Hepatitis B


Hepatitis B
Hepatitis B is a viral liver infection with hepatitis B.

In 1963, Baruch S. Blumberg, a geneticist working at the National Institute of Health, the USA, highlighted an unusual reaction between the serum of individuals polytransfusés and an aboriginal Australian. It is thought to have discovered a new lipoprotein in the Aboriginal population that designation under the name of the antigen "Australia".

In 1967, after several studies, Blumberg published an article showing the relationship between this antigen and hepatitis. The name antigen HBs was thereafter required to designate this antigen. Blumberg in 1976 received the Nobel Prize for Medicine for discovering this antigen and for the design of the first generation of vaccines against hepatitis.

Virus hepatitis B
The hepatitis B virus (HBV) is a DNA virus belonging to the family hepadnaviridae. HBV, as the virus Hepatitis C virus (HCV), can survive the drying unlike HIV. HBV is still infectious after seven days of drying, while HCV infection is left for a few hours. The reservoir of hepatitis B is humane and high contagiousness of the virus, 50 to 100 times higher than that of HIV. In the blood of a patient into an active phase of viral synthesis can be observed 3 types of structures:

1. spheres of 20nm in diameter, consisting of antigens HBs, non-infectious
2. tubular of 20nm in diameter and 200 to 700nm long, which are a stack of spheres, non-infectious
3. "particles Dane" 42nm in diameter, corresponding to complete viral particles and infectious, consisting of a core (nucléocapside containing a double-stranded DNA associated with a ADNpol) and an envelope.

An issue of Public Health
The hepatitis B virus causes hepatitis most serious. There are several forms of hepatitis B. The acute hepatitis B is uncommon, it is characterized by a pre-ictérique syndrome (yellowing of the skin and mucous membranes by failure of a liver enzyme). The bulk of hepatitis B are asymptomatic and recover spontaneously. But they can develop into chronic hepatitis (10% of cases).

The transition to chronicity is inversely proportional to the age at which infection occurs. The major risk is when infection occurs before age 5 (90% of children infected before the age of one year and 30% to 50% of children infected between one year and four years, will develop a chronic infection). In less than 1% of cases, acute hepatitis B may also evolve into a so-called fulminant hepatitis. This form is lethal in 90% of cases.

The World Health Organization (WHO) estimates that 2 billion people who are or have been infected, of whom 370 to 400 million are chronic carriers. Hepatitis B causes the death of one to two million people per year. Indeed, the high contagiousness of the virus is linked to its presence in the majority of fluids: blood, semen, vaginal secretions and even a small proportion in the saliva.

HBV has risk factors in common with HIV, HCV and VHD (Virus Hepatitis C and D).

Hepatitis B is both:

* A contagious disease
* Sexually Transmitted Infection
* Illness
* A disease associated with AIDS, drug addiction and alcoholism
* A congenital disease and family

Duration incubation
The incubation period varies from 45 to 180 days, but the average is 60 to 90 days, the duration may increase or decrease depending on the severity of infection.

Modes of contamination

* Transmission through blood transfusions or blood products (rare since the exclusion of donors HBsAg + Ac and anti-HBc +).
* Iatrogenic transmission equipment by non-sterilized (surgery, invasive exploration, acupuncture, mesotherapy, dental), the changing rules of sterilization and the widespread use of single-use equipment can be avoided.
* Transmission through intravenous drug abuse, tattooing, piercing.
* Sexual transmission. (Condoms are here a good way of protection).
* Transmission from mother to child (vertical transmission); screening for HBsAg during pregnancy can sérovaccination the newborn (in the first 48 hours).

Various levels of seroprevalence of HBV are explained by the socio-economic and vaccination: it allows low prevalence, such as Reunion Island (or only 0.7% of the population is affected), then that 'Black Africa it often exceeds 15% (ex: Madagascar, the prevalence is 16%, due to frequent MTCT and the low use of condoms, which promotes a frequent sexual transmission).

In France, in 2003-2004, the number of persons with chronic antigen HBs (indicating the presence of virus circulating in the blood) was estimated at between approximately 180 000 and 380 000.

And yet, since 1982, we can avoid infection with a vaccine. The vaccine against hepatitis B does not heal the chronic carriers, but it is effective from 90 to 95% to prevent the emergence of this state. The HBV vaccine is also the first vaccine against cancer and the first vaccine against a sexually transmitted infection.

Thanks to the actions of the WHO, in recent years, many countries have added the vaccine against hepatitis B into their national immunization programme. However, in poor countries, where endemic areas are most important, the cost of this vaccination is a problem. The WHO has launched in 1999 the creation of the Global Alliance for Vaccines and Immunization (GAVI), one of whose aim is to vaccinate as many children as possible in order to protect against some diseases for which there is a vaccine, such as hepatitis B.

Vaccination is mandatory for personal health since January 18, 1991. This prevention is essential because the risk for these professionals is 5 to 8 times higher than the general population.

Nature of vaccine
The vaccine against hepatitis B is made up of antigen HBs. There are two types of vaccines available. One is prepared from HBs antigens purified from plasma from healthy carriers. The second is prepared by genetic engineering is a recombinant protein produced by inserting the gene coding for HBV protein envelope viral antibodies (HBs) in yeast cells or hamster ovary cells. A rate of anti-HBs protectors (10 mIU / ml) is obtained 2 to 3 months after the vaccination. Only vaccines derived from genetic engineering are allowed in France.

Risks to the vaccination?
Numerous studies on millions of subjects have documented the safety of anti-HBV vaccine. The reactions after vaccination, most commonly seen are minor skin reactions at the injection site or muscle and joint pain transients. A little over a hundred central demyelinating attacks were reported between 1989 and 1995 to about 17.5 million people vaccinated in France, less than 0.6 ‰ of them. Given the sex and age of vaccinees, frequencies sclerosis slabs observed are not greater than those expected in the general population.

In February 2001, following two studies, published in the journal "New England Journal of Medicine": Vaccinations and the Risk of Relapse in Multiple Sclerosis (C. Confavreux et al.) And Hepatitis B Vaccination and the Risk of Multiple Sclerosis (A. Ascherio et al.) Disculpaient the vaccine of hepatitis B, accused can lead to the emergence of cases of multiple sclerosis.

In 2004, The statistical study, which had relaunched the debate on the hepatitis B vaccine in 2004 was made from medical records of more than 3 million Britons among which 713 cases of MS had been identified. These data were processed by Hernan Boston who sat on a strong reputation in medical statistics. It eliminated 550 cases especially for the reason that these people had not been recorded using a software defined at least 3 years before symptoms appear. This severe restriction can be understood in order to avoid controversy over the timing of the emergence of such symptoms. It was therefore upheld only 163 cases of multiple sclerosis on 713 of which 11 had been vaccinated less than 3 years before the identification of the disease.

In these 163 cases, it was decided to add 1 604 witnesses obtained by lot from among persons not sick and selected for the study. Among them, there were 39 people vaccinated and hence 1 565 unvaccinated, or 2.43% of vaccinated among the witnesses, without doubt proportion similar to that of all the data, the sample was obtained randomly and being of sufficient size. The most long and tedious for such work lies in collecting the necessary data and sorting it be done.

With these data Hernan found that the risk of MS within 3 years following vaccination was 3.1 times greater in the absence of vaccination. He probably wanted to do too. The main objective was first whether the risk was greater, not measure it. It was possible to qualitatively without having to embark on values quantified risk.

Failure of vaccination

The non-or low responders are:

* The elderly: the effectiveness of the vaccine decreases with age (this is notable from 40 years)
* HIV-positive individuals: people immunocompromised
* Subjects suffering from chronic renal failure
* Individuals alcoholics
* Persons HLA DR3 or DR7 + +: the answer is not due to failures at T-helper cells.

You should know that smoking and obesity are also factors that promote non-response to the vaccine.

Improving the anti-HBV vaccination for non-or low responders
A vaccine based surface antigens PréS2 and S produced by the yeast induces securities protective antibodies after 2 injections in 80 to 91% of subjects who had not previously been protected with a vaccine "conventional". Another vaccine containing antigens PréS1, PréS2 and S (vaccine Hepa-Gene-3) was tested on subjects suffering from renal failure and not answering the classic vaccine. After a year, 70% of them had titles of protective antibodies. Other approaches exist and are being searched as vaccines based on DNA plasmid.

Towards a DNA vaccine?
This type of vaccine is based on a direct injection of naked DNA (without protein or lipid vector associate) by intramuscular or intradermal. DNA is captured by cells and the viral genome is expressed by them. The corresponding protein is then synthesized by the cells. One of the major advantages of such a vaccine is the long-term expression of the antigen. This could provide a more sustained immune response and more durable and therefore can delete injections reminder. Another advantage is the synthesis in vivo antibody, and its presentation in the form of antigenic peptides associated with MHC molecules Class I, to induce a cytotoxic response mediated by CD8 + T lymphocytes.

The injection of DNA in humans raises questions about the future of this DNA and injected the possibility of its integration into a host cell chromosome. If this were the case, a insertional mutagenesis would be possible. The choice of injection of such a vaccine at muscle cells is not arbitrary. Indeed, muscle cells are post-mitotic and thus the absence of divisions helps little integrations.

Infection acute
The acute hepatitis B is uncommon, it is characterized by a pre-ictérique syndrome (yellowing of the skin and mucous membranes by failure of a liver enzyme). It occurs after an incubation period of 2 to 3 months. The acute hepatitis B is presented in different forms:

* An asymptomatic form or anicteric: 70% of cases.
* A form symptomatic: 30% of cases. The subjects are suffering from jaundice, they have dark urine, faeces or discoloured normal ...
* A fulminating: 1 to 2% of cases. Patients have prothrombin time <45% and neurological signs of liver failure. This form is lethal in 90% of cases.

Infection Chronic
The cytopathic effect of the virus itself is unimportant. The liver damage are, in reality, due to a combination of immunological reactions mediated primarily cell. The destruction of liver cells by the immune system leads to the release of liver enzymes, as Alanine Amino Transférase (ALAT) and Aspartate Amino Transférase (ASAT). The increase in serum transaminases is therefore easily detectable and sign a hepatic cytolysis important. In the case of a chronic active hepatitis, the immune response is directed against hepatocytes where the viral replication and expressing their surface antigens HBc and HBe. The absence of absolute effectiveness of cytotoxic thymocytes can be linked:

* Is a deficient T lymphocytes helpers specific antigen HBc.
* Either too weak an expression of MHC molecules Class I.
* Is an expression of insufficient membrane antigen HBc as masked by the anti-HBc.

The chronic infection is defined by the persistence of the antigen HBs for more than 6 months after the viral infection. It is most often asymptomatic. The most common symptoms are asthenia, which may be due to many causes. Thus, HBV infection is often discovered late and so fortuitous. For example, during a blood donation, pregnancy or a blood test. The chronic HBV is confirmed by the absence of anti-HBc. Chronic hepatitis is histologically characterized by liver damage involving hepatocyte necrosis, fibrosis and inflammatory infiltration.

Traditionally, chronic infection with HBV wild moves in 3 phases.

First phase: multiplication intense HBV
On the serology, this phase is characterized by the presence of viral replication markers in the serum, namely DNA viruses and HBe antigen. This phase lasts from one to several years.

Second phase: phase HBe seroconversion
This is the phase during which the immune response intensifies. There are declining, then disappearing in serum markers of viral replication, first DNA then HBe antigen. The activity of the liver disease is currently very strong and can lead to severe injuries: extensive fibrosis or cirrhosis. Several attempts seroconversion, finally abortion, are remarkable during this phase.

Third phase
It does not occur in all cases. It is characterized by the absence of markers replication and the presence of anti-HBe. However, although DNA is no longer detectable in the serum by conventional hybridization techniques, it remains a low multiplication detectable by PCR. During this phase, the activity of the liver disease is low, even zero. But it can happen again reactivation during this phase.

These 3 phases have in common the presence of the antigen in the serum HBs.

Evolution to cirrhosis
Cirrhosis represents approximately 20% of the natural evolution of chronic hepatitis. A high consumption of alcohol, more than 20 grams per day for women and more than 30 grams per day for men, is a major risk factor in the development of cirrhosis.

Evolution towards HCC
The hepatitis B virus is a potent carcinogen. The risk of developing liver cancer is multiplied by 100 in carriers of hepatitis B. It said 530 000 cases of hepatocellular carcinoma per year, of which 82% are caused by viral hepatitis, and two thirds of which are hepatitis B.

After vaccination against HBV, it was shown a decrease in the frequency of occurrence of hepatocellular carcinoma.

Several mechanisms, direct and indirect, have been suggested for the induction of hépatocarcinogénèse with HBV. The mechanisms include indirect damage such as necro-inflammation and fibrosis, induced by a liver infection with HBV.

The HBV genome does not contain an oncogene. The integration of the viral genome may activate the expression of cellular oncogenes controlling cell multiplication by insertional mutagenesis. In liver tumors associated with HBV, the activation of certain growth factors could be shown. The deregulation of factors tumor suppressor has also been identified in some cases. For example, a point mutation in the p53 gene lead to a mutated protein responsible for the proliferation of hepatocytes. An integration of the region X of the viral genome of HBV genome in the cell may also be responsible for mechanisms of cell transformation by transactivation of genes.

The severity of infection with HBV is mainly linked to the possible evolution of chronic hepatitis to cirrhosis and liver cancer. The diagnosis is largely based on serology.

Diagnostic Clinic
Clinical examination, in a chronic carriers of hepatitis B, is normal, if not the existence of a moderate fatigue in some cases.

In the case of a chronic active hepatitis, some symptoms may occur. They are a small fever, liver enlargement and / or the spleen (hepatomegaly and / or splenomegaly), pushed ictériques (symptoms of flu-like allure: headache, joint pain and muscle, but also nausea, diarrhea , Dark urine) and extra-hepatic events, due to deposits of immune complexes (eg perished Nodosa arteritis).

In patients with cirrhosis, one can find clinical signs of hepatocellular failure and portal hypertension.

Diagnostic virological
The specific diagnosis of viral hepatitis HBV based on the detection of certain serum markers:

* Antibodies: IgG anti-HBs, anti-HBe IgG, IgM and IgG anti-HBc
* Antigens: HBs and HBe

The detection of antigens is via tests RIA (Radio Immuno Assay). The search for serum HBV DNA is made by molecular techniques hybridizations (PCR).

The treatment is intended to affect the natural history of chronic hepatitis B by shortening its duration. It allows in some cases to prevent progression to cirrhosis and thus avoid the occurrence of hepatocellular carcinoma. The treatment stops the replication of HBV and thus advance the timing of HBs seroconversion.

Nucleoside and nucleotide analogues
The nucleoside analogs, or nucleotide, are administered in the form of prodrugs. The cellular kinases go phosphoryler upon their entry into the cell and thus form the active ingredient. Therefore, the nucleoside analogs compete with the natural substrates of the polymerase. If the latter incorporates a similar antiviral, elongation of the DNA chain during synthesis is blocked. The drug does not have the chemical structure to form a liaison with the nucleotide phosphodiester following (lack of a 3-OH).

There is a greater affinity for these similar antiviral drugs for viral DNA polymerase for cellular polymerase, which has not yet explained. However, selectivity is not absolute and side effects caused by these drugs can be partially explained by their action on cellular enzymes.

Research on HIV were profiteuses for anti-HBV. Indeed, several molecules that inhibit reverse transcriptase HIV are also active on the HBV polymerase. The first of these molecules, allowed France to treat against chronic infection with HBV, was the lamiduvine.

Lamivudine is an L-nucleoside analogue of the didésoxycytidine. It inhibits HBV polymerase incorporation by competitive with the didésoxycytidine. During treatment with lamivudine, a daily administration of 100 mg, serum HBV DNA drops considerably, until it became undetectable in some cases. However, upon cessation of treatment, the rate quickly returned to its pre therapeutic values. The problem lies in the mode of action of this molecule. Indeed, lamivudine inhibits polymerase but no action on initial DNA superenroulé and maintaining the pool of this DNA in hepatocytes.

This compound, adenine arabinoside monophosphate, is an analogue of adenosine and also inhibits the activity of the HBV DNA polymerase. But this compound is somewhat selective viral DNA polymerase, it has proved very toxic.

The famciclovir is the prodrug of penciclovir. The penciclovir is a nucleoside analogue of the désoxyguanosine. After oral absorption, famciclovir is transformed into penciclovir by liver and digestive enzymes. The famciclovir is mainly used in the fight against the herpes virus (HSV-1 and HSV-2), zoster (VZV) and the Epstein-Barr (EBV).

Adefovir dipivoxil
Adefovir, or PMEA (9 - (2-phosphonylméthoxyéthyl) adenine), belongs to a family of antiviral drugs recently, phosphonates nucleotide acyclic. The active form di-phosphorylated adefovir inhibits virus DNA and some retroviruses. The PMEApp, the active metabolite of PMEA, is a competitive inhibitor of deoxy-ATP natural substrate of the HBV polymerase. The PMEApp also inhibits the polymerases of HBV mutants resistant to lamiduvine or famciclovir.

The entécavir is an analogue of the cyclopentylguanosine and specifically inhibits polymerase HBV. This molecule has an inhibitory action on both the synthesis of L-strand (inhibition of reverse transcriptase activity) and on the strand S + (inhibition of DNA polymerase activity DNA-dependent). Its effect on polymerases cell is low.

It is an L-nucleoside analogue thymidine, which specifically inhibits the activity of the HBV polymerase. The first clinical trials show greater effectiveness of this molecule compared to the lamiduvine on the decline in viral load. Like entécavir, the drug blocks the synthesis of the two strands of viral DNA.

Tenofovir is a molecule close to adefovir is an analogue of the didésoxy-adenosine. It inhibits polymerase HBV and HIV, even in the resistant forms lamiduvine. The effectiveness of tenofovir has been shown in patients co-infected HIV-HBV.

Other molecules are under clinical evaluation will include emtricitabine (structure near the lamiduvine), clévudine (similar pyrimidine), elvucitabine and thymosine.

Read also Hepatitis A