Chronic hepatitis B: treatment

The patient should be examined for contagiousness. This is especially important if it is HBeAg-positive. Separately, the family and the sexual partner of the patient should be examined for HBsAg and anti-HBc, in case of negative results of the research they are recommended to vaccinate against hepatitis B.

Bed rest is not required. The physical load must be dosed. Power is normal. Alcohol intake should be avoided, as this improves the prognosis for HBsAg carriers. However, 1-2 glasses of wine or beer per day are acceptable if it is part of the patient's lifestyle.

Most patients with chronic hepatitis B lead a normal life. Psychological support is needed to prevent "withdrawal to illness".

It is necessary to find out how sick the patient is, how severe the symptoms or liver failure are. Puncture liver biopsy usually precedes the appointment of therapy. The presence of severe chronic hepatitis with cirrhosis, obviously, makes it necessary to resolve the issue of treatment as a matter of urgency. The approach to patients with high contagiousness in the replicative phase and patients with low contagiosity in the phase of virus integration is different.

[1], [2], [3], [4], [5], [6], [7],

HBeAg- and HBV-DNA positive patients

Treatment of chronic viral hepatitis B is aimed at suppressing the contagiousness, destroying the virus, preventing the development of liver cirrhosis and, possibly, hepatocellular carcinoma. No method of treatment does not relieve the patient of the virus, nevertheless successful antiviral therapy allows to reduce the severity of the process and the necrosis of hepatocytes caused by it.

Interferon-a

Consider the possibility of using interferon-a (IFN-a), both lymphoblastoid and recombinant. Interferon improves the expression of HLA class I proteins and can increase the activity of interleukin-2 (IL-2) and, thus, destroy the affected hepatocytes.

Interferon in the treatment of HBeAg-positive patients: meta-analysis (15 studies)

	Disappearance,%
	HBsAg	HBeAg
When treating IFN	7.8	33
Spontaneous	1.8	12

Interferon-a is used only in patients with replicating HBV, which is established by positive tests for HBeAg and HBV-DNA and, if necessary, HBeAg in hepatocytes.

According to the scheme adopted in the United States, 5 million units are administered daily or 10 million units 3 times per week subcutaneously for 16 weeks. These doses are higher than those in Europe and cause many side effects, which is why the frequency of interruption of treatment is high. The increase in the duration of treatment or the use of higher doses of the drug does not affect the effectiveness of treatment.

Early systemic side effects are usually transient, occur during the 1 st week of treatment 4-8 hours after injection and are stopped by paracetamol. Later complications in the form of mental disorders, especially against the background of the already existing mental illness, are an indication for stopping treatment with interferon. The presence of an anamnesis of mental disorders is a contraindication to the appointment of interferon. Autoimmune changes develop 4-6 months after the start of treatment and include the appearance of antinuclear, antimitochondrial and antithyroid antibodies. The presence of antibodies to the thyroid gland microsomes before the start of treatment is a contraindication to the appointment of interferon. It is also possible the development of a bacterial infection, especially with cirrhosis of the liver.

A positive response is characterized by the disappearance of HBeAg and HBV DNA and a transient increase in serum transaminase activity at about 8 weeks, due to the lysis of infected hepatocytes. A liver biopsy shows a decrease in inflammation and hepatocellular necrosis. Replicative forms of HBV disappear from the liver. Anti-HBe appear after about 6 months. HBsAg disappears only in 5-10%, usually when the treatment starts at the earliest possible time of the disease. Elimination of HBsAg can be delayed for many months.

Side Effects of Interferon

Early

• The flu-like syndrome
• Myalgia, usually transient
• Headache
• Nausea

Late

• Weakness
• Myalgia
• Irritability
• Anxiety and Depression
• Decreased body weight
• Diarrhea
• Alopecia
• Myelosuppression
• Bacterial infections
• The appearance of autoimmune antibodies
• Neuropathy of the visual tract
• Exacerbation of red flat lichen

Interferon treatment is undoubtedly effective. According to a meta-analysis of 15 controlled trials of interferon efficacy, HBeAg-positive patients experience a 4-fold more frequent disappearance of HBsAg and a 3-fold more frequent disappearance of HBeAg compared to controls.

Patients with decompensated cirrhosis suffer from side effects, especially from infections that serve as an excuse for stopping interferon treatment or lowering the dose. In Child's A group, even low doses (eg, 1 million units 3 times a week) of fractional interferon-a can be effective, but in groups B or C the results of treatment are poor and many side effects are observed.

The effectiveness of interferon-a treatment was expressed in the long-term remission of liver disease in 8 of 15 patients with chronic HBV infection and glomerulonephritis. In the course of kidney disease there is usually an improvement.

These results were obtained in adult patients of the white race with a good general condition and compensated liver disease. Less favorable results were obtained in patients of Chinese origin, among whom exacerbations after remission achieved with interferon are observed in 25%, and HBV-DNA ceases to be detected in only 17% of patients with HBeAg disappearing.

Interferon can be effective in children. A total dose of 7.5 million units / m ², administered 3 times a week for 6 months, resulted in 30% of the development of seroconversion of HBeAg in anti-HBe.

A low success rate combined with a high cost of treatment and side effects make it difficult to select patients for treatment with interferon. It is shown to medical workers (surgeons, dentists, nurses, medical students, laboratory technicians) and to individuals who frequently change their sexual partner. The greatest effectiveness of treatment is observed in persons who have suffered acute viral hepatitis, having high ALT activity and low level of viremia.

Analogues of nucleosides

At present, the effectiveness of nucleoside analogs in the treatment of chronic HBV infection is being investigated. Adenine-arabinoside-5-monophosphate (APA-AMP) is a synthetic purine nucleoside with antiviral activity against HBV. Early observations confirmed this effect, but further studies were not carried out because of neurotoxicity (myalgia, peripheral neuropathy), noted throughout the treatment. In recent studies, it has been shown that as a result of the treatment of APA-AMP in 37% of patients with chronic HBV infection, HBV DNA disappears in the blood, but a full and persistent response is achieved only with a low level of HBV replication. Myalgia caused the termination of treatment in 47% of patients.

Nucleoside analogs do not have intrinsic activity against HBV and are activated by enzymes present in the cells. These enzymes are highly specific for each host species (human or animal), each cell type and each stage of the cell cycle. This makes it difficult to compare the data of experimental studies conducted, for example, on the culture of animal cells infected with hepadnaviruses, with data obtained from human examination. Species features can also cause differences in the toxicity of these compounds.

New oral analogues of nucleosides include fialuridine, lamivudine and famciclovir. The toxicity profile is determined by their affinity for mitochondrial and nuclear DNA. If the affinity for nuclear DNA predominates, the toxicity manifests itself within a few weeks. However, if the affinity for mitochondrial DNA prevails, the symptoms of toxic effects appear only a few months from the start of treatment. This can be explained by the large functional reserve of mitochondria and a significant number of DNA copies per mitochondria. Severe manifestations of toxic syndrome include myopathy, neuropathy, pancreatitis, impaired liver function and lactic acidosis.

In the preliminary study, good results of treatment with phialuridine with a significant decrease in HBV-DNA level were revealed. However, the long-term study was reasonably suspended due to the development of severe mitochondrial toxicity and lethal outcomes in volunteers.

Lamivudine inhibits the reverse transcriptase necessary for the transcription of HBV-RNA pregenoma in HBV DNA. Treatment at doses of 100-300 mg / day for 12 weeks gives encouraging results. HBV-DNA disappears. Controlled studies are currently ongoing. Particular attention should be paid to the possible mitochondrial toxicity. Abolition of the drug may be accompanied by exacerbation of hepatitis.

Lamivudine and famciclovir were used to prevent reinfection after transplantation in HBV-DNA positive patients with cirrhosis of the liver.

[8], [9], [10], [11], [12], [13], [14], [15], [16],

Corticosteroids

Corticosteroids enhance the replication of the virus, and after their abolition, an "immune ricochet" is noted in the form of a drop in the concentration of HBV-DNA. After corticosteroids, a full course of treatment with interferon is prescribed. But severe patients are not prescribed, as strengthening the immune response can lead to hepatic-cell insufficiency. Moreover, a controlled study comparing interferon monotherapy with treatment with prednisolone followed by interferon administration did not reveal the benefits of combination therapy. However, in patients with a baseline serum transaminase activity of less than 100 IU / L, the addition to treatment with prednisolone improved its results.

[17], [18], [19], [20], [21], [22], [23]

Mutations of HBV

Specific mutations of the core protein prevent T cells from performing their function at a later stage of chronic HBV infection and can reduce the effectiveness of interferon treatment. These mutations develop throughout the disease and affect the ability of the host's immune recognition by the body. The data of some studies on the relationship of mutations with a poor response to interferon are inconsistent and not confirmed in other studies. The appearance of pr-core mutants on the background of therapy usually portends a failure in attempts to get rid of the virus, but changes in the core region do not affect the outcome of the disease as a whole. Pre-core mutants can cause severe recurrence of HBV infection after liver transplantation.

Factors determining the response of patients with chronic hepatitis B to antiviral therapy

• Favorable
  • Female
  • Heterosexuality
  • Adherence to treatment
  • Small prescription of infection
  • High activity of serum transaminases
  • The presence of histological signs of activity
  • Low level of HBV-DNA
• Unfavorable
  • Homosexuality
  • HIV infection
  • Long-term infection
  • Eastern origin

At observation for 3-7 years for 23 patients responding to interferon treatment, an exacerbation was detected in 3, while 20 remained HBeAg-negative and asymptomatic, and 13 became HBsAg-negative.

[24], [25], [26], [27], [28], [29], [30], [31], [32], [33]

HBeAg- and HBV DNA negative patients

These patients are characterized by a more advanced age and a later stage of liver disease. Specific treatment for this category of patients is not, it is mostly symptomatic and includes the whole complex of known drugs. Ursodeoxycholic acid - a safe, non-toxic hydrophilic bile acid - weakens the effect of toxic bile acids, delayed in patients with hepatocellular lesions. In a daily dose of 500 mg, it reduces the activity of serum transaminases in patients with chronic hepatitis. In some cases, anti-HBe is detected, but in the presence of HBV-DNA in the serum.

Screening patients for hepatocellular carcinoma

HBsAg-positive patients with chronic hepatitis or cirrhosis, especially men older than 45, regularly undergo a preventive checkup for the early detection of hepatocellular carcinoma, when liver resection is possible. Serum a-fetoprotein and ultrasound are examined at 6-month intervals