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Cyclopiano/Sandbox

Treatment[edit]

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).[1][2] However, the majority of patients with chronic hepatitis C will not clear it without treatment.

Medications (interferon and ribavirin)[edit]

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),[3] 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.[4][5]

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 .[6] 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 [7] 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[edit]

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

Genotype Description
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.[8] 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.[4]
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.[9] 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 some patients who have a sustained virological response still appear to have actively replicating virus in their liver and peripheral blood mononuclear cells.[10]

Special factors affecting patients[edit]

Host factors[edit]

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,[11] 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. A later report from Nature [12] demonstrated the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.

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.[13][14] 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.[15]

Viral factors[edit]

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.[16]

Depression during therapy[edit]

In the study by Leutscher et al., evaluating 325 chronically infected genotype 2 or 3 patients, it was observed that (1) depressive symptoms among patients undergoing HCV therapy are commonly overlooked by routine clinical interviews, (2) the emergence of depression compromises the outcome of HCV therapy, and (3) the major depression inventory (MDI) scale may be useful in identifying patients at risk for treatment-induced depression.[17]

Pregnancy and breastfeeding[edit]

If a woman who is pregnant has risk factors for hepatitis C, she should be tested for antibodies against HCV. About 4% infants born to HCV-infected women become infected. While there is no preventative treatment, there is a high probability of the babies ridding themselves the HCV in the first 12 months.

In a mother who 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.

HCV antibodies from the mother may persist in infants until 15 months of age. If an early diagnosis is desired, testing for HCV RNA can be performed between the ages of 2 and 6 months, with a repeat test done independent of the first test result. 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 should avoid breastfeeding if her nipples are cracked and bleeding.[18]

Additional recommendations and alternative therapies[edit]

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 infection with a second virus could 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. There is also evidence that smoking increases the fibrosis (scarring) rate.

Several alternative therapies aim to maintain liver functionality, rather than treat the virus itself, thereby slowing the course of the disease to retain quality of life. As an example, extract of Silybum marianum and Sho-saiko-to are sold for their HCV related effects; the first is said to provide some generic help to hepatic functions, and the second claims to aid in liver health and provide some antiviral effects.[19] Milk thistle is a herb that may have properties that help repair liver damage from HCV, but studies have been small and possibly unreliable. [20] There has never been any verifiable histologic or virologic benefit demonstrated with any of the alternative therapies.[citation needed]

Epidemiology[edit]

Prevalence of hepatitis C worldwide (1999, WHO)
Disability-adjusted life year for hepatitis C per 100,000 inhabitants.
  no data
  ≤ 5
  5-10
  10-20
  20-30
  30-40
  40-50
  50-60
  60-75
  75-100
  100-150
  150-200
  ≥ 200

It is estimated that hepatitis C has infected nearly 200 million people worldwide, and infects 3-4 million more people per year.[21][22] 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;[23] 82% of subjects diagnosed with hepatitis C have previously been in jail,[24] and transmission while in prison is well described.[25]

Prevalence is higher in some countries in Africa and Asia.[26] 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.[27] Regardless of how the epidemic started, a high rate of HCV transmission continues in Egypt, both iatrogenically and within the community and household.

Coinfection with HIV[edit]

Approximately 350,000 people (35% of patients) in the USA infected with HIV are coinfected with the hepatitis C virus, mainly because both viruses are blood-borne and are present in similar populations. 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 coinfection.

In a study involving 21 HIV coinfected patients (DICO),[28] pretreatment baseline plasma levels of IP-10 predicted the reduction of HCV RNA during the first days of interferon/ribavirin therapy (“first phase decline”) for HCV genotypes 1-3,[29] as is also the case in HCV monoinfected patients.[13][14][15] Pretreatment IP-10 levels below 150 pg/mL are predictive of a favorable response, and may thus be useful in encouraging these otherwise difficult-to-treat patients to initiate therapy.[29]

History[edit]

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 posttransfusion 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 from CDC, used a novel molecular cloning approach to identify the unknown organism and develop a diagnostic test.[30] In 1988, the virus was confirmed by Alter by verifying its presence in a panel of NANBH specimens. In April 1989, the discovery of the virus, renamed hepatitis C virus (HCV), was published in two articles in the journal Science.[31][32] The discovery led to significant improvements in diagnosis and improved antiviral treatment.[30]

Chiron filed for several patents on the virus and its diagnosis.[33] 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.[34][35]

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."[36]

In 2004, Chiron held 100 patents in 20 countries related to hepatitis C, and had successfully sued many companies for infringement. Scientists and competitors have complained the company hinders the fight against hepatitis C by demanding too much money for its technology.[34]

Research[edit]

The drug viramidine, which is a prodrug of ribavirin that has better targeting for the liver, and therefore may be more effective against hepatitis C for a given tolerated dose, is in phase III experimental trials against hepatitis C. It will be used in conjunction with interferons, in the same manner as ribavirin. However, this drug is not expected to be active against ribavirin-resistant strains, and the use of the drug against infections which have already failed ribavirin/interferon treatment, is unproven.

There are new drugs under development, like the protease inhibitors (including telaprevir/VX 950), entry inhibitors (such as SP 30 and ITX 5061)[37][38][39] and polymerase inhibitors (such as RG7128, PSI-7977 and NM 283), but development of some of these is still in the early phase. VX 950, also known as Telaprevir[40] is currently in Phase III trials. [41][42] 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[43] and Zadaxin.[44] Antisense phosphorothioate oligos have been targeted to hepatitis C.[45] Antisense Morpholino oligos have shown promise in preclinical studies[46] however, they were found to cause a limited viral load reduction.[47]

Some studies have shown that HCV viral replication is dependent upon the host factor miR-122. As a result, pharmaceutical companies are developing potential HCV drugs that target miR-122. HCV therapies that target this host factor necessary for viral replication, rather than the virus itself, are promising, as they show little to no potential for viral resistance. [48] One such drug is miravirsen, developed by Santaris Pharma a/s, a locked nucleic acid based miR-122 antagonist in Phase II clinical trials as of late 2010. [49]

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. needle sticks). They do have a limited role in transplant patients.

In addition to the standard treatment with interferon and ribavirin, some studies have shown higher success rates when the antiviral drug amantadine (Symmetrel) is added to the regimen. Sometimes called "triple therapy", it involves the addition of 100 mg of amantadine twice a day. Studies indicate this may be especially helpful for "nonresponders" - patients who have not been successful in previous treatments using interferon and ribavirin only.[50] 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 and when it is a risk due to their liver deterioration.

See also[edit]

References[edit]

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