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. Hep C genotypes 2A & 3A have the highest cure rates at 81% and 74% respectively.The hepatitis C virus is usually detectable in the blood within one to three weeks after infection by PCR, and antibodies to the virus are generally detectable within 3 to 15 weeks. Spontaneous viral clearance rates are highly variable and between 10–60%^[2] of persons infected with HCV clear the virus from their bodies during the acute phase as shown by normalization in liver enzymes (alanine transaminase (ALT) & 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 monthsPrevious 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. Chronic

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 (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.Recent data suggest 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. In contrast the NIH consensus guidelines state that the risk of progression to cirrhosis over a 20-year period is 3-20 percent.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, flu-like symptoms, joint pains, itching, sleep disturbances, appetite changes, nausea, and depression.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, varices (enlarged veins, especially in the stomach and esophagus), jaundice, and a syndrome of cognitive impairment known as hepatic encephalopathy. Hepatic encephalopathy is due to the accumulation of ammonia and other substances normally cleared by a healthy liver.Liver enzyme tests show variable elevation of ALT and AST. Periodically they might show normal results. Usually prothrombin and albumin results are normal, but may become abnormal, once cirrhosis has developed. 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 always show liver injury until it is fairly advanced. However, non-invasive tests (blood sample) are coming, with FibroTest and ActiTest, respectively estimating liver fibrosis and necrotico-inflammatory. These tests are validated and recommended in Europe (FDA procedures initiated in USA)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.^[ Virology

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.Although injection drug use is 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 that causes open sores and bleeding is also present and makes blood contact more likely. Transmission


Hepatitis C infection in the US by source. (CDC,n.d.


Sexual activities and practices were initially identified as potential sources of exposure to the hepatitis C virus. More recent studies question this route of transmission Currently, heterosexual vaginal intercourse is thought to be a rare means of transmission of hepatitis C infection. The following are the currently known modes of transmission. There may be other, as yet unknown, means of transmission. Injection drug use

Those who currently use or have used drug injection as their delivery route for 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 intravenous recreational drug users in the United States have been infected with HCV 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. For reasons that are not clear transmission by this route currently appears to be declining in the USA.The VA Testimony before the Subcommittee on Benefits Committee on Veterans’ Affairs, U.S. House of Representatives, April 13, 2000, Gary A. Roselle, M. D., Program Director for Infectious Diseases, Veterans Health Administration, Department of Veterans Affairs, state, "One in 10 US Veterans are infected with HCV", a rate 5 times greater than the 1.8% infection rate of the general population."A study conducted in 1999, by the Veterans Health Administration (VHA), and involving 26,000 veterans shows that up to 10% of all veterans in the VHA system tested positive for hepatitis C.Of the total number of persons who were hepatitis C antibody positive, and reported an era of service, 62.7% were noted to be from the Vietnam. The second most frequent group is listed as post-Vietnam at 18.2%, followed by 4.8% Korean conflict, 4.3% post-Korean conflict, 4.2% from WWII, and 2.7% Persian Gulf era veterans. 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.A cDNA clone from the hepatitis C virus genome was first isolated in 198and 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 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. 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. Blood

[ Exposure

Occupation

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.[edit] Recreation

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. 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. 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).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).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 either before the mid 1980s, "underground," or non-professionally 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. Indeed, it is this method of transmission that caused Pamela Anderson to officially state :"I contracted hepatitis C while sharing a tattoo needle with my ex-husband Tommy Lee. Tommy has the disease and never disclosed it to me during our marriage." 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 non-sterile 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 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. Appropriate caution should be taken regarding any medical condition which results in bleeding such as canker sores, cold sores, and immediately after flossing.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 transmitting 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 breastfeeding. Diagnosis


Serologic profile of Hepatitis C 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 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. 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. 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). 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. Prevention

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:^[

• Injection drug use (currently the most common means of HCV transmission in the United States)
  
• 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)
  
• Needlestick injuries in healthcare settings
  
• Birth to an HCV-infected mother
  

HCV can also be spread infrequently through

• Sex with an HCV-infected person (an inefficient means of transmission)
  
• Sharing personal items contaminated with infectious blood, such as razors or toothbrushes (also inefficient vectors of transmission)
  
• Other healthcare procedures that involve invasive procedures, such as injections (usually recognized in the context of outbreaks)
  

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. Treatment

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. Medications (interferon and ribavirin)

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 .^[36] 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%. 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. Cure rates by genotype

Responses can vary by genotype. (Approximately 80% of hepatitis C patients in the United States have genotype 1. Genotype 4 is more common in the Middle East and Africa.)GenotypeDescription

2 and 3	Sustained cure rates (sustained viral response) of 75% or better are seen in people with HCV genotypes 2 and 3 with 24 weeks of treatment.Patients achieving HCV RNA below 1000 IU/mL by day 7 (i.e. just prior to the second dose of pegylated interferon) may be treated for as little as 12 weeks with retained sustained cure rates.
1	Sustained response is about 50% in patients with HCV genotype 1 given 48 weeks of treatment. In patients with HCV genotype 1, if treatment with pegylated interferon + ribavirin does not produce a 2-log viral load reduction or complete clearance of RNA (termed "early virological response") after 12 weeks the chance of treatment success is less than 1%.
4	Sustained response is about 65% in those with genotype 4 given 48 weeks of treatment.
6	The evidence for treatment in genotype 6 disease is currently sparse, and the evidence that exists is for 48 weeks of treatment at the same doses as are used for genotype 1 disease. Physicians considering shorter durations of treatment (e.g., 24 weeks) should do so within the context of a clinical trial.

Early virological response is typically not tested in non-genotype 1 patients, as the chances of attaining it are greater than 90%. The mechanism of cure is not entirely clear, because even patients who appear to have a sustained virological response still have actively replicating virus in their liver and peripheral blood mononuclear cells.^[[ Special factors affecting patients

Host factors

For genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) 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 possibly to achieve sustained virological response after the treatment than others. Later report from Nature demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.Similarly baseline pre-treatment 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 days of elimination of HCV RNA (“first phase decline”) during interferon/ribavirin therapy for all HCV genotypes[edit] Viral factors

The basis for the differential response to treatment between viral genotypes is still being worked out. Mutations in the core arginine70glutamine (R70Q) and in the nonstructural protein 5A within its interferon sensitivity determining region have been associated with responsiveness at weeks 12 and 4 respectively

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