Thursday, January 16, 2014

"The deadly disease called hepatitis B" by Ashoke K. Roy

Hepatitis B is a liver disease caused by HBV infection. HBV can cause short-term (acute) illness that may lead to flu-like symptoms (loss of appetite, diarrhoea and vomiting, fever) and jaundice (yellow skin or eyes), and long-term (chronic) illness that may lead to liver damage (cirrhosis), liver cancer and death. Individuals with chronic infection may become carriers capable of spreading the disease to others.

World-wide, the disease is a major health problem: more than 2 billion people have been infected with HBV, about 400 million are estimated to be HBV carriers, and HBV-associated liver cancer and cirrhosis account for over 1 million deaths each year. About 75 per cent of the long-term carriers live in Asia Pacific.

Global Situation: It is estimated that at least 1 million people worldwide die prematurely each year as a result of Hepatitis B infection and there are more than 350 million long-term carrier of the disease.

* High endemicity - Hepatitis B is highly endemic in developing regions with high population densities such as South East Asia, parts of China, sub-Saharan Africa and the Amazon Basin. In these areas, 70–95 per cent of the population show serological evidence of previous or current HBV infection. Most infections occur during infancy or childhood. Carrier rates are therefore also high, at 8–20 per cent of the population.

* Intermediate endemicity - In parts of Eastern and Southern Europe, the Middle East, Japan, North Africa, Central and Latin America. 20–55 per cent of the population have HBV markers of infection and 2–7 per cent are carriers. There is a high proportion of infection in children, but infection in adults is also quite common.

* Low endemicity - The endemicity of HBV is low in North America, Northern and Western Europe and Australia. In these regions, HBV infects 4–6 per cent of the population. The disease most commonly affects adolescents and young adults. 0.5–2 per cent of the population are chronic carriers.The patterns of HBV prevalence and the incidence of hepatitis B are constantly shifting. For example, in the 1980s in the US, the number of hepatitis B infections in homosexuals showed a significant decrease, yet the number of infections in heterosexuals increased significantly.Changes in living standards, behavior and vaccination policies can all influence disease patterns.

Population groups at high-risk: In low endemicity countries, the prevalence of hepatitis B in some population groups may be markedly higher than average. For example, in the US 70–85 per cent of immigrants from high endemicity areas have HBV markers indicating past infection, and about 13 per cent are carriers.

Other groups with a high prevalence of hepatitis B include the institutionalized mentally retarded and the staff caring for them, homosexual males, intravenous drug abusers, household contacts of carriers, patients who require regular blood transfusions or hemodialysis, prisoners and prison staff, health care workers, people with sexually transmitted diseases, prostitutes and the sexually promiscuous. All of these are at increased risk as their activities may bring them into contact with infected body fluids.

Morbidity and mortality: HBV is one of the most significant viruses in terms of world-wide morbidity and mortality. In fact, the data shown here may be grossly underestimating the problem.

The virus has infected over 2000 million people and there are over 350 million chronic carriers. The pool of carriers is increasing by 2–3 per cent a year. These carriers make up an enormous reservoir from which hepatitis B can spread to susceptible individuals.

HBV is responsible for 1 million deaths a year, the majority of fatalities being due to cirrhosis and primary hepatocellular carcinoma (PHC), a form of liver cancer. Epidemiological data indicate that there is a consistent and specific causal association between infection with HBV and hepatocellular carcinoma.

Hepatocellular carcinoma is the most common form of primary liver cancer, and one of the ten most common cancers in the world. Up to 80 per cent of the world’s primary liver cancer cases are attributed to HBV. HBV is second in importance only to tobacco among the known human carcinogens. After introduction of vaccine in America in 1981 the incidence of Hepatitis B started to fall down from 1985.

In Bangladesh: Not very well studied. Several studies found huge number of patients and carriers. It is estimated that 7-9 per cent of our population may be suffering from the disease or carrying the virus. This is a great cause of concern.

HBV and the chronic carrier state: Every year millions of people are newly infected by the hepatitis B virus. About two-thirds of infected adults will show clinical symptoms which can vary in seriousness from mild to severe. In a small but significant number of cases, the infection is fatal.

Some people who are infected are unable to mount an effective immune response to eliminate the virus. They become long-term HBV carriers.

The risk of becoming a chronic carrier depends on age. Up to 80–90 per cent of newborns and infants infected with HBV may become long-term chronic hepatitis B patients. 5–10 per cent of infections in adults will also lead to a chronic carrier state. The milder the primary infection, the greater the risk of becoming a chronic carrier. Most chronic HBV carriers do not suffer from any clinical symptoms and seem perfectly healthy. However, their livers are being progressively damaged and, eventually, severe chronic liver disease may result.

Chronic carriers are also able to infect others and therefore represent a constant public health risk. It is estimated that there are over 350 million carriers of HBV world-wide - that is about 5 per cent of the world’s population!

How it spreads: HBV is spread through contact with the blood or other body fluids of an infected person, for example, by sexual contact, from mother to child during birth, by intravenous drug use with infected needles or by needle-stick injuries in certain occupations, even sharing toothbrushes or razors. In travelers from developed countries it is the second most frequent vaccine preventable disease.

Prevention of hepatitis B : Vaccination is the most effective way of preventing hepatitis B disease. Vaccination against hepatitis B is recommended for inclusion in childhood immunization programs worldwide and for groups at risk of HBV infection (e.g. healthcare workers and travelers to countries with a high prevalence of hepatitis B). More than 100 countries world wide have implemented this program already. Hepatitis B vaccines are the first which have been shown to prevent cancer (liver cancer).

Vaccination: Vaccination is the most effective and convenient way of preventing hepatitis B disease and the chronic carrier state or liver cancer that can result from it.
From that point of view Hepatitis B vaccine is the first anti-cancer vaccine.

Protection from acute and chronic infection, as well as clinical illness, is virtually complete among persons who develop a protective antibody response (anti-HBs>=10 mIU/ml) following vaccination. It is generally accepted that the threshold anti-HBs titer for protection is 10 mIU/ml. However, some health authorities (e.g. in the UK) have set the limit more conservatively at 100 mIU/ml.

The magnitude of the antibody response induced by the primary vaccination series is predictive of the persistence of detectable antibodies. Current follow-up studies indicate that protection from clinically significant HBV infection and chronic carriage remains intact for at least 15 years in immunocompetent individuals, and that immune memory continues to provide protection even when anti-HBs levels have become undetectable.

Widespread use of hepatitis B vaccine has been shown to dramatically reduce hepatitis B virus infection and the development of liver cancer from chronic hepatitis B infection. Consequently, the Centres for Disease Control and Prevention (CDC) and the World Health Organization (WHO) regard hepatitis B vaccine as the first anti-cancer vaccine since it prevents this serious consequence of hepatitis B infection. The WHO states that hepatitis B vaccine is the first and currently the only vaccine against a major human cancer.

The two main types of hepatitis B vaccine currently available are-

* plasma-derived vaccines
* genetically-engineered vaccines

Plasma-derived vaccines: Preparation of a plasma-derived vaccine.
During an HBV infection, large quantities of the surface antigen HBsAg are synthesized in the liver and released into the blood stream. This phenomenon is exploited in the production of plasma derived vaccines, when HBsAg particles are isolated from the blood of chronic carriers, purified and incorporated into a vaccine.

Plasma derived vaccines were the first vaccines to be used against hepatitis B. They have since been widely used and have been found to be safe and effective. However, with a production cycle of 1 year, supplies of these plasma-derived vaccines were limited, and there were widespread, but unjustified, fears that the vaccines could be contaminated with other blood-borne diseases such as HIV. Also the complex production procedures and lengthy testing mean that plasma-derived vaccines were expensive. 

Genetically engineered vaccines: Preparation of a genetically-engineered vaccine.
The discovery of the gene expressing HBsAg in the 1970s together with developments in molecular biology have made it possible to produce genetically-engineered vaccines against hepatitis B. Today large quantities of HBsAg can be generated by inserting the gene expressing HBsAg into a suitable vehicle such as yeast. As the vehicle multiplies, the implanted DNA induces the production of HBsAg. The surface antigen is then extracted and purified and incorporated into a vaccine.

These genetically-engineered vaccines provide effective protection against hepatitis B. They also have a number of advantages compared to plasma-derived vaccines:

* They can be produced more quickly.
* They can be manufactured in larger quantities. 
* They are produced from cells which contain only part of the genetic code of the hepatitis B virus, so they are free from infectious virus particles. 
* Their production does not rely on the availability of carrier plasma, with its associated risk of contaminants.

Treatment: Till last year the treatment option for Hepatitis B was very limited. Only Interferon was the drug that was very expensive, toxic and the treatment success was less than 20 per cent. Now an oral medicine is available that developed in the laboratory of GlaxoSmithKline. It available at an affordable price and well tolerated. Still prevention is better and preferable. Emphasis should be given on Vaccination. Prevention is better than cure. Vaccination is preferred and easy means of preventing the deadly disease.

Prevention and Vaccination

Prevention Measures

Hepatitis B is a vaccine-preventable disease. There is a safe and effective vaccine to protect infants, children and adults from hepatitis B. Billions of doses have been given worldwide.
All sex partners, family and close household members of a chronically infected person should be screened and vaccinated. Reassure patients and families that hepatitis B is not casually transmitted - it is spread through blood, not by coughing, sneezing, hugging or sharing food.

Additional Prevention Measures

In addition to vaccination, there are other simple ways to help stop the spread of hepatitis B:
§  Wash your hands thoroughly after any potential exposure
§  Practice safe sex with all partners
§  Avoid direct contact with blood and bodily fluids
§  Clean up blood spills with a fresh diluted bleach solution
§  Cover all cuts carefully
§  Avoid sharing sharp items such as razors, nail clippers, toothbrushes, and earrings or body rings
§  Discard sanitary napkins and tampons into plastic bags
§  Avoid illegal street drugs (injecting, inhaling, snorting, popping pills)
§  Do not donate blood or body organs
§  Make sure new, sterile needles are used for ear or body piercing, tattoos, and acupuncture

Hepatitis B Vaccine
Side Effects and Safety - Vaccine Recommendations - Vaccine Schedule - Vaccine Cost - Approved Hepatitis B Vaccines

It takes only 3 shots to protect your`self and your loved ones against hepatitis B for a lifetime.
In 1981, the Food and Drug Administration approved the first vaccine for hepatitis B, which was plasma-derived (i.e. made from blood products). This vaccine was discontinued in 1990 and is no longer available in the U.S. 
The currently used hepatitis B vaccines are made synthetically (i.e. they do not contain blood products) and have been available in the U.S. since 1986. You cannot get hepatitis B from the vaccine.
This safe and effective vaccine is recommended for all infants at birth and for children up to 18 years. Adults, especially those who fall into a high-risk group, should also seriously consider getting the hepatitis B vaccine.

Vaccine Side Effects and Safety
Common side effects include soreness, swelling and redness at the injection site. The vaccine may not be recommended for those with documented yeast allergies or a history of an adverse reaction to the vaccine.
The Hepatitis B vaccine is considered one of the safest and most effective vaccines ever made. Numerous studies looking at the vaccine's safety have been conducted by the Centers for Disease Control, World Health Organization, and other professional medical associations. They have not found any evidence that the vaccine causes sudden infant deaths (SIDs), multiple sclerosis, or other neurological disorders.

Vaccine Recommendations
The hepatitis B vaccine is recommended specifically for all infants and children by the Centers for Disease Control and the American Academy of Pediatrics. The CDC also recommends that adults in high-risk groups be vaccinated.
The following list is a general guide for vaccination, but since every person is at some risk for infection, these guidelines should be individualized for each situation.
§  All infants at birth and all children up to 18 years.
§  Health care professionals and emergency personnel.
§  Sexually active teens and adults
§  Men who have sex with men.
§  Sex partners or close family/household members living with an infected person.
§  Families considering adoption, either domestic or international.
§  Travelers to countries where hepatitis B is common (Asia, Africa, South America, the Pacific Islands, Eastern Europe, and the Middle East).
§  Patients with kidney disease or undergoing dialysis.
§  Residents and staff of correctional facilities and group homes.
§  Any person who may fall into a high risk group due to occupation or lifestyle choices.

Vaccine Schedule
The vaccine is readily available at your doctor's office or local health clinic. Three doses are generally required to complete the hepatitis B vaccine series, although there is an accelerated two-dose series for adolescents.
§  First Injection - At any given time
§  Second Injection - At least one month after the first dose
§  Third Injection - Six months after the first dose

Cost of Vaccine
The three-shot vaccine series for children in the United States usually costs $75 to $165, but this can vary. Infants up to age 18 months, and sometimes older children, can receive the vaccine free of charge from most local public health clinics.
Insurance companies will usually cover the cost of vaccines for infants and children. There is also a federal program to help cover the cost of children's vaccines.
The hepatitis B vaccine costs more for adults. If an adult is in a high-risk group, the cost may be also covered by insurance. Contact your insurance company for more information about the hepatitis B vaccine.

Approved Hepatitis B Vaccines
There are currently two commercial vaccines used to prevent hepatitis B infection among infants, children and adults in the United States. They are both manufactured using recombinant technology and neither contains blood products. You cannot get hepatitis B from these vaccines.
§  Engerix-B, produced by GlaxoSmithKline
§  Recombivax HB, produced by Merck
§  There is also a combination vaccine for hepatitis A and B available for adults: TwinRix, produced by GlaxoSmithKline.

Treatment Options

Approved Drugs for Adults

The future looks bright for individuals living with chronic hepatitis B. Only a decade ago there were no treatment options. Although there is still no complete cure for hepatitis B, there are 6 approved drugs for adults (2 for children) and many promising new drugs in development. Current treatments seem to be most effective in those who show signs of active liver disease
Not every person with chronic hepatitis B needs to be on medication. You should talk to your doctor about whether you are a good candidate for drug therapy or a clinical trial. Be sure that you understand the pros and cons of each treatment option.
Whether you decide to start treatment or not, it is very important to be seen by a liver specialist or doctor knowledgeable about hepatitis B on a regular basis.

Approved Hepatitis B Drugs in the United States
§ Interferon-alpha (Intron A) is given by injection several times a week for six months to a year, or sometimes longer. The drug can cause side effects such as flu-like symptoms, depression, and headaches. Approved in 1991 and available for both children and adults.

§ Pegylated Interferon (Pegasys) is given by injection once a week usually for six months to a year. The drug can cause side effects such as flu-like symptoms, depression and other mental health problems. Approved May 2005 for adults.

§ Lamivudine (Epivir-HBV, Zeffix, or Heptodin) is a pill that is taken once a day, with almost no side effects, for at least one year or longer. The possible development of hepatitis B virus mutants during and after treatment is a concern. Approved in 1998 and available for both children and adults.

§ Adefovir dipivoxil (Hepsera) is a pill taken once a day, with few side effects, for at least one year or longer. Kidney problems can occur while taking the drug and is a concern, but are reversible once the drug is stopped. Approved September 2002 for adults. Pediatric clinical trials are being planned.

§ Entecavir (Baraclude) is a pill taken once a day, with almost no side effects for up to one year. It is considered to be the most potent oral antiviral drug for chronic hepatitis B to date. Approved April 2005 for adults. Pediatric clinical trials may be planned for the future.

§ Telbivudine (Tyzeka, Sebivo) is a pill taken once a day, with almost no side effects for up to one year. Studies have shown that it rapidly and profoundly suppresses HBV levels. Approved October 2006 for adults.
Although the FDA has approved these six drugs for chronic hepatitis B, they do not provide a complete cure, except in rare cases (a "cure" generally means that a person loses the hepatitis B virus and develops protective surface antibodies).
The drugs, however, significantly decrease the risk of liver damage from the hepatitis B virus by slowing down or stopping the virus from reproducing. As with HIV, it appears that combination therapy will probably be the most effective method of combating chronic hepatitis B infections.

Who Should Be Treated
The decision of whether to start treatment (or enroll in a clinical trial) should be based on careful evaluation of your physical exam, blood tests, and liver biopsy (if one is done). Be sure you see a liver specialist (hepatologist) for the most current information about hepatitis B therapies.
Studies show that the current treatments appear to be of greatest benefit to those who show signs of active liver disease:
§ Elevated liver enzymes (ALT)
§ Positive blood tests for:
          Hepatitis B virus (HBsAg)
          Hepatitis B e-antigen (HBeAg)
§ Elevated levels of hepatitis B DNA
Some doctors may order a liver biopsy (this involves taking a small sample of your liver to examine under the microscope) to help decide whether treatment is needed, but this practice is not as common as it used to be.
It is always a good idea to get a second opinion before starting any treatment.

Hepatitis B Clinical Trials
The future is bright for people with chronic hepatitis B, thanks in a large part to advancements in medical science. All drugs must go through a testing process, which involves three phases of clinical trials, to evaluate its safety and effectiveness before being approved.
Volunteering for a clinical trial program can be very valuable. Expensive blood work, treatment medications, and doctor’s visits are usually provided free of charge for those accepted into a study. Clinical trials also provide the opportunity to potentially benefit from the latest advances in medical science.

Compounds in Development for Chronic Hepatitis B                                         
Updated July 2007
FAMILY/DRUG NAME
MECHANISM
COMPANY
STATUS
Interferons - Mimic naturally-occurring, infection-fighting immune substance produced in the body
Intron A
(Interferon
alfa-2b
Immunomodulator
Schering-Plough
Madison, NJ
FDA Approved
1991
Pegasys
(Peginterferon alfa-2a)
Immunomodulator
Roche
Switzerland
FDA Approved 2005
There are other brands of interferon approved for HCV treatment, but they have not been FDA-approved for HBV: Wellferon (Glaxo), Roferon(Hoffman-La Roche), and Infergen (Amgen)
Nucleoside Analogues -  Interfere with the viral DNA polymerase enzyme used for hepatitis B virus reproduction
Epivir-HBV
(Lamivudine)
Inhibits viral DNA polymerase
GlaxoSmithKline Philadelphia, PA
FDA Approved
1998
Hepsera
(Adefovir Dipivoxil)
Inhibits viral DNA polymerase
Gilead
Foster City, CA
FDA Approved
2002
Baraclude
(Entecavir)
Inhibits viral DNA polymerase
Bristol-Myers Squibb
Princeton, NJ
FDA Approved
2005
Tyzeka
Sebivo (Europe)
(Telbivudine)
Inhibits viral DNA polymerase
Idenix
Cambridge, MA
FDA Approved
2006
Emtricitabine
(FTC)
Inhibits viral DNA polymerase
Gilead
Foster City, CA
Phase III
Clevudine
(L-FMAU)
Levovir (S. Korea)
Inhibits viral DNA polymerase
Pharmasset
Princeton, NJ
Bukwang

South Korea
Eiasai, Japan
Phase III, USA
Approved S. Korea (Nov. 2006)
Viread
(Tenofovir)
Inhibits viral DNA polymerase
Gilead
Foster City, CA
Phase III
Valtorcitabine
(monoval LdC)
Inhibits viral DNA polymerase
Idenix
Cambridge, MA
Phase II
Amdoxovir
(DAPD)
Inhibits viral DNA polymerase
RFS Pharm LLC
Tucker, GA
Phase II
ANA 380
(LB80380)
Inhibits viral DNA polymerase
Anadys
San Diego, CA
Phase II
Pradefovir
(Remofovir)
Inhibits viral DNA polymerase
Schering-Plough
Madison, NJ
Phase II
RCV
(Racivir)
Inhibits viral DNA polymerase
Pharmasset
Princeton, NJ
Phase II
Non-Nucleoside Antivirals -  Interfere with proteins involved in viral reproduction
NOV-205
(BAM 205)
Small Molecule
Novelos
Newton, MA
Approved in Russia
HepeX-B
(XTL-001)
Human monoclonal antibodies
XTL Biopharm
and Cubist Pharm, Cambridge, MA
Phase II/III
Orphan drug approval in US for liver cancer
Nitazoxanide (Alinia)
Small Molecule
Romark Labs
Tampa, FL
Phase II Egypt
UT 231-B
*Discovered by HBF Scientists
Small Molecule
United Therapeutics
Silver Spring, MD
Preclinical HBV
(Phase II HCV)
Bay 41-4109
Inhibits viral nucleocapsid
Bayer AG
Germany
Preclinical
Non-Interferon Immune Enhancers -  Boost T-cell infection-fighting immune cells and natural interferon production
EHT899
Oral Viral Protein
Enzo Biochem
New York, N.Y.
Phase II Israel
Zadaxin
(Thymosin alpha-1)
Immune stimulator
SciClone
San Mateo, CA
Orphan drug approval in US for liver cancer
Hi-8 HBV
Therapeutic HBV Vaccine
Oxxon
U.K.
Phase II
HepX (eiRNA)
Expressed Interfering RNA
Nucleonics
Horsham, PA
Phase I
HepaVaxx B
Therapeutic HBV Vaccine
Virexx
Canada
Phase I
HBV Core Antigen Vaccine
Therapeutic HBV Vaccine
Phase I
SpecifEx-HepB
Immunological Cell Transfer
Chromos
Burnaby, BC
Preclinical/
Phase I
Post-Exposure and/or Post-Liver Transplant Treatment
HyperHEP S/D
HBV Immuneglobulin
Talecris
RTP, NC
FDA Approved 1977
Nabi-HB
HBV Immuneglobulin
Nabi
Boca Raton, FL
FDA Approved
1999
Hepa Gam B
HBV Immuneglobulin
Cangene
Canada
FDA Approved 2006