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Hepatitis C

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Hepatitis C
SpecialtyInfectious diseases Edit this on Wikidata
Frequency22% (Egypt), 48% (Pakistan), 32% (People's Republic of China)

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Hepatitis C is a form of inflammatory disease of the liver caused by a virus, the hepatitis C virus (HCV). Almost always, Hepatitis C is spread by contact with an infected person's blood. The majority of the people with HCV infections have no symptoms. Therefore, they are unaware of the need to seek treatment.

Hepatitis C infected 150 to 200 million people around the world and is now the leading cause of liver transplants, and a frequent cause of liver cancer. Co-infection with HCV is common for people with HIV/AIDS and often causes their death.

Signs and symptoms

NIH/National Digestive Diseases Information Clearinghouse[1]

Acute Hepatitis C

Hepatitis C is one of 5 viruses, called hepatitis A,B,C,D, and E, that can cause an acute disease lasting several weeks. Most cases (between 60% and 70%), even those that develop chronic infection, are asymptomatic.

For persons with acute symptoms, abdominal pain, jaundice, itching and flu-like symptoms are the most prominent causes for seeking medical attention.

Chronic Hepatitis C

For persons with silent disease, some are diagnosed because of certain medical phenomena associated with the presence of hepatitis C virus, such as thyroiditis (inflammation of the thyroid), cryoglobulinemia (a form of vasculitis)[3] and glomerulonephritis (inflammation of the kidney), specifically membranoproliferative glomerulonephritis (MPGN)[4]. Carriers of the virus may begin to develop symptoms after only a few years. Symptoms, when developed, are variable and dependent on individual carrier. They may include prolonged flu-like symptoms and any combination of the following: body aches, headaches, night sweats, loss of appetite, diarrhea, fatigue, nausea, mild abdominal pain, typically located in the upper right quadrant.

Diagnosis

Hepatitis C may be suspected on the basis of the medical history and symptoms, because of abnormal liver function tests or as part of routine blood tests in many situations. Occasionally, people are diagnosed as a result of targeted screening such as blood donation (for which every donor is screened for numerous blood-borne diseases) or as a result of contact tracing.

Presence of HCV is generally screened with serological blood tests, all based on ELISA testing (ELISA-1, 2 and 3 are in use). These tests have a strong positive predictive value for the presence of the virus, but may take 6 months to become positive (seroconversion); in the meanwhile, a patient may have a false-negative result. Confirmation of the presence of the virus is by reverse transcriptase-polymerase chain reaction (rtPCR). This test is more expensive and hence avoided when risk of infection is deemed low. It may come up positive much earlier after infection (sometimes several weeks). rtPCR can also confirm which genomic type (see below) of the virus is present, which may determine the treatment regimen best suited for the patient.

Virology

The hepatitis C virus (HCV) is an enveloped, single-stranded, positive sense RNA virus in the family Flaviviridae. This virus is thought to be primarily liver-tropic. When circulating in the bloodstream, it binds to receptors on liver tissue. Two putative receptors are CD81 and Scavenger Receptor class B1 (SR-BI). However as these molecules are found throughout the body, the determinants of liver tropism remain unknown.

Based on genetic differences between HCV isolates, this virus species is classified into six genotypes, with many subtypes within each genotype. Genotype 1a is the most common in North America, and 1b in Europe. Genotypes 1 and 4 are less responsive to treatment than are the other genotypes (2,3,5 and 6)[5]. Therefore, treatment protocols may vary depending on the HCV genotype.

Though hepatitis A, hepatitis B, and hepatitis C have similar names (because they all cause liver disease) the viruses themselves are quite different. Unlike hepatitis A and B, there is no vaccine for hepatitis C.

Transmission

Hepatitis C virus is transmitted by blood-blood contact. In developed countries, it is estimated that 90% of persons with chronic HCV infection are current and former injecting drug users and those with a history of transfusion of unscreened blood or blood products.

In developing countries where unscreened blood and blood products are still being used, the major means of transmission are unsterilized injection equipment and unscreened blood transfusions. In addition, people who use traditional scarification and circumcision practices are at risk if they use or re-use unsterilized tools.

Risk factors

CDC Hepatitis C: Slide Set [2]

Several risk factors that qualify one for a higher risk of exposure to HCV virus. They include:

  • Needle sharing. Those who inject drugs are at a high risk of getting hepatitis C because they may be sharing needles and other drug paraphernalia, which may be contaminated with HCV-infected blood. In fact, 60% to 80% of all IV drug users in the United States have hepatitis C infection.
  • Unprotected sex. Although HCV is not classed as a sexually transmitted disease (STD), there is some transmission due to sexual activity. This is often as a result of infection with an actual STD. Many STDs cause sores or wounds around the genitals, and thus sexual activity will lead to the spread of HCV. It is important to note however, that the spread is due to blood-blood contact, rather than the presence of the virus in vaginal fluid or semen.
  • Multiple piercings or tattoos. Tattooing dye or needles used in tattooing or body piercing can carry HCV-infected blood from one customer to another if the tattoo/body piercing parlors do not use sterile techniques or supplies. Tattoos done non-professionally, as in a penal institution, are therefore of great concern.
  • Blood transfusions prior to the early 1990s. Those who have had a blood transfusion before this time, and hemophiliacs who have received purified human clotting factor before that time are considered at risk because blood banks did not fully test the blood supply for hepatitis C before this time. Nowadays, the risk of getting hepatitis C from a blood transfusion is almost zero.
  • Other risk factors include needlestick injuries, especially among health care workers, hemodialysis (equipment that filters blood may not be adequately sterilized between patients), and organ transplants before the early 1990s.

Epidemiology

Hepatitis C infects an estimated 170 million persons worldwide and 4 million persons in the United States. There are around 35,000 to 185,000 new cases of infections 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 test are expected to become apparent. An August 2003 Harper's article estimated that "somewhere between 20 and 40 percent of American prisoners are, at this very moment, infected with hepatitis C"[6].

One of the countries with the highest seroprevalence for HCV is Egypt (up to 20% in some areas). This was linked, in 2000, to a mass-treatment campaign for schistosomiasis, which is endemic in that country[7].

Co-infection with HIV

Approximately 40% of U.S. patients infected with HIV are also infected with the hepatitis C virus, mainly because both viruses are blood-borne and they are present in similar populations. In other countries, co-infection is less common due to differing drug policies. HCV is one of the most important causes of chronic liver disease in the U.S. It has been demonstrated in clinical studies that HIV infection causes a more rapid progression of chronic hepatitis C to cirrhosis and liver failure in HIV-infected persons. This is not to say treatment is not an option for those living with co-infection. The APRICOT international trial indicated that a svr (sustained viral response) was high in those with the genotype 2 & 3. Less favorable results where associated with genotype 1, however it became evident that 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%.

Treatment

Current standard of care treatment is a combination of (pegylated) interferon alpha and the antiviral drug ribavirin. Current indication for treatment include patients with proven hepatitis C virus infection through qualitative and quantitative confirmation of the RNA of the virus with persistent abnormal liver tests. Studies have shown sustained cure rates (sustained viral response) of 75% or better in people with genotypes HCV 2 or 3 in 24 weeks of combination therapy, and about 50% in those with genotype HCV 1 and 65% for those with genotype 4 in 48 weeks of therapy. About 80% of those infected in the United State have genotype 1. Genotype 4 is more common in the Middle East and Africa. 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 experienced physicians in the fields of gastroenterology, hepatology, or infectious disease, and a substantial percentage of people will experience a panoply of minor side effects ranging from a 'flu'-like syndrome (the most common) to severe adverse events, such as anemia, cardiovascular events, and other disorders.

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 2-3 times a day, for a total of 200-300mg per day. This may be especially helpful to "nonresponders" - patients who have not been successful in previous treatments using interferon/ribavirin only. It has been suggested that the related antiviral drug rimantadine may have a similar positive effect on treatment success rates.

Current guidelines suggest that individuals with hepatitis C should 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. It is well known that alcohol makes HCV associated liver disease progress faster; 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, they 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.

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 milk thistle) may inhibit the metabolism of certain medications, leading to accumulation and increased toxicity.

Experimental treatments

There are new drugs under development like the protease inhibitor NM 283,BILN 2061 or VX 950 that are looking promising but are all in early phase of development.[8] [9] Unfortunately, the 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. [10] [11]

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

Immunoglobulins against the hepatis 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 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 the 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. [12] [13] [14]

Prominent patients

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

Francisco Varela, biologist, recorded his experiences, including a liver transplant, in "Intimate Distances"[15].

References

  1. ^ "NIH/National Digestive Diseases Information Clearinghouse". 2005-12-18.
  2. ^ Pascual M, Perrin L, Giostra E, Schifferli JA. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis 1990;162:569-570. PMID 2115556.
  3. ^ Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi CE, Hartwell P, Couser WG, Corey L, Wener MH, Alpers CE, Willson R. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 1993;328:465-70. PMID 7678440.
  4. ^ Simmonds P, Bukh J, Combet C, Deleage G, Enomoto N, Feinstone S, Halfon P, Inchauspe G, Kuiken C, Maertens G, Mizokami M, Murphy DG, Okamoto H, Pawlotsky JM, Penin F, Sablon E, Shin-I T, Stuyver LJ, Thiel HJ, Viazov S, Weiner AJ, Widell A. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 2005;42:962-73. PMID 16149085.
  5. ^ "CDC Hepatitis C: Slide Set". 2005-12-18.
  6. ^ Hylton WJ. Sick on the Inside" - Correctional HMOs and the Coming Prison Plague. Harper's Magazine Aug 2003. Fulltext.
  7. ^ Frank C, Mohamed MK, Strickland GT, Lavanchy D, Arthur RR, Magder LS, El Khoby T, Abdel-Wahab Y, Aly Ohn ES, Anwar W, Sallam I. The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet 2000;355:887-91. PMID 10752705.
  8. ^ Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, Sentjens RE, Calleja JL, Forns X, Erhardt A, Crönlein J, Chaves RL, Yong CL, Nehmiz G, Steinmann GG. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 127(5): 1347-1355. November 2004. PMID 15521004.
  9. ^ Lamarre, D. et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature, published online, doi:10.1038/nature02099 (2003).
  10. ^ Zhang H, Hanecak R, Brown-Driver V, Azad R, Conklin B, Fox MC, Anderson KP. Antisense Oligonucleotide Inhibition of Hepatitis C Virus (HCV) Gene Expression in Livers of Mice Infected with an HCV-Vaccinia Virus Recombinant. Antimicrob. Agents Chemother. 1999 43: 347-353. PMID 9925530
  11. ^ McCaffrey AP, Meuse L, Karimi M, Contag CH, Kay MA. A potent and specific morpholino antisense inhibitor of hepatitis C translation in mice. Hepatology. 2003 Aug;38(2):503-8. PMID 12883495.
  12. ^ Chiron Corporation Chiron Hepatitis C Research Honored with 2000 Lasker Award for Clinical Medical Research Press release, Sept. 18 2000.
  13. ^ Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244:359-62. PMID 2523562.
  14. ^ Kuo G, Choo QL, Alter HJ, Gitnick GL, Redeker AG, Purcell RH, Miyamura T, Dienstag JL, Alter MJ, Stevens CE, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 1989 Apr 21;244(4902):362–364. PMID 2496467.
  15. ^ Varela F. Intimate Distances - Fragments for a Phenomenology of Organ Transplantation. J of Consciousness Stud 2001;8:259-71. Fragment.
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