Hepatitis B is a major public health problems worldwide.
Approximately 2 billion people (one third of the world population) serological markers indicating the existence of an old infection (and healed) or chronic infection (persistent) by the hepatitis B virus (HBV), and approximately 350 million people have chronic HBV infection. Morbidity and mortality from hepatitis B are less due to acute hepatitis, fulminant rarely (less than 1% of symptomatic patients) to chronic infection that can be responsible for chronic liver disease occurring in 20% to 25% of cases to cirrhosis with the risk of fatal complication (severe liver failure or primary liver cancer) responsible for over one million deaths per year worldwide. Primary liver cancer (hepatocellular carcinoma) is one of the most common cancers worldwide and HBV is responsible for 75% of these cancers.
MODE OF TRANSMISSION IN THE WORLD:
Infectiousness of HBV is related to its presence in biological fluids of infected individuals: blood, saliva, semen and vaginal secretions.
In subjects with chronic HBV infection, viremia is very variable but may in some cases be very high (up to 109 virions per ml of blood). There are four main modes of infection with HBV (i) sex, heterosexual or homosexual; (Ii) contact with blood or blood products during medical procedures (blood transfusion, surgery, hemodialysis, invasive procedures, acupuncture, dental, etc …) or intravenous drug use or tattoos or piercing; (Iii) transmission from mother to child during childbirth; (Iv) the contacts in the family or in a community.
Transmission occurs rarely through saliva and often by sharing toilet articles or skin lesions. The relative importance of these different modes of transmission is extremely variable depending on geographical areas and is related to the prevalence of chronic HBV infection in the population.
In areas of high prevalence (8% to 20%) (Southeast Asia, sub-Saharan Africa, China and Amazon), contamination usually occurs at birth (vertical transmission) or in the first years of life (horizontal transmission). The risk is higher in children born to mothers with positive HBeAg: the incidence of infection varies from 70% to 90% during the first 6 months after birth. In children born to mothers with HBe antigen-negative, the incidence of infection varies from 40% to 70%.
In the intermediate prevalence areas (2% to 7%) (Central Asia, India, Central and South America, Middle East and South and East Europe), contamination occurs at all ages and according age, the transmission is vertical, horizontal in childhood or parenteral or sexual.
In areas of low prevalence (less than 2%) (Western and Northern Europe, North America, Australia), contamination occurs mostly in adulthood, mainly by sexual or parenteral route.
The HBV infection can lead to acute hepatitis more or less severe or fulminant, chronic hepatitis, more or less active with a higher or lower risk of progress to cirrhosis and hepatocellular carcinoma (HCC).
The proportion of symptomatic cases of acute hepatitis B increases with age whereas the risk of progression to chronic infection decreases (Fig. 1). Indeed, when it occurs at birth or in early childhood, the HBV infection leads generally asymptomatic acute hepatitis but is associated with a high risk (90% at birth to 30% to 4 years) of progression to chronic infection (source WHO-CDC). Conversely, when it takes place after 5 years, infection with HBV can drag symptomatic acute hepatitis (30% to 50% of cases) and is associated with a low risk of evolution towards a chronic infection (5% 10%). The fulminant hepatitis is rare (between 1% and 0.1% of symptomatic cases).
Knowing that chronic HBV infection is usually asymptomatic (to the stage of decompensated cirrhosis), this explains why most chronic HBV carriers are undiagnosed and therefore unsupported and untreated. Thus, the disease progresses silently and often is discovered late or fortuitously either cirrhosis during a first complication (jaundice and / or ascites due to liver failure often on the occasion of exacerbation of hepatitis, gastrointestinal bleeding by variceal CHC).
Chronic infection is defi ned by positive HBsAg persisting more than 6 months. Among the chronic HBV carriers, there are two situations: inactive patients with HBsAg (formerly designated by the terms “healthy carriers” or “asymptomatic carriers”) and patients with chronic hepatitis.
We distinguish these two situations by using two simple tests: the determination of transaminases (which reflects the existence of inflammatory lesions of the liver, or hepatitis) and the measurement of the viral load by the amount of HBV DNA present in the serum ( which reflects the degree of viral replication). In the case of an inactive chronic carrier, transaminases are normal and HBV DNA present in relatively small quantities (less than 100 000 copies per mL). This distinction is important because the prognosis is good in the first case with a low risk of liver damage development, especially of occurrence of cirrhosis and HCC; there is no indication for treatment. Conversely, in the second case, there is a high risk of developing progressive liver damage with the risk of cirrhosis and complications and HCC, the treatment may be indicated depending on the stage of chronic hepatitis.
Schematically, chronic hepatitis B is characterized by three phases (Fig. 2): a first phase called “immune tolerance” with high viral replication (large amount of detectable HBV DNA in serum) and a low level of chronic hepatitis (normal or low transaminases and liver histological lesions of necrosis and inflammation absent or minimal); a second phase called “immune response” with low viral replication moderate (moderate amount of HBV DNA in serum) and strong activity of chronic hepatitis (elevated transaminase levels and histological lesions marked);
– A third phase called “non-replicative” with low viral replication (small amount of HBV DNA) and the lack of activity of chronic hepatitis (normal transaminases and lack of histological activity lesions).
The first two phases have a very variable duration (from several months to decades) according to the date of infection and immune status. In case of perinatal infection, immune tolerance phase is prolonged and the transition to the “immune reaction” phase is infrequent and late. If contamination occurs in adulthood, the transition to the phase of “immune response” is more frequent and faster than the immune response is stronger with activity more pronounced chronic hepatitis. The transition from the second phase to the third phase is usually accompanied by a “HBe seroconversion hepatitis” with peak transaminases monitoring the negativity of the HBe antigen (HBeAg) and positivation of anti-HBe antibodies . This exacerbation of chronic hepatitis can be severe or fulminant.
The third phase is the status of “inactive carrier HBsAg” the patient remains positive HBsAg, HBeAg but is negative and anti-HBe positive serum HBV DNA with less than 100 000 copies per mL and normal transaminases. It is important to confirm the status of “real” inactive carrier by verifying the absence of clinical, biological or ultrasound suggestive of advanced liver fibrosis or cirrhosis. Indeed, advanced fibrosis or cirrhosis, was able to be in the phase of chronic active hepatitis, before the stage of inactive carrier. This distinction is important because the “real” inactive HBsAg carriers have an excellent prognosis with virtually no risk of complications (especially HCC), whereas the risk of complications is significant in “false” inactive carriers. If in doubt, a liver biopsy may be offered. In all cases, regular monitoring is recommended.
HBsAg disappears spontaneously and rarely late (incidence of approximately 1% per year).
In this case, the anti-HBs does not always appear (HBs seroconversion) and the subject can not keep that anti-HBc antibodies detectable. This corresponds to the healing of chronic hepatitis B although we know that it is not usually an eradication of HBV infection as HBV DNA can remain detectable in the liver or in serum, with sensitive methods.
In inactive HBsAg carriers, a relatively large proportion (about 20% to 30%) may have a reactivation of chronic hepatitis with increased viral replication (HBV DNA greater than 100 000 copies per mL) and higher transaminases, this reactivation is usually mild but can be severe or fulminant, especially if underlying cirrhosis) and reactivations may be prolonged or repeated.
HBeAg may remain negative, corresponding to the appearance of a negative HBeAg chronic active hepatitis due to HBV variant ( “mutant pre-C”) unable to express HBeAg.
The HBeAg negative chronic active hepatitis appears late in the natural history of the disease, which explains why the most often diagnosed in subjects with an old contamination and the proportion of suejts with this form of chronic hepatitis B is prevalent in areas where most of the patients were infected long ago (80% to 100% of the Mediterranean basin).
HBeAg negative chronic active hepatitis is characterized by a low rate of spontaneous remission lasting and severe changes (high risk of complications of cirrhosis and HCC). Note that in France, the proportion of patients with chronic HBeAg negative hepatitis is increasing: it was 20% 10 years ago and it now seems to be the order of 50%.
Prevention through universal vaccination has effectively reduced the incidence of cirrhosis and HCC and treatment of chronic hepatitis B could by delaying or preventing the onset of cirrhosis reduce the risk or prevent the occurrence of HCC.
Principles of Treatment:
The goal of treatment is to reduce HBV replication to reduce the activity of chronic hepatitis B and so prevent the progression of fibrosis (Box 1). Stopping the progression of fibrosis prevents the progression to cirrhosis and its complications, particularly HCC, which should logically lead to improved survival.
Response to treatment can be schematically divided into three phases. The first phase is characterized by a decrease in viral replication, as reflected by the decrease in viral load (HBV DNA); chronic hepatitis activity diminishes, fibrosis stabilized and may even regress, but the risk of reactivation persists. If the anti-viral effect is sufficient (decrease in viral load below 100,000 copies of DNA HBV mL) and if prolonged and accompanied by an effective immune response with clearance of infected hepatocytes, an HBeAg seroconversion can occur (negativity of HBeAg and appearance of anti-HBe) the risk of reactivation is so low. If viral replication is completely interrupted (undetectable HBV DNA in serum with a sensitive technique) HBeAg seroconversion is stable and can be observed HBsAg loss (with or without the appearance of anti-HBs) the activity of chronic hepatitis disappears and the risk of reactivation.
Box 1. Chronic hepatitis B treatment goals
• Inhibition of viral replication
• Reduced the histological activity
• Stopping the progression of fibrosis
• Prevention of cirrhosis
• Prevention of hepatocellular carcinoma
• Improved survival
• No viral eradication
Indication of treatment: interest of liver biopsy
The main factor to consider in the treatment indication is the severity of liver disease. This is best appreciated at present, by liver biopsy. This is part of the care of the patient. In assessing the degree of activity (necrosis lesions and inflammation) and fibrosis, it can appreciate the prognosis. In chronic hepatitis B (even more than in chronic hepatitis C), there is a poor correlation between serum transa activity and the degree of liver damage, especially in patients with HBeAg-negative chronic hepatitis. The limitations of liver biopsy are firstly the possibility of underestimating the damage due to sampling bias, and secondly its morbidity with pain, and the exceptional risk of severe complications (3 for 1000 with an estimated risk of death between 0 and 3 to 10 000).
An antiviral treatment is indicated in patients with moderate to severe fibrosis and / or moderate or severe activity.Thus, when using the Metavir, treatment is recommended in patients with a score of activity of at least A2 and / or a fibrosis score of at least F2. It is obvious that the patient’s age, general health, the existence of comorbidities, and the likelihood of response to treatment, must be taken into account.
In recent years, the treatment of chronic hepatitis B has actually increased due to the development of new antiviral molecules.
Today to treat patients with chronic hepatitis B, there are two different therapeutic strategies:
– The first is the use of a treatment of limited duration, and aims to achieve a sustained response after the end of treatment.
This is the strategy proposed with interferon has two mechanisms of action: an anti-viral effect and an immunomodulator effect;
– The second is based on the long-term administration of treatment to achieve a sustained response. This is the strategy used with nucleoside or nucleotide analogs that have only one mechanism of action: an antiviral effect which appears higher than that of interferon.
This strategy has two problems: the risk of developing resistance to the phenomenon of “escape” and the risk of rapid reactivation after stopping treatment.
The arrival of new antiviral molecule how entecavir, telbivudine and tenofovir is a breakthrough for the treatment of chronic hepatitis B because they seem to show an anti-HBV activity bigger and / or better resistance profile.
However, the long-term evaluation of the exhaust to these treatments has yet to be determined.
The occurrence of viral resistance is one of the major problems of long-term treatment, it is urgent to assess treatment strategies for antiviral combinations immediately or very early addition of another antiviral when the B viral load does not decrease, to prevent the onset of clinical resistance. From a virologic point of view, the best choice would be the antiviral novo combination did not cross resistant.
But this obviously has to be evaluated in clinical trials to determine the best therapeutic strategy in terms of antiviral efficacy and cost.