Chronic hepatitis B

Chronic hepatitis B is not always preceded by a recognizable acute form of hepatitis B. However, chronicization sometimes occurs immediately after an acute episode. In other cases, despite the sudden onset similar to the acute disease, chronic hepatitis is already present. In approximately 10% of adult patients with acute hepatitis B, HBsAg does not disappear from the serum within 12 weeks, and they become chronic carriers. Newborns with hepatitis B become chronic carriers in 90% of cases.

The main routes of transmission of the hepatitis B virus are parenteral (various injections, especially intravenous, transfusions of blood, its substitutes and components), sexual and from mother to fetus.

Acute viral hepatitis B manifests itself in anicteric, icteric or fulminant forms. After resolution of acute viral hepatitis B, HBsAg disappears from the serum within 4-6 weeks from the onset of the disease.

The transition of the process to chronic viral hepatitis is accompanied by HBsAgemia. Chronic viral hepatitis B (CHVH-B) can evolve into liver cirrhosis (LC), against which liver cancer can develop.

Chronic hepatitis B is an outcome of acute hepatitis B caused by persistence of the hepatitis B virus in the body. Chronic hepatitis B is usually divided into 2 main variants based on infection with the "wild" (HBe-positive chronic B) or mutant HBV variant (HBe-negative anti-HBe-positive viral hepatitis B - pre-core/core-promoter mutant variants). Each of these variants has an uneven distribution in different regions, is distinguished by a certain biochemical and replication profile of HBV activity and response to treatment with both interferon and nucleoside analogues. In the early stages of chronic hepatitis B, a patient may have both the "wild" type of HBV and the HBeAg-negative mutant strain. As the duration of infection increases, the "wild" strain of the virus evolves under the influence of the body's immune system and the percentage of mutant forms gradually begins to prevail. and subsequently the mutant variant displaces the "wild" type of the virus. In this regard, it is believed that HBeAg-negative chronic viral hepatitis B is a phase of the natural course of chronic HBV infection, and not a separate nosological form. It is also proposed to distinguish chronic hepatitis B with high and low replicative activity. The use of PCR made it possible to identify patients with low viremia and establish a relationship between a constantly high viral load and unfavorable disease outcomes - liver cirrhosis and hepatocellular carcinoma. A constantly high viral load is currently proposed to be considered as one of the criteria for prescribing antiviral therapy to a patient with chronic HBV infection.

However, only the results of a morphological study of the liver can diagnose hepatitis of a particular activity and stage based on the assessment of such indicators as the severity of inflammation and fibrosis. Thus, each patient with a detectable level of HBV should be considered as a patient with chronic hepatitis B, and the morphologically diagnosed degree of hepatitis activity and stage of fibrosis in combination with the dynamics of ALT activity and viral load level allows the clinician to make an accurate diagnosis and decide on the appropriateness or inappropriateness of starting antiviral therapy at this point in time.

The criteria for asymptomatic HBV carriage are a combination of a number of features: persistence of HBsAg for 6 months or more in the absence of serological markers of HBV replication (HBeAg, anti-HBcIgM), normal liver transaminase levels, absence of histological changes in the liver or a picture of chronic hepatitis with minimal necroinflammatory activity [histological activity index (HAI) 0-4] and HBV DNA level <105 ^copies /ml.

In terms of liver morphology, "inactive HBsAg carriage" can be defined as persistent HBV infection without pronounced inflammatory-necrotic process in the liver and fibrosis. Despite the generally favorable prognosis for most of these patients, the status of "inactive virus carrier" cannot be considered a permanent condition, since in patients who were in the phase of "inactive HBsAg carriage", reactivation of HBV infection and repeated development of pronounced inflammatory-necrotic process in the liver are possible. In this category of people, the formation of cirrhosis and development of hepatocellular carcinoma is also possible, which justifies the need for lifelong dynamic monitoring of this group of patients. At the same time, spontaneous elimination of HBsAg occurs annually in 0.5% of "inactive HBsAg carriers", and anti-HBs are subsequently registered in the blood of most of these patients.

Chronic HBV infection is characterized by a wide range of clinical variants of the course and outcomes of the disease. There are 4 phases of the natural course of chronic HBV infection depending on the presence of HBeAg in the patient's blood, the degree of increase in ALT and the level of viremia: the phase of immune tolerance, the phase of immune clearance, the phase of immune control and the phase of reactivation.

Independent risk factors for the development of hepatocellular carcinoma are male gender of the patient, smoking, alcohol abuse, elevated ALT levels, the presence of HBeAg, and persistently high levels of HBV DNA (>10 ⁵ copies/ml, or 20,000 IU).

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Chronic HBe-positive hepatitis B

Chronic hepatitis caused by HBV infection caused by the "wild" type of the HBV virus is widespread mainly in Europe and North America, but also occurs in regions with a high level of HBsAg carriage. It is characterized by constantly increased activity of liver transferases and high levels of viremia. Depending on the age at the time of infection, this variant of viral hepatitis B proceeds differently. In children infected in utero or perinatally up to 18-20 years of age, a phase of immune tolerance is observed - normal ALT levels, no clinical signs of the disease, minimal histological changes in the liver, but the presence of a high level of HBV DNA replication and HBeAgemia. Upon reaching adulthood, spontaneous clearance of HBeAg occurs in some of these patients. Immune clearance of HBeAg may be asymptomatic or accompanied by clinical signs of acute hepatitis B. Subsequently, remission of the disease may occur and transition to the phase of chronic HBV infection with an undetectable level of HBV DNA against the background of persistent HBsAgemia.

However, a significant proportion of individuals infected in utero or perinatally subsequently develop HBeAg-positive chronic viral hepatitis B with elevated ALT levels in the blood serum, HBeAg/anti-HBe seroconversion never occurs, and progressive hepatitis develops with a possible outcome in liver cirrhosis. If infection occurs in childhood, most HB Ag-positive children have elevated ALT levels in the blood serum, and HBeAg seroconversion to anti-HBe usually occurs at the age of 13-16 years. In patients infected in adulthood (typical for Europe and North America), the disease is characterized by the presence of clinical symptoms, persistently elevated ALT activity, the presence of HBeAg and HBV DNA in the blood, and a histological picture of chronic hepatitis. Among patients of all age groups with HBV infection acquired in childhood or adulthood, the rate of spontaneous elimination of HBeAg from the body ranges from 8 to 12% per year. The rate of spontaneous clearance of HBsAg is 0.5-2% per year. Overall, 70-80% of patients with chronic HBV infection become asymptomatic carriers over time, and 20-50% of patients with chronic HBV infection develop progressive disease and may develop liver cirrhosis and hepatocellular carcinoma within 10-50 years.

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Chronic HBeAg-negative hepatitis B

Chronic hepatitis caused by a mutant variant of HBV is characterized by the presence of anti-HBe in the blood, the absence of HBeAg, and lower concentrations of HBV compared to HBcAg-positive viral nepatitis B. Chronic HBeAg-negative viral hepatitis B is the most common form in southern Europe and Asia, in northern Europe and the USA it occurs in 10-40% of persons with chronic HBV infection. In the Mediterranean region, infection with this variant of viral hepatitis B usually occurs in childhood, is asymptomatic for 3-4 decades, leading to liver cirrhosis on average by the age of 45. The course of HBeAg-negative chronic viral hepatitis B is characterized by either persistently elevated AST and ALT activity (3-4 times higher than normal), which is observed in 3-40% of patients, or fluctuating AST and ALT activity (45-65%) and rare long-term spontaneous remissions (6-15%) of cases. The transition of HBeAg-negative chronic hepatitis B to an inactive non-replicative phase of virus carriage or spontaneous recovery is almost never observed.

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Treatment of chronic hepatitis B

The constituent components of the concept of "response to treatment" are now defined and standardized.

• Biochemical response (meaning that the patient had an elevated ALT level before treatment) - normalization of ALT levels during therapy.
• Histological response - improvement in histological activity indices by 2 points (according to the IGA scale - histological activity index - 0-18 points) without worsening fibrosis indices or with improvement in this index when comparing liver biopsy results before and after the end of treatment.
• Virological response - a decrease in the level of viral load in the blood to an undetectable level (depending on the sensitivity of the method and test system used) and the disappearance of HBeAg in a patient with the presence of HBeAg in the blood before the start of treatment.
• Complete response - presence of biochemical and virological response criteria and disappearance of HBeAg.

The following concepts are also distinguished: response to treatment during therapy, persistent response during therapy (throughout the course), response at the end of therapy (at the end of the planned course of treatment), sustained response after the end of therapy at the sixth month, and sustained response after the end of therapy at the 12th month.

The following terms are also used to describe exacerbations:

• virological breakthrough - the appearance or increase in the HBV DNA viral load by more than 1xIg10 (tenfold increase) after achieving a virological response against the background of antiviral therapy;
• virological breakthrough (rebound) - an increase in the HBV DNA viral load level of more than 20,000 IU/ml or an increase in the HBV DNA viral load level greater than that recorded before treatment while continuing antiviral therapy. The duration of treatment, including after achieving the final treatment goal (consolidation of the result, consolidation therapy), depends on the type of chronic viral hepatitis B and the type of drug used for treatment.

Treatment of chronic hepatitis B is carried out with interferon preparations or nucleoside analogues.

In Ukraine, 2 types of interferon drugs (standard interferon alpha, pegylated interferon alpha-2) and 3 nucleoside analogues are registered for the treatment of chronic hepatitis B: lamivudine, entecavir and telbivudine.

Interferon treatment

Treatment with standard interferon is recommended for patients with chronic hepatitis B with a low viral load and elevated serum aminotransferase levels (more than 2 normal values), since treatment is ineffective with a high viral load and normal ALT levels. Treatment with standard interferon in patients with HBe-positive chronic hepatitis B allows achieving HBeAg/anti-HBe seroconversion in 18-20% of patients, a stable biochemical response is recorded in 23-25% of patients, and a virological response to treatment in 37% of patients. In 8% of patients who responded to treatment, a complete response to therapy (disappearance of HBsAg) can be achieved. In HBeg-negative chronic hepatitis B, despite a higher percentage of patients responding to therapy, during treatment (60-70% virological and biochemical response), a stable response is recorded only in 20% of patients, and in most cases an exacerbation is recorded after discontinuation of therapy. Treatment is carried out for 16 weeks at a dose of 5 million IU daily or 10 million IU three times a week subcutaneously.

Pegylated interferon alpha-2 has the same indications as standard interferon, but the treatment efficacy is higher in terms of seroconversion (27-32%). Treatment is administered for 48 weeks at a dose of 180 mcg once a week subcutaneously.

Treatment with lamivudine

In patients with HBe-positive chronic hepatitis B, HBeAg/anti-HBe seroconversion is achieved in 16-18% of cases when using 100 mg of the drug orally once a day for a year and in 27% of cases when using this drug for 2 years. Improvement in the histological picture of the liver was recorded regardless of seroconversion in approximately 50% of patients. In patients with HBeAg-negative chronic hepatitis B, during treatment with lamivudine for 48-52 weeks, virological and biochemical response is noted in 70% of patients, but after discontinuation of therapy, a return to viremia and an increase in ALT activity are recorded in 90% of patients. Improvement in the histological picture of the liver is also recorded in more than half of the patients after a one-year course of therapy. A complete virological response, as a rule, is not recorded. Combination therapy with interferon and lamivudine showed no advantage over monotherapy with pegylated interferons.

A significant drawback of lamivudine therapy is the high probability of developing resistance to the drug (17-30% after 2 years) due to virus mutation. Treatment can be stopped 6 months after achieving seroconversion (6 months of consolidated therapy). Treatment is carried out at a dose of 100 mg daily per os. Lamivudine is characterized by a good safety profile.

Treatment with entecavir

Entecavir most effectively and rapidly suppresses HBV replication within 48 weeks of treatment (67 and 90% efficiency in HBe-positive and HBe-negative chronic hepatitis B, respectively) and with more than 70% efficiency in forming biochemical remission in both forms of chronic hepatitis B. The effect of rapid reduction of viral load level is registered including in patients with initially high replicative activity. Histological response is registered in 70-72% of patients with HBe-positive and HBe-negative chronic hepatitis B after 48 weeks of therapy. The frequency of HBe/anti-HBe seroconversion after one year of therapy does not exceed 21%, but increases with increasing duration of treatment (in 11% of patients who continued treatment for another year). A significant advantage of entecavir is the low probability of developing resistance to treatment (less than 1% after 5 years of therapy). The optimal duration of treatment has not been determined. Entecavir is administered at a dose of 0.5 mg daily orally. The duration of consolidation therapy for HBe-positive hepatitis B virus infection is recommended for at least 6 months. For patients with developed resistance or refractoriness to lamivudine, treatment is administered at a dose of 1.0 mg daily for at least 6 months. Entecavir has a good safety profile.

Treatment with telbivudine

Telbivudine is characterized by effective suppression of HBV replication within 48 weeks of treatment (60 and 88% effectiveness in HBe-positive and HBe-negative chronic hepatitis B, respectively, and with more than 70% effectiveness in forming biochemical remission in both forms of chronic viral hepatitis B). Histological response is recorded in 65-67% of patients with HBe-positive and HBe-negative chronic hepatitis B. The frequency of HBe, anti-HBe seroconversion after one year of therapy does not exceed 23%. The risk of developing resistance to telbivudine) is significantly lower than to lamivudine, but higher than with entecavir treatment (8-17% after 2 years of therapy). Telbivudine is characterized by a good safety profile. Treatment with telbivudine is carried out at a dose of 600 mg daily per os. The duration of consolidation therapy for HBe-positive viral hepatitis B is recommended for at least 6 months.

Patients with chronic hepatitis B are able to work. It is recommended to be observed by an infectious diseases specialist; a polyclinic, a specialist in the hepatology center. In case of enzymatic: exacerbation of the disease, it is recommended to leave work, with an increase in ALT activity of more than 10 norms, hospitalization is recommended. Patients with liver cirrhosis have limited ability to work in the absence of decompensation and are incapacitated in the presence of symptoms of decompensation of the disease.

Entecavir (Baraclude) is a guanosine nucleoside analogue with potent and selective activity against hepatitis B virus DNA polymerase. It rapidly and strongly inhibits viral replication to undetectable levels and is also characterized by a low level of resistance.

Indications for use. The drug is indicated for the treatment of adult patients with chronic hepatitis B, accompanied by compensated liver function, signs of active viral replication and liver inflammation.

Currently, the clinical efficacy of entecavir has been established in six phase II-III clinical trials, and another twelve phase II-IV trials are planned to study the efficacy of entecavir in certain categories of patients, as well as to determine comparative efficacy with other antiviral drugs. It should be noted that most clinical trials of entecavir were conducted with the participation of Russian research centers.

Based on the results of registrational clinical studies, which involved a total of approximately 1,700 patients with chronic hepatitis B, entecavir demonstrated the maximum ability to suppress hepatitis B virus replication and a minimal risk of resistance development, especially in patients who had not previously received nucleoside analogues.

Baraclude is well tolerated, has a high safety profile, like lamivudine, and is easy to use (one tablet per day). Based on this, the drug is included in modern recommendations for the treatment of patients with chronic hepatitis B as a first-line drug (e.g., recommendations of the American Association for the Study of Liver Diseases, 2007; recommendations of the European Association for Liver Diseases, 2008).

Method of administration and dosage. Baraclude should be taken orally on an empty stomach (i.e., at least 2 hours after a meal and no later than 2 hours before the next meal). The recommended dose of Baraclude is 0.5 mg once daily. In patients refractory to lamivudine (i.e., patients with a history of hepatitis B virus viremia that persists during lamivudine therapy or patients with confirmed resistance to lamivudine), the recommended dose is 1 mg of entecavir once daily.