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Hepatitis C | Understanding and defisini of Hepatitis C | Causes and prevention of Hepatitis C

Hepatitis C is an infectious disease affecting the liver, caused by the hepatitis C virus (HCV). The infection is often asymptomatic, but once established, chronic infection can progress to scarring of the liver (fibrosis), and advanced scarring (cirrhosis) which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure or other complications of cirrhosis, including liver cancer or life threatening esophageal varices and gastric varices.

The hepatitis C virus is spread by blood-to-blood contact. Most people have few, if any symptoms after the initial infection, yet the virus persists in the liver in about 85% of those infected. Persistent infection can be treated with medication, peginterferon and ribavirin being the standard-of-care therapy. Overall, 51% are cured. Those who develop cirrhosis or liver cancer may require a liver transplant, and the virus universally recurs after the transplant takes place.

Acute hepatitis C refers to the first 6 months after infection with HCV although symptoms may appear within a day if infection was caused by any method of intravenous injection. Between 60% and 70% of people infected develop no symptoms during the acute phase unless infection was caused by direct access to the blood stream as crossing the blood brain barrier is then made up to 100 times easier. Main symptoms consist of general cold and flu like symptoms with increased loss of senses. 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. Hepatitis C genotypes 2A and 3A have the highest cure rates, at 81% and 74% respectively.

The hepatitis C virus is usually detectable in the blood by PCR within one to three weeks after infection, and antibodies to the virus are generally detectable within three to 15 weeks. Spontaneous viral clearance rates are highly variable; between 10 and 60% of persons infected with HCV clear the virus from their bodies during the acute phase, as shown by normalization of the liver enzymes alanine transaminase (ALT) and aspartate transaminase (AST), and plasma HCV-RNA clearance (this is known as spontaneous viral clearance). However, persistent infections are common and most patients develop chronic hepatitis C, i.e., infection lasting more than 6 months.

Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for more than six months. Clinically, it is often asymptomatic, and it is mostly discovered accidentally (e.g. usual checkup).

The natural course of chronic hepatitis C varies considerably from one person to another. Although almost all people infected with HCV have evidence of inflammation on liver biopsy, the rate of progression of liver scarring (fibrosis) shows significant variability among individuals. Accurate estimates of the risk over time are difficult to establish because of the limited time that tests for this virus have been available.

Chronic hepatitis C, more than other forms of hepatitis, can be associated with extrahepatic manifestations associated with the presence of HCV, such as porphyria cutanea tarda, cryoglobulinemia (a form of small-vessel vasculitis) and glomerulonephritis (inflammation of the kidney), specifically membranoproliferative glomerulonephritis (MPGN). Hepatitis C is also rarely associated with sicca syndrome (an autoimmune disorder), thrombocytopenia, lichen planus, diabetes mellitus and with B-cell lymphoproliferative disorders.

The hepatitis C virus is a small (50 nm in size), enveloped, single-stranded, positive sense RNA virus. It is the only known member of the hepacivirus genus in the family Flaviviridae. There are six major genotypes of the hepatitis C virus, which are indicated numerically (e.g., genotype 1, genotype 2, etc.).

The hepatitis C virus 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 sexual exposure. In developing countries, the primary sources of HCV infection are unsterilized injection equipment and infusion of inadequately screened blood and blood products. There has not been a documented transfusion-related case of hepatitis C in the United States for over a decade, as the blood supply is vigorously screened with both EIA and PCR technologies.

A cDNA clone from the hepatitis C virus genome 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. In 2001, the Centers for Disease Control and Prevention reported the risk of HCV infection from a unit of transfused blood in the United States is less than one per million transfused units.

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, jet air guns, etc. Scrupulous use of appropriate sterilization techniques and proper disposal of used equipment can reduce the risk of iatrogenic exposure to HCV to virtually zero. Limitations in the implementation and enforcement of stringent standard precautions in public and private medical and dental facilities is known to be the primary cause of the spread of HCV in Egypt, the country with highest rate of infection in the world.

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 either before the mid 1980s, "underground," or nonprofessionally are of particular concern, since sterile techniques in such settings may have been insufficient to prevent disease; sharing unsterilized tattooing equipment (for example, in the prison system) has an obvious increased risk of acquiring HCV. The U.S. Centers for Disease Control and Prevention's position on this subject states that, "Whenever tattoos or body piercings are performed in informal settings or with nonsterile instruments, transmission of hepatitis C and other infectious diseases is possible." Despite these risks, it is rare for tattoos in an approved facility to be directly associated with HCV infection.

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. 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. 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. Immunocompromised individuals infected with HCV may 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). However, liver function tests alone are not useful in predicting the severity of infection and normal results do not exclude the possibility of liver disease.

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.

According to Centers for Disease Control, hepatitis C virus is spread by exposure to large quantities of blood, either through the skin or by injection:
  1. Injection drug use (currently the most common means of HCV transmission in the United States)
  2. Receipt of donated blood, blood products, and organs (once a common means of transmission, but now rare in the United States since blood screening became available in 1992)
  3. Needle stick injuries in healthcare settings
  4. Birth to an HCV-infected mother
HCV can also be spread infrequently through
  1. Sex with an HCV-infected person (an inefficient means of transmission)
  2. Sharing personal items contaminated with infectious blood, such as razors or toothbrushes (also inefficient vectors of transmission)
  3. Other healthcare procedures that involve invasive procedures, such as injections (usually recognized in the context of outbreaks)
  4. Sharing drug products via insufflation
Strategies such as the provision of new needles and syringes, and education about safer drug injection procedures, greatly decrease the risk of hepatitis C spreading between injecting drug users.

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

The hepatitis C virus induces chronic infection in 50%-80% of infected persons. Approximately 50% of these do not respond to therapy. There is a very small chance of clearing the virus spontaneously in chronic HCV carriers (0.5% to 0.74% per year). However, the majority of patients with chronic hepatitis C will not clear it without treatment.

Current treatment is a combination of pegylated interferon-alpha-2a or pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending on hepatitis C virus genotype. In a large multicenter randomized control study among genotype 2 or 3 infected patients (NORDymanIC), patients achieving HCV RNA below 1000 IU/mL by day 7 who were treated for 12 weeks demonstrated similar cure rates as those treated for 24 weeks.

Pegylated interferon-alpha-2a plus ribavirin may increase sustained virological response among patients with chronic hepatitis C as compared to pegylated interferon-alpha-2b plus ribavirin according to a systematic review of randomized controlled trials . The relative benefit increase was 14.6%. For patients at similar risk to those in this study (41.0% had sustained virological response when not treated with pegylated interferon alpha 2a plus ribavirin), this leads to an absolute benefit increase of 6%. About 16.7 patients must be treated for one to benefit (number needed to treat = 16.7; click here to adjust these results for patients at higher or lower risk of sustained virological response). However, this study's results may be biased due to uncertain temporality of association, selective dose response.

Treatment is generally recommended for patients with proven hepatitis C virus infection and persistently abnormal liver function tests.

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 400,000 IU/mL). Current combination therapy is usually supervised by physicians in the fields of gastroenterology, hepatology or infectious disease.

The treatment may be physically demanding, particularly for 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. The latter are exacerbated by the general physiological stress experienced by the patient.

Boceprevir is a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site on hepatitis C genotype 1. There have been been several recent randomized double blinded clinical trials studying boceprevir in conjunction with peginterferon-ribavirin as therapy for untreated chronic HCV genotype 1 infection and previously treated chronic HCV genotype 1 infection. These studies have shown improved sustained virologic response at 44 weeks compared to therapy with peginterferon-ribavirin therapy alone. Anemia was a common side effect in these two studies.

For genotype 1 hepatitis C treated with pegylated interferon-alpha-2a or pegylated interferon-alpha-2b combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. This finding, originally reported in Nature, showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more likely to achieve sustained virological response after the treatment than others. A later report from Nature demonstrated the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus. It has subsequently been reported that polymorphisms in IL28B are strongly associated with the elimination of HCV RNA during the first days of peginterferon-α/ribavirin therapy (“first phase decline”), irrespective of HCV genotype.

Similarly, baseline pretreatment plasma levels of IP-10 (also known as CXCL10) are elevated in patients chronically infected with hepatitis C virus (HCV) of genotypes 1 or 4 who do not achieve a sustained viral response (SVR) after completion of antiviral therapy. IP-10 in plasma is mirrored by intrahepatic IP-10 mRNA, and both strikingly predict the first first phase decline during interferon/ribavirin therapy for all HCV genotypes. And combining both pre-treatment levels of IP-10 and IL28B polymorphism further improves prognostication of therapeutic outcome.

It is estimated that hepatitis C has infected nearly 200 million people worldwide, and infects 3-4 million more people per year. There are about 35,000 to 185,000 new cases a year in the United States. It is currently a leading cause of cirrhosis, a common cause of hepatocellular carcinoma, and as a result of these conditions it is the leading reason for liver transplantation in the United States. Coinfection with HIV is common, and rates among HIV positive populations are higher. Annual deaths from HCV in the United States range from 10,000 to 20,000; 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 a 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.

Prevalence is higher in some countries in Africa and Asia. Egypt has the highest seroprevalence for HCV, up to 20% in some areas. 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. Regardless of how the epidemic started, a high rate of HCV transmission continues in Egypt, both iatrogenically and within the community and household.

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