Hepatitis Information

Hepatitis Virus (ABCDE):

Hepatitis Virus (ABCDE). Rice University researchers have systematically mapped out, atom by atom, the structure of the shell of the hepatitis E virus. Obviously, the knowledge of the morphology of this particularly nasty strain of hepatitis may help us to develop vaccines or therapies against Hep E.Tao’s [Yizhi Jane Tao, assistant professor of biochemistry and cell biology] lab specializes in X-ray crystallography, a powerful technique that can pinpoint the exact location of every atom in a biomacromolecule or a large biomacromolecular assembly. In this case, the assembly was the viral capsid shell, made from a network of individual capsid proteins from a strain of HEV that had been made in insect cells, then purified and crystallized.After two years of intense study, Guu [Rice graduate student Tom Guu --ed.] calculated the position of each of the approximately 500,000 atoms that make up the capsid, an icosahedron-shaped particle that roughly resembles a buckyball. The resulting 3-D computer model gives researchers the ability to identify the particle’s host-cell binding sites, through which HEV spreads.

Hepatitis A What is hepatitis?

The liver is one of the organs that helps with digestion but is not part of the digestive tract. It is the largest organ in the body and carries out many important functions, such as making bile, changing food into energy, and cleaning alcohol and poisons from the blood.Hepatitis is inflammation of the liver that sometimes causes permanent damage. It is caused by viruses, bacteria, certain medications, or alcohol. It may also be caused by certain diseases such as: autoimmune diseases, metabolic diseases, and congenital (present at birth) abnormalities (biliary atresia, Wilson’s disease). Generally, symptoms of hepatitis include fever, jaundice, and an enlarged liver. There are several types of hepatitis.

• Illustration of the anatomy of the biliary system
• Click Image to Enlarge

What is hepatitis A?

Hepatitis A is a highly contagious and sometimes serious liver disease caused by the hepatitis A virus. Once calledc infectious hepatitis, today it is more ommonly known as hepatitis A. Approximately one-third of Americans have been exposed to hepatitis A.Hepatitis A does not result in chronic infection, but complete recovery from hepatitis A can be slow. In adult patients with hepatitis A, the illness may last for at least one month, with recovery taking up to six months. Hepatitis A rates in the United States have declined by 92 percent since the vaccine (hepatitis A) first became available in 1995

What are the symptoms of hepatitis A?

The following are the most common symptoms of hepatitis A. However, each individual may experience symptoms differently. Symptoms of hepatitis A often resemble flu-like symptoms.

Symptoms may include:

• fever
• chills
• joint pain
• fatigue
• general feeling of weakness
• loss of appetite
• nausea
• vomiting
• abdominal discomfort
• dark urine
• clay-colored stools
• jaundice – yellowing of the skin and eyes
• diarrhea

In some adults, and in children (about 70 percent), especially in those younger than 6 years of age, there are often no symptoms. The symptoms of hepatitis A may resemble other medical conditions or problems. Always consult your physician for a diagnosis.

What causes hepatitis A?

This type of hepatitis is usually spread by fecal-oral contact or fecal-infected food and water, and may also be spread by blood-borne infection (which is rare). The following is a list of modes of transmission for hepatitis A:

• consuming food made
• by someone who touched infected feces
• drinking water that is contaminated by infected feces (a problem in
• developing countries with poor sewage removal)
• touching an infected person’s feces, which may occur with poor hand
• washing
• outbreaks may occur in large childcare centers, especially when there
• are children in diapers
• residents of American Indian reservations or Native Alaskan villages
• where hepatitis A may be more common
• sexual contact with an infected person

Generally, casual contact in school or the workplace does not cause spread of the virus.

What are the risk factors for hepatitis A?

Children, teens, and adults who may be at high risk of hepatitis A include the following:

• people traveling to areas of where hepatitis A is prevalent, including, but
• not limited to: Africa, Asia (except Japan), the Mediterranean basin,
• Eastern Europe, the Middle East, Central and South America, Mexico,
• and parts of the Caribbean
• people living in or relocating to any community in the US or abroad with
• one or more recorded hepatitis A outbreaks within the past five years
• military personnel
• people who engage in high-risk sexual activit
• users of illegal intravenous (IV) drugs
• hemophiliacs and other recipients of therapeutic blood products
• employees of daycare centers
• institutional care workers
• laboratory workers who handle live hepatitis A virus
• people who handle primate animals that may be carrying the hepatitis A
• virus

Hepatitis A is sometimes called a traveler’s disease because it is the most frequently occurring, vaccine-preventable infection in travelers. However, it is possible to become infected with hepatitis A virus without ever leaving the United States. Some cases reported in the United States have occurred in people with no identifiable risk factors.

Prevention of hepatitis A:

In addition to avoiding risky behaviors, there are two methods for immune globulin a preparation of antibodies that is given both before anticipated exposure to the hepatitis A virus and soon after exposure.
hepatitis A vaccine Researchers at the National Institute of Allergy and Infectious Diseases have found the genes that make hepatitis A virulent. However, when the researchers altered those genes to weaken the virus, the virus quickly reverted itself back to its natural infectious form, making it difficult to create an improved vaccine. Currently, the vaccine consists of killed hepatitis A virus. Please consult your physician if you have any questions about its use.

Hepatitis B Antigens

The various components produced by hepatitis B, while reproducing, are detailed below. Some of these components enter the blood stream and cause detectable changes, some may only be determined via liver biopsy and others require sophisticated, experimental or unreliable tests.

Hepatitis B DNA (HBV DNA)

This is one of the first things that can be detected in the bloodstream after initial infection. It can be detected as soon as 1 week after infection using sensitive tests. It is believed that the level of HBV DNA may indicate how fast the virus is replicating(?). The test for HBV DNA is performed using PCR which is expensive and difficult to perform and therefore not frequently used. Tests for HBV DNA are generally not performed as standard as other Hepatitis B markers such as the “e” antigen can be used to determine viral activity. It is generally only used research purposes, however in can be used to confirm the presence of hepatitis B and or measure viral load for viral mutants that do not produce the “e” and/or normal surface antigens.

Hepatitis B DNA polymerase. (HBV DNA Polymerase, DNAp)

This enzyme can be detected in the bloodstream soon after initial infection by hepatitis B at about the same time as HBV DNA. I.e. generally within a 1 week or so after infection. Tests for HBV DNA polymerase are not performed as a standard test and generally only used as indicators of disease progression, suitability for therapy and research purposes.

Hepatitis B Core protein. (HBcAg)

The core protein (HBc) is not detectable in the bloodstream, however it can be detected in the sample of liver cells taken after a liver biopsy. Generally the HBc proteins link together to form the hepatitis B core that encapsulate HBV DNA and DNA Polymerase.

Hepatitis B Surface protein(s). (HBsAg)

The outer surface coat composed of hepatitis B surface proteins is produced in larger quantities than required for the virus to reproduce. The excess surface proteins clump together into spherical particles of between 17-25nm in diameter but also form rods of variable length. In some cases these particles encapsulate a core particle and produce a complete, and infectious, virus particle that enters the blood stream and can infect other liver cells. The excess spheres, rods and also complete viral particles enter the blood stream in large numbers and are easily detectable. It does however take a while for these proteins to appear.The incubation of the Hepatitis B Virus (hepatitis B) is between 6 to 25 weeks. After infection and 1 to 6 weeks before symptoms occur HBsAg appears. A positive test for the presence of hepatitis B surface protein (HBsAg), is the standard currently taken to indicate current infection with hepatitis B. If HBsAg is present for more than 6 months this is generally taken to indicate chronic infection.It is thought that excess HBs proteins produced may allow infectious viral particles to escape the immune system by mopping up any low levels of surface antibodies that may be produced by the immune system(?).

The Hepatitis B Virus

Hepatitis B is a DNA Virus of the hepadnaviridae family of viruses. It replicates within infected liver cells (hepatocytes ). The infectious (“Dane”) particle consists of an inner core plus an outer surface coat.
In real life the virus is a spherical particle with a diameter of 42nm (1nm = 0.000000001 metres) and is composed as follows. There is an outer shell (or envelope) composed of several proteins known collectively as HBs or surface Proteins.This outer shell is frequently referred to as the surface coat. The outer surface coat surrounds an inner protein shell, composed of HBc protein. This inner shell is referred to as the core particle or capsid. Finally the core particle surrounds the viral DNA and the enzyme DNA Polymerase.

Hepatitis C
INFORM-1

This is the first clinical trial of the combination of an HCV polymerase inhibitor, RG7128, and an HCV protease inhibitor, RG7227.  What is noteworthy is the absence of interferon and ribavirin.  The theory behind this clinical trial is that by combining two different types of direct HCV antiviral medications there is a different mechanism of action to attack the virus at different parts of the replication process to help to prevent the virus from becoming resistant to either medication.  Also of note is that the drugs are eliminated differently from the body—one from the kidneys and one from the liver.  Another compelling reason for hoping this combination will work is that both are oral medications that only have to be taken twice a day—which will make adherence much easier compared to taking a shot of interferon, multiple doses of ribavirin and possibly 3 daily doses of an HCV direct antiviral a day. All patients in this study were HCV genotype 1 patients who did not have cirrhosis.  Treatment relapsers, partial responders and null responders as well as treatment-naïve patients were included in the trial.

Part 1

In April 2009 the results from part 1 of the phase I study were released.  In part 1 the combination dosing for 14 days produced a median reduction of HCV RNA of -4.8 to -5.2 log10 IU/ml in the highest doses; all doses of the combination produced HCV RNA reductions (less than 40 IU/mL) in 63% of the trial participants  The drugs were well-tolerated over the 14-day dosing period with no serious treatment-related adverse events, dose reductions or discontinuations

Part 2

The objective of the second part of the study was to assess the safety and tolerability of a combination of the two drugs for up to 13 days.
All of the study medications were dosed at BID (twice a day) and in each group two patients received a placebo (sugar pill).  A total of 24 patients were randomized to one of three treatment arms; the RNA decline is listed after the dosing regimen below:

• 8 patients who were treatment failure but NOT null-responders received 1000 mg RG7128 plus 600 mg RG7227
• -4.0 log10 IU/ml (range -6.0 to -2.5); HCV RNA < 15 IU/mL = 1 patient
• 8 patients who were null-responders received 1000 mg RG7128 and
• 900 mg RG7227.
• -4.9 log10 IU/mL (range -5.3 to -3.5);  HCV RNA <15 IU/mL = 2 patients
• 8 patients who were treatment-naïve received 1000 mg RG7128 and
• 900 mg RG7227.
• -5.1 log10 IU/mL (range -5.9 to -3.0);  HCV RNA <15 IU/mL – 5 patients

Safety:

Similar to part 1 of the study results released earlier this year, headache was the most common side effect followed by nausea, diarrhea, and rash that were possibly related to the study drugs.  There were no treatment discontinuations due to side effects.  One person dropped out of the study due to personal reasons.
Resistance:

There was no treatment-emergent resistance identified.  One patient in the low dose group had a rebound of HCV RNA viral load, but it was suppressed with treatment of pegylated interferon plus ribavirin. The authors noted that this is the first interferon-free study to demonstrate that HCV RNA could be suppressed to the same extent as that shown with the use of the combination of HCV protease inhibitors, pegylated interferon and ribavirin over a two week period.

Comments:

The results from this study are remarkable although it is important to remember that the number of people who actually took the drugs was very small and the people were only given the study drugs for a short period of time.  The next steps (INFORM-2) are to study the combination of RG7128 and RG7227 with and without pegylated interferon and ribavirin for a longer period of time.  The companies expect to start the studies in the first half of 2010.

TELAPREVIR

Telaprevir is currently in phase III studies, but other on-going studies are being conducted and data is being released.  Included in this report are results from three different telaprevir studies.

Hepatitis C in Wales

Antibody tests for hepatitis C infection became widely available in the early 1990s and increased rates of diagnostic testing for hepatitis C have been sustained due to changes in referral patterns, increased clinical awareness and intention to treat.In Wales, studies suggest that 0.5% of the general population (approximately 14,700 people) have been infected with hepatitis C and an estimated 12,000 people have chronic hepatitis C giving a prevalence of 0.4% of the population. About three-quarters of these individuals are unaware that they are infected.

Hepatitis D
History:

In 1977, an Italian doctor named Mario Rizzetto discovered a new nuclear antigen in the liver cells of patients infected with Hepatitis B Virus (HBV). The antigen was thought to be a new protein encoded by HBV, and it was labeled as the delta antigen. Subsequent research on chimpanzees, however, indicated that this antigen was derived from a new virus, named the Hepatitis Delta Virus (HDV).

Classification:

HDV is the only virus in the genus, Deltaviridae. HDV is not classified into a viral family because it is a unique virus dependent on HBV. HDV is a co-infection of HBV. The envelope of HDV particles contains the Hepatitis B surface antigen (HBsAg). The production and transmission of HDV is entirely dependent on HBV to provide HBsAg. Thus, HDV is considered a satellite virus of HBV. Unlike a classical satellite virus, however, HDV does not share sequence similarity with HBV, and it can replicate independently of HBV.There are at least three HDV genotypes: I, II, and III. HDV isolates of Genotype I have been reported in every part of the world, and the pathogenesis of Genotype I infections varies from fulminant hepatitis to asymptomatic chronic liver disease. The milder HDV II genotype is found primarily in Asia, including Japan, Taiwan, and Russia. Some sequences from Taiwan and the Okinawa islands have been assigned to a subtype of Genotype II, called Genotype IIB. HDV genotype III has been isolated only in northern South America (Peru, Venezuela, and Columbia) and is associated with severe acute hepatitis. Furthermore, HDV genotype I is the only genotype found in some locations, including Europe and North America. Multiple genotypes have been detected in Africa and in Asia. Mixed infections of genotypes I and II or II and IIb have been reported in Taiwan. Furthermore, 15 of 22 recently characterized African sequences formed new lineages and the other 7 are scattered within genotype I. Therefore, recent work has indicated that the current classification of HDV into only three genotypes is incomplete.

Molecular Biology:

HDV consists of a single stranded, negative sense, circular RNA virus, with an envelope made up of HBAg. Virions are 35-43 nm and are roughly spherical, with no distinct nucleocapsid structure. The nucleocapsid is made up of 60 large and small delta antigens. These are the only proteins encoded by HDV. HDV relies on host cell machinery for replication, and the viral genome (and antigenome) serves as ribozymes for self-ligation and cleavage. Viral replication occurs in the nucleus of primary hepatocytes using a double-rolling circle mechanism. New virions can be assembled only in the presence of hepatitis B virus. The stages of the viral life cycle, including replication, assembly, and transport, depend on the ratio of small to large delta antigen.

Hepatitis E

More than 50% of acute viral hepatitis occurring in some developing countries appears to be unrelated to infection by HAV or HBV and accumulating evidence suggests that a high proportion of this NANBH is enterically transmitted (Hepatitis E). Outbreaks of hepatitis E have been documented in the India, Pakistan, USSR, Borneo, Sudan, Ivory Coast, Algeria, and Mexico. These outbreaks affected young to middle aged adults and are often associated with a high mortality in pregnant women, approaching 20% in some epidemics. Several investigators described finding 27 to 34nm virus-like particles in the stools of acutely infected stools by IEM. Virus in the infected stools were transmitted to monkeys and chimpanzees and other primates who excreted similar 27 to 34nm in the stools in the pre-acute phase, and were shown to seroconvert. The disease had also been transmitted to a human volunteer using a pool of 14 stool extracts from infected patients. The morphological, physical and chemical properties of these particles were very similar to the caliciviruses.

PROPERTIES

• Calicivirus-like virions
• unenveloped RNA virus, 32-34nm in diameter
• +ve stranded RNA genome, 7.6 kb in size.
• very labile and sensitive
• not yet cultured

NATURAL_HISTORY

Hepatitis E disease occur in both sporadic and epidemic forms and is primarily associated with the ingestion of faecally contaminated drinking water. Little secondary household transmission has been documented to occur unlike HAV. Hepatitis E was first documented in New Delhi in 1955 when 29000 cases of icteric hepatitis occurred following the contamination of the city’s drinking water. Several other large epidemics have occurred since in the Indian subcontinent and the USSR;

• The Delhi Epidemic 1955-56
• Ahmedaban, India 1975-76
• Pune, India 1978
• Kashmir 1980
• Tashkent, USSR 1983

These outbreaks were originally thought to be due to HAV but retrospective analysis of stored serum identified HEV as the causative agent. Epidemics have also been reported from parts of China, Africa and Mexico. Sporadic cases predominantly occur in the Indian subcontinent. One notable feature of hepatitis E is the relatively low incidence of clinical disease in case contacts. For example, only 2.4% of household contacts of HE cases developed clinical illness during the 1981-82 epidemic in Kathmandu Valley, whereas the secondary attack rate for HAV was 10 to 20% among household contacts in the same region.

How is HEV transmitted?

HEV is transmitted via the faecal-oral route. Hepatitis E is a waterborne disease, and contaminated water or food supplies have been implicated in major outbreaks. Consumption of faecally contaminated drinking water has given rise to epidemics, and the ingestion of raw or uncooked shellfish has been the source of sporadic cases in endemic areas. There is a possibility of zoonotic spread of the virus, since several non-human primates, pigs, cows, sheep, goats and rodents are susceptible to infection. The risk factors for HEV infection are related poor sanitation in large areas of the world, and HEV shedding in faeces.

Person-to-person transmission is uncommon. There is no evidence for sexual transmission or for transmission by transfusion.

Where is HEV a problem?

The highest rates of infection occur in regions where low standards of sanitation promote the transmission of the virus. Epidemics of hepatitis E have been reported in Central and South-East Asia, North and West Africa, and in Mexico, especially where faecal contamination of drinking water is common. However, sporadic cases of hepatitis E have also been reported elsewhere and serological surveys suggest a global distribution of strains of hepatitis E of low pathogenicity.

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