Hepatitis C

Hepatitis C is an infectious disease affecting primarily the liver, caused by the hepatitis C virus (HCV).[1] The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure, liver cancer or life-threatening esophageal and gastric varices.[1]

HCV is spread primarily by blood-to-blood contact associated with intravenous drug use, poorly sterilized medical equipment and transfusions. An estimated 130–170 million people worldwide are infected with hepatitis C. The existence of hepatitis C (originally "non-A non-B hepatitis") was postulated in the 1970s and proven in 1989.[2] Hepatitis C only infects humans and chimpanzees.[3] The virus persists in the liver in about 85% of those infected. This persistent infection can be treated with medication: the standard therapy is a combination of peginterferon and ribavirin, with either boceprevir or telaprevir added in some cases. Overall, 50–80% of people treated are cured. Those who develop cirrhosis or liver cancer may require a liver transplant. Hepatitis C is the leading cause of liver transplantation, though the virus usually recurs after transplantation.[4 ] No vaccine against hepatitis C is available.

Acute infection
Hepatitis C infection causes acute symptoms in 15% of cases.[5] Symptoms are generally mild and vague, including a decreased appetite, fatigue, nausea, muscle or joint pains, and weight loss.[6] Most cases of acute infection are not associated with jaundice.[7] The infection resolves spontaneously in 10-50% of cases, which occurs more frequently in individuals who are young and female.[7]

Chronic infection
About 80% of those exposed to the virus develop a chronic infection.[8] Most experience minimal or no symptoms during the initial few decades of the infection,[9] although chronic hepatitis C can be associated with fatigue.[10] Hepatitis C after many years becomes the primary cause of cirrhosis and liver cancer.[4] About 10–30% of people develop cirrhosis over 30 years.[4] [6] Cirrhosis is more common in those co-infected with hepatitis B or HIV, alcoholics, and those of male gender.[6] Those who develop cirrhosis have a 20-fold greater risk of hepatocellular carcinoma, a rate of 1–3% per year,<sup class="reference" id="cite_ref-NEJM2011_3-3">[4] <sup class="reference" id="cite_ref-AFP2010_5-3">[6] and if this is complicated by excess alcohol the risk becomes 100 fold greater.<sup class="reference" id="cite_ref-10">[11] Hepatitis C is the cause of 27% of cirrhosis cases and 25% of hepatocellular carcinoma worldwide.<sup class="reference" id="cite_ref-World2007_11-0">[12]

Liver cirrhosis may lead to portal hypertension, ascites (accumulation of fluid in the abdomen), easy bruising or bleeding, varices (enlarged veins, especially in the stomach and esophagus), jaundice, and a syndrome of cognitive impairment known as hepatic encephalopathy. It is a common cause for requiring a liver transplant.<sup class="reference" id="cite_ref-Tah2009_12-0">[13]

Extrahepatic
Hepatitis C is also rarely associated with Sjögren's syndrome (an autoimmune disorder), thrombocytopenia, lichen planus, diabetes mellitus, and B-cell lymphoproliferative disorders.<sup class="reference" id="cite_ref-Extrahepatic_13-0">[14] Thrombocytopenia is estimated to occur in 0.16% to 45.4% of people with chronic hepatitis C.<sup class="reference" id="cite_ref-14">[15] Putative associations with Hyde's prurigo nodularis <sup class="reference" id="cite_ref-15">[16] and membranoproliferative glomerulonephritis have been reported.<sup class="reference" id="cite_ref-ID2010_9-1">[10] Hepatitis C infection is also associated with a condition called mixed cryoglobulinemia, which is inflammation of small and medium sized blood vessels (or vasculitis) caused by deposition of immune complexes involving cryoglobulins.<sup class="reference" id="cite_ref-16">[17]

Virology
The hepatitis C virus (HCV) is a small, enveloped, single-stranded, positive-sense RNA virus.<sup class="reference" id="cite_ref-NEJM2011_3-4">[4] It is a member of the hepacivirus genus in the family Flaviviridae.<sup class="reference" id="cite_ref-ID2010_9-2">[10] There are seven major genotypes of HCV, which are indicated numerically from one to seven.<sup class="reference" id="cite_ref-Nakano2011_17-0">[18] In the United States, about 70% of cases are caused by genotype 1, 20% by genotype 2, and about 1% by each of the other genotypes.<sup class="reference" id="cite_ref-AFP2010_5-4">[6] Genotype 1 is also the most common in South America and Europe.<sup class="reference" id="cite_ref-NEJM2011_3-5">[4]

Transmission
Hepatitis C infection in the United States by sourceThe primary route of transmission in the developed world is intravenous drug use (IDU), while in the developing world the main methods are blood transfusions and unsafe medical procedures.<sup class="reference" id="cite_ref-Mah2010_18-0">[19] The cause of transmission remains unknown in 20% of cases;<sup class="reference" id="cite_ref-Pon2011_19-0">[20] however, many of these are believed to be accounted for by IDU.<sup class="reference" id="cite_ref-Book2011p4_6-2">[7]

Intravenous drug use
IDU is a major risk factor for hepatitis C in many parts of the world.<sup class="reference" id="cite_ref-China2008_20-0">[21] Of 77 countries reviewed 25 (including the United States) were found to have prevalences of hepatitis C in the intravenous drug user population of between 60% and 80%.<sup class="reference" id="cite_ref-Lancet2011_7-1">[8] <sup class="reference" id="cite_ref-China2008_20-1">[21] While twelve countries had rates greater than 80%.<sup class="reference" id="cite_ref-Lancet2011_7-2">[8] It is believed that ten million intravenous drug users are infected with hepatitis C; China (1.6 million), the United States (1.5 million), and Russia (1.3 million) have the highest absolute totals.<sup class="reference" id="cite_ref-Lancet2011_7-3">[8] Occurrence of hepatitis C among prison inmates in the United States are ten to 20 times that of the occurrence observed in the general population; this has been attributed to high-risk behavior in prisons such as IDU and tattooing with nonsterile equipment.<sup class="reference" id="cite_ref-Jail2010_21-0">[22] <sup class="reference" id="cite_ref-22">[23]

Healthcare exposure
Blood transfusion, transfusion of blood products, or organ transplantation without HCV screening carry significant risks of infection.<sup class="reference" id="cite_ref-AFP2010_5-5">[6] The United States instituted universal screening in 1992<sup class="reference" id="cite_ref-Rosen2011_23-0">[24] and Canada instituted universal screening in 1990.<sup class="reference" id="cite_ref-24">[25] This decreased the risk from one in 200 units of blood<sup class="reference" id="cite_ref-Rosen2011_23-1">[24] to one in 10,000 to one in 10,000,000 per unit of blood.<sup class="reference" id="cite_ref-Book2011p4_6-3">[7] <sup class="reference" id="cite_ref-Pon2011_19-1">[20] This low risk remains as there is a period of about 11–70 days between the potential blood donor acquiring hepatitis C and their blood testing positive depending on the method.<sup class="reference" id="cite_ref-Pon2011_19-2">[20] Some countries do not screen for hepatitis C due to the cost.<sup class="reference" id="cite_ref-World2007_11-1">[12]

Those who have experienced a needle stick injury from someone who was HCV positive have about a 1.8% chance of subsequently contracting the disease themselves.<sup class="reference" id="cite_ref-AFP2010_5-6">[6] The risk is greater if the needle in question is hollow and the puncture wound is deep.<sup class="reference" id="cite_ref-World2007_11-2">[12] There is a risk from mucosal exposures to blood; but this risk is low, and there is no risk if blood exposure occurs on intact skin.<sup class="reference" id="cite_ref-World2007_11-3">[12]

Hospital equipment has also been documented as a method of transmission of hepatitis C including: reuse of needles and syringes, multiple-use medication vials, infusion bags, and improperly sterilized surgical equipment, among others.<sup class="reference" id="cite_ref-World2007_11-4">[12] Limitations in the implementation and enforcement of stringent standard precautions in public and private medical and dental facilities are known to be the primary cause of the spread of HCV in Egypt, the country with highest rate of infection in the world.<sup class="reference" id="cite_ref-25">[26]

Sexual intercourse
Whether hepatitis C can be transmitted through sexual activity is controversial.<sup class="reference" id="cite_ref-Sex2010_26-0">[27] While there is an association between high-risk sexual activity and hepatitis C, it is not known whether transmission of the disease is due to drug use that has not been admitted to or sex as a risk factor.<sup class="reference" id="cite_ref-AFP2010_5-7">[6] The majority of evidence supports there being no risk for monogamous heterosexual couples.<sup class="reference" id="cite_ref-Sex2010_26-1">[27] Sexual practices that involve higher levels of trauma to the anogenital mucosa, such as anal penetrative sex, or that occur when there is a concurrent sexually transmitted infection, including HIV or genital ulceration, do present a risk.<sup class="reference" id="cite_ref-Sex2010_26-2">[27] The United States government only recommends condom use to prevent hepatitis C transmission in those with multiple partners.<sup class="reference" id="cite_ref-27">[28]

Body piercings
Tattooing is associated with two to threefold increased risk of hepatitis C.<sup class="reference" id="cite_ref-Tato2010_28-0">[29] This can be due to either improperly sterilized equipment or contamination of the dyes being used.<sup class="reference" id="cite_ref-Tato2010_28-1">[29] Tattoos or piercings performed either before the mid-1980s, "underground," or nonprofessionally are of particular concern, since sterile techniques in such settings may be lacking. The risk also appears to be greater for larger tattoos.<sup class="reference" id="cite_ref-Tato2010_28-2">[29] It is estimated that nearly half of prison inmates share unsterilized tattooing equipment.<sup class="reference" id="cite_ref-Tato2010_28-3">[29] It is rare for tattoos in a licensed facility to be directly associated with HCV infection.<sup class="reference" id="cite_ref-29">[30]

Shared personal items
Personal-care items such as razors, toothbrushes, and manicuring or pedicuring equipment can be contaminated with blood. Sharing such items can potentially lead to exposure to HCV.<sup class="reference" id="cite_ref-pmid16907842_30-0">[31] <sup class="reference" id="cite_ref-CDC12_31-0">[32] Appropriate caution should be taken regarding any medical condition that results in bleeding, such as cuts and sores.<sup class="reference" id="cite_ref-CDC12_31-1">[32] HCV is not spread through casual contact, such as hugging, kissing, or sharing eating or cooking utensils.<sup class="reference" id="cite_ref-CDC12_31-2">[32]

Vertical transmission
Vertical transmission of hepatitis C from an infected mother to her child occurs in less than 10% of pregnancies.<sup class="reference" id="cite_ref-Preg10_32-0">[33] There are no measures that alter this risk.<sup class="reference" id="cite_ref-Preg10_32-1">[33] It is not clear when during pregnancy transmission occurs, but it may occur both during gestation and at delivery.<sup class="reference" id="cite_ref-Pon2011_19-3">[20] A long labor is associated with a greater risk of transmission.<sup class="reference" id="cite_ref-World2007_11-5">[12] There is no evidence that breast-feeding spreads HCV; however, to be cautious, an infected mother is advised to avoid breastfeeding if her nipples are cracked and bleeding,<sup class="reference" id="cite_ref-33">[34] or her viral loads are high.<sup class="reference" id="cite_ref-Pon2011_19-4">[20]

Diagnosis
Serologic profile of Hepatitis C infectionThere are a number of diagnostic tests for hepatitis C including: HCV antibody enzyme immunoassay or ELISA, recombinant immunoblot assay, and quantitative HCV RNA polymerase chain reaction (PCR).<sup class="reference" id="cite_ref-AFP2010_5-8">[6] HCV RNA can be detected by PCR typically one to two weeks after infection, while antibodies can take substantially longer to form and thus be detected.<sup class="reference" id="cite_ref-Tah2009_12-1">[13]

Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for more than six months based on the presence of its RNA.<sup class="reference" id="cite_ref-Book2011_8-1">[9] Chronic infections are typically asymptomatic during the first few decades,<sup class="reference" id="cite_ref-Book2011_8-2">[9] and thus are most commonly discovered following the investigation of elevated liver enzyme levels or during a routine screening of high risk individuals. Testing is not able to distinguish between acute and chronic infections.<sup class="reference" id="cite_ref-World2007_11-6">[12]

Serology
Hepatitis C testing typically begins with blood testing to detect the presence of antibodies to the HCV using an enzyme immunoassay.<sup class="reference" id="cite_ref-AFP2010_5-9">[6] If this test is positive, a confirmatory test is then performed to verify the immunoassay and to determine the viral load.<sup class="reference" id="cite_ref-AFP2010_5-10">[6] A recombinant immunoblot assay is used to verify the immunoassay and the viral load is determined by a HCV RNA polymerase chain reaction.<sup class="reference" id="cite_ref-AFP2010_5-11">[6] If there are no RNA and the immunoblot is positive it means that the person had a previous infection but cleared it either with treatment or spontaneously; if the immunoblot is negative, it means that the immunoassay was wrong.<sup class="reference" id="cite_ref-AFP2010_5-12">[6] It takes about 6–8 weeks following infection before the immunoassay will test positive.<sup class="reference" id="cite_ref-ID2010_9-3">[10]

Liver enzymes are variable during the initial part of the infection<sup class="reference" id="cite_ref-Book2011_8-3">[9] and on average begin to rise at seven weeks after infection.<sup class="reference" id="cite_ref-ID2010_9-4">[10] Liver enzymes are poorly related with disease severity.<sup class="reference" id="cite_ref-ID2010_9-5">[10]

Biopsy
Liver biopsies are used to determine the degree of liver damage present; however, there are risks from the procedure.<sup class="reference" id="cite_ref-NEJM2011_3-6">[4] The typical changes seen are lymphocytes within the parenchyma, lymphoid follicles in portal triad, and changes to the bile ducts.<sup class="reference" id="cite_ref-NEJM2011_3-7">[4] There are a number of blood tests available that try to determine the degree of hepatic fibrosis and alleviate the need for biopsy.<sup class="reference" id="cite_ref-NEJM2011_3-8">[4]

Screening
It is believed only 5–50% of those infected in the United States and Canada become aware of their status.<sup class="reference" id="cite_ref-Tato2010_28-4">[29] Testing is recommended in those at high risk, which includes those with tattoos.<sup class="reference" id="cite_ref-Tato2010_28-5">[29] Screening is also recommended in those with elevated liver enzymes as this is frequently the only sign of chronic hepatitis.<sup class="reference" id="cite_ref-34">[35] Routine screening is not currently recommended in the United States.<sup class="reference" id="cite_ref-AFP2010_5-13">[6] However, as of 2012, the U.S. Centers for Disease Control and Prevention (CDC) is considering a recommendation for a single screening test for those born between 1945 and 1965.<sup class="reference" id="cite_ref-35">[36]

Prevention
As of 2011, no vaccine protects against contracting hepatitis C. However, a number are under development and some have shown encouraging results.<sup class="reference" id="cite_ref-36">[37] A combination of harm reduction strategies, such as the provision of new needles and syringes and treatment of substance use, decrease the risk of hepatitis C in intravenous drug users by about 75%.<sup class="reference" id="cite_ref-37">[38] The screening of blood donors is important at a national level, as is adhering to universal precautions within healthcare facilities.<sup class="reference" id="cite_ref-ID2010_9-6">[10] In countries where there is an insufficient supply of sterile syringes, medications should be given orally rather than via injection.<sup class="reference" id="cite_ref-World2007_11-7">[12]

Treatment
HCV induces chronic infection in 50–80% of infected persons. Approximately 40-80% of these clear with treatment.<sup class="reference" id="cite_ref-38">[39] <sup class="reference" id="cite_ref-39">[40] In rare cases, infection can clear without treatment.<sup class="reference" id="cite_ref-Book2011p4_6-4">[7] Those with chronic hepatitis C are advised to avoid alcohol and medications toxic to the liver,<sup class="reference" id="cite_ref-AFP2010_5-14">[6] and to be vaccinated for hepatitis A and hepatitis B.<sup class="reference" id="cite_ref-AFP2010_5-15">[6] Ultrasound surveillance for hepatocellular carcinoma is recommended in those with accompanying cirrhosis.<sup class="reference" id="cite_ref-AFP2010_5-16">[6]

Medications
In general, treatment is recommended in those with proven HCV infection liver abnormalities.<sup class="reference" id="cite_ref-AFP2010_5-17">[6] Current<sup class="noprint Inline-Template" style="white-space:nowrap;">[when?] treatment is a combination pegylated interferon alpha and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending on HCV genotype.<sup class="reference" id="cite_ref-AFP2010_5-18">[6] When combined with ribavirin, pegylated interferon-alpha-2a may be superior to pegylated interferon-alpha-2b, though the evidence is not strong.<sup class="reference" id="cite_ref-pmid20187106_40-0">[41] Improved outcomes are seen in 50–60% of people.<sup class="reference" id="cite_ref-AFP2010_5-19">[6] Combining either boceprevir or telaprevir with ribavirin and peginterferon alfa improves antiviral response for hepatitis C genotype 1.<sup class="reference" id="cite_ref-pmid21828346_41-0">[42] <sup class="reference" id="cite_ref-pmid21558488_42-0">[43] <sup class="reference" id="cite_ref-pmid21898493_43-0">[44] Adverse effects with treatment are common, with half of people getting flu like symptoms and a third experiencing emotional problems.<sup class="reference" id="cite_ref-AFP2010_5-20">[6] Treatment during the first six months is more effective than once hepatitis C has become chronic.<sup class="reference" id="cite_ref-Tah2009_12-2">[13] If someone develops a new infection and it has not cleared after eight to twelve weeks, 24 weeks of pegylated interferon is recommended.<sup class="reference" id="cite_ref-Tah2009_12-3">[13] In people with thalassemia, ribavirin appears to be useful but increases the need for transfusions.<sup class="reference" id="cite_ref-44">[45]

Alternative medicine
Several alternative therapies are claimed by their proponents to be helpful for hepatitis C including milk thistle, ginseng, and colloidal silver.<sup class="reference" id="cite_ref-NCCAM_45-0">[46] However, no alternative therapy has been shown to improve outcomes in hepatitis C, and no evidence exists that alternative therapies have any effect on the virus at all.<sup class="reference" id="cite_ref-NCCAM_45-1">[46] <sup class="reference" id="cite_ref-46">[47] <sup class="reference" id="cite_ref-47">[48]

Prognosis
Responses to treatment vary by genotype. Sustained response is about 40-50% in people with HCV genotype 1 given 48 weeks of treatment.<sup class="reference" id="cite_ref-NEJM2011_3-9">[4] Sustained response is seen in 70-80% of people with HCV genotypes 2 and 3 with 24 weeks of treatment.<sup class="reference" id="cite_ref-NEJM2011_3-10">[4] Sustained response is about 65% in those with genotype 4 given 48 weeks of treatment. The evidence for treatment in genotype 6 disease is sparse, and the evidence that exists is for 48 weeks of treatment at the same doses as are used for genotype 1 disease.<sup class="reference" id="cite_ref-48">[49]

Epidemiology
Prevalence of hepatitis C worldwide in 1999Disability-adjusted life year for hepatitis C in 2004 per 100,000 inhabitants{| border="0" cellpadding="0" cellspacing="0" style="table-layout:fixed;" width="100%" It is estimated that 130–170 million people, or ~3% of the world's population, are living with chronic hepatitis C.<sup class="reference" id="cite_ref-WHO2011_49-0">[50] About 3–4 million people are infected per year, and more than 350,000 people die yearly from hepatitis C-related diseases.<sup class="reference" id="cite_ref-WHO2011_49-1">[50] Rates have increased substantially in the 20th century due to a combination of IDU and intravenous medication or poorly sterilized medical equipment.<sup class="reference" id="cite_ref-World2007_11-8">[12]
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Among those chronically infected, the risk of cirrhosis after 20 years varies between studies but has been estimated at ~10%-15% for men and ~1-5% for women. The reason for this difference is not known. Once cirrhosis is established, the rate of developing hepatocellular carcinoma is ~1%-4% per year.<sup class="reference" id="cite_ref-Yu2009_50-0">[51]

In the United States, about 2% of people have hepatitis C,<sup class="reference" id="cite_ref-AFP2010_5-21">[6] with about 35,000 to 185,000 new cases a year. Rates have decreased in the Western world since the 1990s due to improved screening of blood before transfusion.<sup class="reference" id="cite_ref-Tah2009_12-4">[13] Annual deaths from HCV in the United States range from 8,000 to 10,000; expectations are that this mortality rate will increase, as those infected by transfusion before HCV testing become apparent.<sup class="reference" id="cite_ref-51">[52]

Prevalence is higher in some countries in Africa and Asia.<sup class="reference" id="cite_ref-52">[53] Countries with particularly high rates of infection include Egypt (22%), Pakistan (4.8%) and China (3.2%).<sup class="reference" id="cite_ref-WHO2011_49-2">[50] It is believed that the high prevalence in Egypt is linked to a now-discontinued mass-treatment campaign for schistosomiasis, using improperly sterilized glass syringes.<sup class="reference" id="cite_ref-World2007_11-9">[12]

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 how most post-transfusion hepatitis cases were not due to hepatitis A or B viruses. Despite this discovery, international research efforts 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. D.W. Bradley at the Centers for Disease Control and Prevention, used a novel molecular cloning approach to identify the unknown organism and develop a diagnostic test.<sup class="reference" id="cite_ref-Boyer_53-0">[54] In 1988, the virus was confirmed by Alter by verifying its presence in a panel of NANBH specimens. In April 1989, the discovery of HCV was published in two articles in the journal Science.<sup class="reference" id="cite_ref-choo_54-0">[55] <sup class="reference" id="cite_ref-kuo_55-0">[56] The discovery led to significant improvements in diagnosis and improved antiviral treatment.<sup class="reference" id="cite_ref-Boyer_53-1">[54] 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.S. from 30% in 1970 to virtually zero in 2000."<sup class="reference" id="cite_ref-56">[57]

Chiron filed for several patents on the virus and its diagnosis.<sup class="reference" id="cite_ref-houghton_57-0">[58] 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 coinventor, and receive damages and royalty income. He dropped the suit in 1998 after losing before an appeals court.<sup class="reference" id="cite_ref-58">[59]

Society and culture
See also: List of people with hepatitis CWorld Hepatitis Day, held on July 28, is coordinated by the World Hepatitis Alliance.<sup class="reference" id="cite_ref-59">[60] The economic costs of hepatitis C are significant both to the individual and to society. In the United States the average lifetime cost of the disease was estimated at 33,407 USD in 2003<sup class="reference" id="cite_ref-Cost2006_60-0">[61] with the cost of a liver transplant as of 2011 costing approximately 200,000 USD.<sup class="reference" id="cite_ref-Cost2011_61-0">[62] In Canada the cost of a course of antiviral treatment is as high as 30,000 CAD in 2003,<sup class="reference" id="cite_ref-62">[63] while the United States costs are between 9,200 and 17,600 in 1998 USD.<sup class="reference" id="cite_ref-Cost2006_60-1">[61] In many areas of the world, people are unable to afford treatment with antivirals as they either lack insurance coverage or the insurance they have will not pay for antivirals.<sup class="reference" id="cite_ref-63">[64]

Research
As of 2011, there are about one hundred medications in development for hepatitis C.<sup class="reference" id="cite_ref-Cost2011_61-1">[62] These include vaccines to treat hepatitis, immunomodulators, and cyclophilin inhibitors, among others.<sup class="reference" id="cite_ref-64">[65] These potential new treatments have come about due to a better understanding of the hepatitis C virus.<sup class="reference" id="cite_ref-65">[66]