as viramidine, codenamed ICN 3142) is an Antiviral drug in Phase III human trials but not yet approved A prodrug is a pharmacological substance ( drug) that is administered in an inactive (or significantly less active form Ribavirin (Copegus Rebetol Ribasphere VilonaVirazole also generics from Sandoz Teva Warrick is an Anti-viral drug which is active against a number of DNA and It will be used in conjunction with interferon, in the same manner as ribavirin. Interferons ( IFN s are natural Proteins produced by the cells of the Immune system of most Vertebrates in response to challenges by foreign agents However, this drug is not expected to be active against ribavirin-resistant strains, and the use of the drug against infections which have already failed ribavirin/interferon treatment, is unproven.

There are new drugs under development like the protease inhibitors (including VX 950) and polymerase inhibitors (such as NM 283), but development of these is still in the early phase. For natural protease inhibitors please see Protease inhibitor (biology Protease inhibitors (PIs are a class of Medications used [35][36] One protease inhibitor, BILN 2061, had to be discontinued due to safety problems early in the clinical testing. Some more modern new drugs that provide some support in treating HCV are Albuferon, Zadaxin, and DAPY. Antisense phosphorothioate oligos have been targeted to hepatitis C. [37] Antisense Morpholino oligos have shown promise in preclinical studies[38] however, they were found to cause a limited viral load reduction. In Molecular biology, a Morpholino is a Molecule used to modify Gene expression.

Immunoglobulins against the hepatitis C virus exist and newer types are under development. Antibodies (also known as immunoglobulins, abbreviated Ig) are Gamma globulin Proteins that are found in Blood or other Bodily Thus far, their roles have been unclear as they have not been shown to help in clearing chronic infection or in the prevention of infection with acute exposures (e. g. needlesticks). They do have a limited role in transplant patients.

Prevention

The following guidelines will prevent infection with the hepatitis C virus, which is spread by blood:

Proponents of harm reduction believe that strategies such as the provision of new needles and syringes, and education about safer drug injection procedures, greatly decreases the risk of hepatitis C spreading between injecting drug users. Harm reduction is a Philosophy of Public health, intended to be a progressive alternative to the prohibition of certain potentially dangerous

No vaccine protects against contracting hepatitis C, or helps to treat it. Vaccines are under development and some have shown encouraging results. [40]

See also

References

  1. ^ a b Ryan KJ; Ray CG (editors) (2004). Hepatitis C is an infectious disease caused by the Hepatitis C virus (HCV which affects the Liver and is transmitted by blood-to-blood contact Hepatitis A, (formerly known as infectious hepatitis) is an acute Infectious disease of the Liver caused by Hepatitis A virus which is Hepatitis D is a Disease caused by a small circular RNA virus ( Hepatitis delta virus or hepatitis D virus, HDV) Hepatitis E is a viral Hepatitis (liver inflammation caused by Infection with a Virus called hepatitis E virus ( HEV) Sherris Medical Microbiology, 4th ed. , McGraw Hill, pp. 551–2. ISBN 0838585299.  
  2. ^ 2000 Albert Lasker Award for Clinical Medical Research, The Lasker Foundation. Accessed 20 February 2008
  3. ^ Choo Q, Kuo G, Weiner A, Overby L, Bradley D, Houghton M (1989). "Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. ". Science 244 (4902): 359-62. doi:10.1126/science.2523562. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 2523562.  
  4. ^ Kuo G, Choo Q, Alter H, Gitnick G, Redeker A, Purcell R, Miyamura T, Dienstag J, Alter M, Stevens C (1989). "An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. ". Science 244 (4902): 362-4. doi:10.1126/science.2496467. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 2496467.  
  5. ^ Houghton, M. , Q. -L. Choo, and G. Kuo. NANBV Diagnostics and Vaccines. European Patent No. EP-0-3 18-216-A1. European Patent Office (filed 18 November 1988, published 31 May 1989). Events 326 - The old St Peter's Basilica is consecrated 1302 - Pope Boniface VIII issues the Papal bull Year 1988 ( MCMLXXXVIII) was a Leap year starting on Friday (link displays 1988 Gregorian calendar) Events 1279 BC - Rameses II (The Great (19th dynasty becomes pharaoh of Ancient Egypt. Year 1989 ( MCMLXXXIX) was a Common year starting on Sunday (link displays 1989 Gregorian calendar)
  6. ^ a b Paul Elias. ""Hepatitis Drug-Maker Complaints Reviewed", The Associated Press, 27 February 20
  7. ^ 2000 Winners Albert Lasker Award for Clinical Medical Research, The Lasker Foundation. Accessed 20 February 2008.
  8. ^ Ulrich P, Romeo J, Lane P, Kelly I, Daniel L, Vyas G (1990). "Detection, semiquantitation, and genetic variation in hepatitis C virus sequences amplified from the plasma of blood donors with elevated alanine aminotransferase." (PDF & scanned pages). J Clin Invest 86 (5): 1609-14. doi:10.1172/JCI114882. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 2173725.  
  9. ^ Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL (1999). "Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection". Hepatology 29 (3): 908–14. doi:10.1002/hep.510290311. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 10051497.  
  10. ^ Cox AL, Netski DM, Mosbruger T, et al (2005). "Prospective evaluation of community-acquired acute-phase hepatitis C virus infection". Clin. Infect. Dis. 40 (7): 951–8. doi:10.1086/428578. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15824985.  
  11. ^ NIH Consensus Development Conference on Management of Hepatitis C: 2002. Retrieved on 2008-02-22. 2008 ( MMVIII) is the current year in accordance with the Gregorian calendar, a Leap year that started on Tuesday of the Common Events 1495 - King Charles VIII of France enters Naples to claim the city's throne
  12. ^ Jaeckel E, Cornberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M, Pastore G, Dietrich M, Trautwein C, Manns MP (Nov 2001). "Treatment of acute hepatitis C with interferon alfa-2b". New England Journal of Medicine 345 (20): 1452-1457. doi:10.1056/NEJMoa011232. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 11794193.  
  13. ^ Pascual M, Perrin L, Giostra E, Schifferli J (1990). "Hepatitis C virus in patients with cryoglobulinemia type II. ". J Infect Dis 162 (2): 569-70. PMID 2115556.  
  14. ^ Johnson R, Gretch D, Yamabe H, Hart J, Bacchi C, Hartwell P, Couser W, Corey L, Wener M, Alpers C (1993). "Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. ". N Engl J Med 328 (7): 465-70. doi:10.1056/NEJM199302183280703. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 7678440.  
  15. ^ Zignego AL, Ferri C, Pileri SA, Caini P, Bianchi FB; for the Italian Association of the Study of Liver (A. I. S. F. ) Commission on Extrahepatic Manifestations of HCV infection (2006). "Extrahepatic manifestations of Hepatitis C Virus infection: A general overview and guidelines for a clinical approach". Dig Liver Dis. : E-publication. PMID 16884964.  
  16. ^ What is hepatitis?, Planned Parenthood, accessed May 15, 2007
  17. ^ [www. Planned Parenthood is the collective name of organizations worldwide who are members of the International Planned Parenthood Federation (IPPF cdc. gov/ncidod/diseases/hepatitis/partners/nvhpc_2005/Thursday/PL4Alter. ppt HCV Prevalence in Selected Groups of Adults by History of Injection Drug Use]. Retrieved on 2008-06-03. 2008 ( MMVIII) is the current year in accordance with the Gregorian calendar, a Leap year that started on Tuesday of the Common Events 350 - Roman usurper Nepotianus, of the Constantinian dynasty, proclaims himself Roman Emperor, entering
  18. ^ Thompson S, Hernberger F, Wale E, Crofts N (1996). "Hepatitis C transmission through tattooing: a case report". Aust N Z J Public Health 20 (3): 317-8. PMID 8768424.  
  19. ^ Karmochkine M, Carrat F, Dos Santos O, Cacoub P, Raguin G (2006). "A case-control study of risk factors for hepatitis C infection in patients with unexplained routes of infection". J. Viral Hepat. 13 (11): 775–82. doi:10.1111/j.1365-2893.2006.00742.x. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17052278.  
  20. ^ Lack of evidence of sexual transmission of hepatit...[Am J Gastroenterol. 2004] - PubMed Result
  21. ^ Hepatitis Central News, Updates and Commentary
  22. ^ Hepatitis C: FAQ | CDC Viral Hepatitis
  23. ^ Hahn JA (2007). "Sex, Drugs, and Hepatitis C Virus". J Infect Dis 195: 1556–9. doi:10.1086/516792. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  24. ^ Ruiz J, Molitor F, Plagenhoef J (2002). "Trends in hepatitis C and HIV infection among inmates entering prisons in California, 1994 versus 1999. ". AIDS 16 (16): 2236-8. PMID 12409752.  
  25. ^ Campbell J, Hagan H, Latka M, Garfein R, Golub E, Coady M, Thomas D, Strathdee S (2006). "High prevalence of alcohol use among hepatitis C virus antibody positive injection drug users in three US cities. ". Drug Alcohol Depend 81 (3): 259-65. doi:10.1016/j.drugalcdep.2005.07.005. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16129567.  
  26. ^ McGovern B, Wurcel A, Kim A, Schulze zur Wiesch J, Bica I, Zaman M, Timm J, Walker B, Lauer G (2006). "Acute hepatitis C virus infection in incarcerated injection drug users. ". Clin Infect Dis 42 (12): 1663-70. doi:10.1086/504327. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16705568.  
  27. ^ Frank C, Mohamed M, Strickland G, Lavanchy D, Arthur R, Magder L, El Khoby T, Abdel-Wahab Y, Aly Ohn E, Anwar W, Sallam I (2000). "The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. ". Lancet 355 (9207): 887-91. doi:10.1016/S0140-6736(99)06527-7. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 10752705.  
  28. ^ Watanabe H, Saito T, Shinzawa H, Okumoto K, Hattori E, Adachi T, Takeda T, Sugahara K, Ito J, Saito K, Togashi H, Suzuki R, Hayashi M, Miyamura T, Matsuura Y, Kawata S (2003). "Spontaneous elimination of serum hepatitis C virus (HCV) RNA in chronic HCV carriers: a population-based cohort study". J Med Virol 71 (1): 56-61. doi:10.1002/jmv.10448. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 12858409.  
  29. ^ Scott J, McMahon B, Bruden D, Sullivan D, Homan C, Christensen C, Gretch D (2006). "High rate of spontaneous negativity for hepatitis C virus RNA after establishment of chronic infection in Alaska Natives". Clin Infect Dis 42 (7): 945-52. doi:10.1086/500938. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16511757.  
  30. ^ Shiffman ML, Suter F, Bacon BR, et al. (2007). "Peginterferon Alfa-2a and Ribavirin for 16 or 24 weeks in HCV genotype 2 or 3". N Engl J Med 357 (2): 124–134. doi:10.1056/NEJMoa066403. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  31. ^ Castillo I, Rodriguez-Iñigo E, López-Alcorocho JM, et al. (2006). "Hepatitis C virus replicates in the liver of patients who have a sustained response to antiviral treatment". Clin Infect Dis 43 (10): 1277–83. doi:10.1086/508198. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  32. ^ Maynard M, Pradat P, Bailly F, Rozier F, Nemoz C, Si Ahmed S, Adeleine P, Trépo C (2006). "Amantadine triple therapy for non-responder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI). ". J Hepatol 44 (3): 484-90. doi:10.1016/j.jhep.2005.11.038. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16426697.  
  33. ^ Mast E. "Mother-to-infant hepatitis C virus transmission and breastfeeding. ". Adv Exp Med Biol 554: 211-6. PMID 15384578.  
  34. ^ NCCAM. Hepatitis C and Complementary and Alternative Medicine: 2003 Update. May 2004. Accessed 2007-02-25. Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. Events 138 - The Emperor Hadrian adopts Antoninus Pius, effectively making him his successor
  35. ^ Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, Sentjens R, Calleja J, Forns X, Erhardt A, Crönlein J, Chaves R, Yong C, Nehmiz G, Steinmann G (2004). "Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. ". Gastroenterology 127 (5): 1347-55. doi:10.1053/j.gastro.2004.08.002. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15521004.  
  36. ^ Lamarre D, Anderson P, Bailey M, Beaulieu P, Bolger G, Bonneau P, Bös M, Cameron D, Cartier M, Cordingley M, Faucher A, Goudreau N, Kawai S, Kukolj G, Lagacé L, LaPlante S, Narjes H, Poupart M, Rancourt J, Sentjens R, St George R, Simoneau B, Steinmann G, Thibeault D, Tsantrizos Y, Weldon S, Yong C, Llinàs-Brunet M (2003). "An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. ". Nature 426 (6963): 186-9. doi:10.1038/nature02099. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 14578911 doi:10. 1038/nature02099.  
  37. ^ Zhang H, Hanecak R, Brown-Driver V, Azad R, Conklin B, Fox M, Anderson K (1999). "Antisense oligonucleotide inhibition of hepatitis C virus (HCV) gene expression in livers of mice infected with an HCV-vaccinia virus recombinant.". Antimicrob Agents Chemother 43 (2): 347-53. PMID 9925530.  
  38. ^ McCaffrey A, Meuse L, Karimi M, Contag C, Kay M (2003). "A potent and specific morpholino antisense inhibitor of hepatitis C translation in mice. ". Hepatology 38 (2): 503-8. doi:10.1053/jhep.2003.50330. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 12883495.  
  39. ^ Hepatitis C: Fact Sheet. Retrieved on 2008-04-15. 2008 ( MMVIII) is the current year in accordance with the Gregorian calendar, a Leap year that started on Tuesday of the Common Events 1450 - Battle of Formigny: Toward the end of the Hundred Years' War, the French attack and nearly annihilate English
  40. ^ Manns MP, Foster GR, Rockstroh JK, Zeuzem S, Zoulim F, Houghton M (2007). "The way forward in HCV treatment—finding the right path". Nat Rev Drug Discov 6 (12): 991–1000. doi:10.1038/nrd2411. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 18049473.  

External links

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