Hepatitis C

Hepatitis C is a blood-borne viral disease which can cause liver inflammation, fibrosis, cirrhosis and liver cancer.

The hepatitis C virus (HCV) is spread by blood-to-blood contact with an infected person's blood. Many people with HCV infection have no symptoms and are unaware of the need to seek treatment. Hepatitis C infects an estimated 150-200 million people worldwide. It is the leading cause of liver transplant in the United States.

Signs and symptoms

Acute Hepatitis C

Hepatitis C is an inflammation of the liver caused by infection with the hepatitis C virus (HCV). The hepatitis C virus is one of five known hepatitis viruses: A, B, C, D, E. Hepatitis C was previously known as non-A, non-B hepatitis prior to isolation of the virus in 1989.

Acute hepatitis C refers to the first 6 months after infection with HCV. Remarkably, 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.

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 25% of persons infected with HCV clear the virus from their bodies during the acute phase; this is known as spontaneous viral clearance. The remaining 75% of persons infected with HCV develop chronic hepatitis C, i.e., infection lasting more than 6 months.

Because testing for Hepatitis C antibodies is not common without there being some symptoms, the statement that 25% of persons infected will spontaneously clear is a suspect number. It's possible that far more people are exposed to the virus without becoming chronically infected, and it's possible that just the opposite is true.

Previous practice was to not treat acute infections to see if the person would spontaneously clear; recent studies (2005) 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. Further studies are being done to see if the treatment time for acute infections can be reduced even further.

Chronic Hepatitis C

Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for more than six months. The 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 inter-individual variability. Recent data suggests that among untreated patients, roughly 1/3 progress to liver cirrhosis in less than 20 years. Another 1/3 progress to cirrhosis within 30 years. The remainder of patients appear to progress so slowly that they are unlikely to develop cirrhosis within their lifetime. 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 debilitating illness prior to the development of advanced liver disease. Generalized signs and symptoms associated with chronic hepatitis C include fatigue, 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, 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. 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.

Some persons with chronic hepatitis C are diagnosed because of medical phenomena associated with the presence of HCV such as thyroiditis (inflammation of the thyroid), cryoglobulinemia (a form of vasculitis) and glomerulonephritis (inflammation of the kidney), specifically membranoproliferative glomerulonephritis (MPGN).

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, unexplained symptoms, or abnormal liver enzymes or liver function tests found during routine blood testing. 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.

Hepatitis C testing begins with serological blood tests used to detect antibodies to HCV. 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. While uncommon, it is important to note that a small minority of people infected with HCV never develop antibodies to the virus and therefore, never test positive using HCV antibody screening.

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-base therapy, but does not indicate disease severity nor the likelihood of disease progression.

In people with confirmed HCV infection, genotype testing is generally recommended. There are six major genotypes of the hepatitis C virus, which are indicated numerically (e.g., genotype 1, genotype 2, etc.). HCV genotype testing is used to determine the required length and potential response to interferon-based therapy.

Virology

The hepatitis C virus (HCV) is a small, enveloped, single-stranded, positive sense RNA virus in the family Flaviviridae. HCV mainly replicates within hepatocytes in the liver, although there are clear evidence for replication in lymphocytes or monocytes. Circulating HCV particles bind to receptors on the surfaces of hepatocytes and subsequently enter the cells. Two putative HCV receptors are CD81 and human scavenger receptor class B1 (SR-BI). However, these receptors are found throughout the body. The identification of hepatocyte-specific cofactors that determine observed HCV liver tropism are currently under investigation.

Once inside the hepatocyte, HCV utilizes the intracellular machinery necessary to accomplish its own replication. Specifically, the HCV genome is translated to produce a single protein of around 3011 amino acids. This "polyprotein" is then proteolytically processed by viral and cellular proteases to produce three structural (virion-associated) and seven nonstructural (NS) proteins. Alternatively, a frameshift may occur in the Core region to produce an Alternate Reading Frame Protein (ARFP). HCV encodes two proteases, the NS2 cysteine autoprotease and the NS3-4A serine protease. The NS proteins then recuit the viral genome into an RNA replication complex, which is associated with rearranged cytoplasmic membranes. RNA replication takes places via the viral RNA-dependent RNA polymerase of NS5B, which produces a negative-strand RNA intermediate. The negative strand RNA then serves as a template for the production of new positive-strand viral genomes. Nascent genomes can then be translated, further replicated, or packaged within new virus particles. New virus particles presumably bud into the secretory pathway and are released at the cell surface.

HCV has a high rate of replication with approximately one trillion particles produced each day in an infected individual. Due to lack of proofreading by the HCV RNA polymerase, HCV also has an exceptionally high mutation rate, a factor that may help it elude the host's immune response.

Early studies of viral loads in eleven asymptomatically infected viral carriers (blood donors in 1989, prior to implementation of blood bank screening for HCV, from whom the donated blood units were rejected because of elevated Alanine transaminase or ALT liver enzyme levels) indicated that asymptomatic viral loads varied between 100/mL and 50,000,000/mL.

Based on genetic differences between HCV isolates, the hepatitis C virus species is classified into six genotypes with several subtypes within each genotype. Subtypes are further broken down into quasispecies based on their genetic diversity. The preponderance and distribution of HCV genotypes varies globally. For example, in North America, genotype 1a predominates followed by 1b, 2a, 2b, and 3a. In Europe, genotype 1b is predominant followed by 2a, 2b, 2c, and 3a. Genotypes 4 and 5 are found almost exclusively in Africa. Genotype is clinically important in determining potential response to interferon-based therapy and the required duration of such therapy. Genotypes 1 and 4 are less responsive to interferon-based treatment than are the other genotypes (2, 3, 5 and 6). Duration of standard interferon-based therapy for genotypes 1 and 4 is 48 weeks, whereas treatment for genotypes 2 and 3 is completed in 24 weeks.

Although hepatitis A, hepatitis B, and hepatitis C have similar names (because they all cause liver inflammation), these are distinctly different viruses both genetically and clinically. Unlike hepatitis A and B, there is no vaccine to prevent hepatitis C infection.

In a recent study, 60 patients received four different doses of an experimental hepatitis C vaccine. All the patients produced antibodies that the researchers believe could protect them from the virus.

Transmission

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. 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.

Potential sources of exposure

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 or have previously injected 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.), 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. HCV is also transmitted by inhalational drugs, such as intranasal cocaine usage.

Blood products

Blood transfusion, blood products, or organ transplantation prior to implementation of HCV screening (in the U.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), immuneglobulin, Rhogam, platelets, and plasma. As of 2001, the Centers for Disease Control and Prevention reports 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. Examples include equipment that may harbor contaminated blood if improperly sterilized include reused needles or syringes, hemodialysis equipment, oral hygiene instruments, and jet air guns, etc. Scrupulous use of appropriate sterilization techniques and proper disposal of used equipment can bring 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. 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 that may result in accidental blood-to-blood exposure are potential sources of exposure to HCV.

Sexual exposure to blood

Although HCV is not a sexually transmitted disease (STD), transmission can occur during unprotected sexual contact if the sexual activity involves blood-to-blood contact. It is important to note that the sexual spread of HCV is due to blood-blood contact rather than the presence of the virus in vaginal fluid or semen.

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 done non-professionally are particularly concerning as sterile techniques in such settings may be lacking.

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. 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. Co-infection with HIV is common and rates among HIV positive populations are higher. 10,000-20,000 deaths a year in the United States are from HCV; expectations are that this will increase, as those who were infected by transfusion before HCV testing are expected to become apparent. A survey conducted in California showed prevalence of up to 34% among prison inmates; 82% of subjects diagnosed with hepatitis C have previously been in jail, and transmission while in prison is well described.

Egypt has the highest seroprevalence for HCV, up to 20% in some areas. This was linked, in 2000, to a mass-treatment campaign for schistosomiasis, which is endemic in that country.

Co-infection with HIV

Approximately 3,000,000, or 40% 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, 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

Current standard of care treatment is a combination of (pegylated) interferon alpha and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending on genotype. Should treatment with pegylated ribivirin-interferon not return a 2-log viral reduction after 12 weeks, the chance of treatment success is less than 1%.

Current indication 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, 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 State have genotype 1. Genotype 4 is more common in the Middle East and Africa.

Treatment during the acute infection phase has much higher success rates (90%+) with a shorter duration of treatment.

Those with low initial viral loads respond much better to treatment than those with higher viral loads (>2 million virons/ml). Current combination therapy can only be supervised by physicians in the fields of gastroenterology, hepatology and infectious disease.

The treatment is physically demanding for some, particularly those with a prior history of drug or alcohol abuse. It can qualify for temporary disability in some cases. A substantial percentage 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 ideation and attempts. The latter are complemented and escalated by the general physiological stress experienced by the patient.

In addition to the standard treatment with interferon and ribavirin, several studies have shown higher success rates when the antiviral drug amantadine (Symmetrel®) is added to the regimen. Sometimes called "triple therapy", it involves the addition of 100mg of amantadine twice a day, for a total of 200mg per day. Studies indicate that this may be especially helpful to "nonresponders" - patients who have not been successful in previous treatments using interferon/ribavirin only. 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.

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.

During pregnancy and breastfeeding

If a pregnant woman has risk factors for hepatitis C, she should be tested for anti-HCV. 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. Ribavirin and interferons are contraindicated during pregnancy. However, avoiding fetal scalp monitoring and prolonged labor after rupture of membranes may reduce the risk of transmission to the infant.

Anti-HCV from the mother might last in the baby until 15 months of age. If an early diagnosis is desired, HCV RNA can be performed between the ages of 2 and 6 months, with a repeat test done independent of the first test result. 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. There is no evidence that breast-feeding spreads HCV. To be cautious, an infected mother could avoid breastfeeding if her nipples are cracked and bleeding.

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. 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. It is important to note that the current standard of treatment with pegylated-interferon and ribavirin is unsurpassed in its ability to control HCV replication.

Doctors recommend reporting all medications one is taking, including herbal ones, as all may influence the disease course, and this holds true especially in post-transplants as Silybum marianum (also known as silymarin or milkthistle) may inhibit the metabolism of certain medications, leading to accumulation and increased toxicity.

Experimental treatments

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. 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 Morpholino oligos have shown promise in preclinical studies and began human clinical trials in 2005 at Veterans Affairs Palo Alto Health Care System, Palo Alto, California and Alpine Clinical Research Center, Inc., Boulder, Colorado.

All of these are not approved remedies and have not yet demonstrated their efficacy in clinical trials.

Immunoglobulins against the hepatitis C virus exist and newer types are under development. 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.

History

In the mid 1970’s, Harvey J. Alter, Chief of the Infectious Disease Section in the Department of Transfusion Medicine at the National Institutes of Health (NIH), and his research team demonstrated that most post-transfusion hepatitis cases were not due to hepatitis A and B viruses. Despite this advance, international research to discover 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 utilized molecular cloning to identify the unknown organism. In 1988, the virus was confirmed by Alter by verifying its presence in a panel of NANBH specimens. In April of 1989, the discovery of the virus, re-named hepatitis C virus, was published in two articles in Science.Chiron Corporation Chiron Hepatitis C Research Honored with 2000 Lasker Award for Clinical Medical Research Press release, 18 September 2000.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).

Prominent patients

Celebrities Naomi Judd and Pamela Anderson have been infected with hepatitis C and gone public with their experiences.

Francisco Varela, biologist, recorded his experiences, including a liver transplant, in "Intimate Distances".

Motorcycle daredevil Evel Knievel was diagnosed with Hepatitis C in 1993 and underwent a liver transplant in 1999.

Grateful Dead bassist Phil Lesh underwent a liver transplant to treat a Hepatitis C and now encourages fans at every show to sign up to be organ donors.

David Crosby

References

External links

Flaviviruses | Hepatitis | Viruses

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