Chronic hepatitis B: treatment

The patient should be examined for contagiousness. This is especially important if he is HBeAg-positive. The patient's family and sexual partner should be examined separately for the presence of HBsAg and anti-HBc; in case of negative test results, they are recommended to be vaccinated against hepatitis B.

Bed rest is not necessary. Physical activity should be dosed. Normal nutrition. Alcohol intake should be avoided, as it improves the prognosis for HBsAg carriers. However, 1-2 glasses of wine or beer per day are acceptable if this is part of the patient's lifestyle.

Most patients with chronic hepatitis B lead normal lives. Psychological support is needed to prevent "escape into illness."

It is necessary to find out how contagious the patient is, what is the severity of symptoms or liver failure. A liver biopsy usually precedes the appointment of therapy. The presence of severe chronic hepatitis with cirrhosis obviously forces the issue of urgent treatment. The approach to patients with high contagiousness in the replicative phase and patients with low contagiousness in the integration phase of the virus 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 contagiousness, destroying the virus, preventing the development of liver cirrhosis and, possibly, hepatocellular carcinoma. No treatment method rids the patient of the virus, however, successful antiviral therapy can reduce the severity of the process and the resulting necrosis of hepatocytes.

Interferon-a

The use of interferon-a (IFN-a), both lymphoblastoid and recombinant, should be considered. Interferon improves the expression of HLA class I proteins and may increase the activity of interleukin-2 (IL-2) and thus destroy diseased hepatocytes.

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

	Disappearance, %
	HBsAg	HBeAg
In the treatment of IFN	7.8	33
Spontaneous	1.8	12

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

The US regimen involves administering 5 million IU daily or 10 million IU 3 times a week subcutaneously for 16 weeks. These doses are higher than those used in Europe and cause many side effects, which is why the frequency of treatment interruptions is high. Increasing the duration of treatment or using higher doses of the drug does not affect the effectiveness of the treatment.

Early systemic side effects are usually transient, occur within the first week of treatment, 4-8 hours after injection, and are relieved by paracetamol. Late complications in the form of mental disorders, especially against the background of a pre-existing mental illness, are an indication for discontinuing interferon treatment. A history of mental disorders is a contraindication to the administration 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 thyroid microsomes before the start of treatment is a contraindication to the administration of interferon. Bacterial infection is also possible, especially in liver cirrhosis.

A positive response is characterized by the disappearance of HBeAg and HBV DNA and a transient increase in serum transaminase activity at approximately the 8th week, due to lysis of infected hepatocytes. Liver biopsy reveals a decrease in inflammation and hepatocellular necrosis. Replicative forms of HBV disappear from the liver. Anti-HBe appear after approximately 6 months. HBsAg disappears in only 5-10%, usually when treatment is started very early in the disease course. HBsAg elimination may take many months.

Side effects of interferon

Early

• Flu-like syndrome
• Myalgias, usually transient
• Headache
• Nausea

Late

• Weakness
• Myalgia
• Irritability
• Anxiety and depression
• Weight loss
• Diarrhea
• Alopecia
• Myelosuppression
• Bacterial infections
• The emergence of autoimmune antibodies
• Optic tract neuropathy
• Exacerbation of lichen planus

Interferon treatment is undoubtedly effective. According to a meta-analysis of 15 controlled studies of interferon efficacy, HBeAg-positive patients have a 4-fold higher rate of HBsAg loss and a 3-fold higher rate of HBeAg loss compared to controls.

Patients with decompensated cirrhosis suffer from side effects, especially infections, which are the reason for stopping interferon treatment or reducing the dose. In Child group A, even low doses (e.g., 1 million units three times a week) of interferon-a given in divided doses may be effective, but in groups B or C, the results are poor and many side effects are observed.

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

These results were obtained in adult patients of the white race with 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 were observed in 25%, and HBV DNA became undetectable only in 17% of patients in whom HBeAg disappeared.

Interferon may be effective in children. A total dose of 7.5 million U/m2 ^given 3 times a week for 6 months resulted in 30% seroconversion of HBeAg to anti-HBe.

The low success rate, combined with the high cost of treatment and side effects, make it difficult to select patients for interferon treatment. It is indicated for health care workers (surgeons, dentists, nurses, medical students, laboratory technicians) and individuals who frequently change sexual partners. The greatest effectiveness of treatment is observed in individuals who have had acute viral hepatitis, have high ALT activity and low viremia.

Nucleoside analogues

Currently, the efficacy of nucleoside analogues in the treatment of chronic HBV infection is being studied. Adenine arabinoside 5-monophosphate (ARA-AMP) is a synthetic purine nucleoside with antiviral activity against HBV. Early observations confirmed this effect, but further studies were not conducted due to neurotoxicity (myalgia, peripheral neuropathy) observed throughout the treatment. Recent studies have shown that as a result of treatment with ARA-AMP, HBV DNA disappears from the blood in 37% of patients with chronic HBV infection, but a complete and sustained response is achieved only at a low level of HBV replication. Myalgia was the reason for discontinuing treatment in 47% of patients.

Nucleoside analogues have no intrinsic activity against HBV and are activated by enzymes present in 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 data from experimental studies, such as those conducted on animal cell cultures infected with hepadnaviruses, with data from human studies. Species-specific differences may also cause differences in the toxicity of these compounds.

New oral nucleoside analogues include fialuridine, lamivudine and famciclovir. The toxicity profile is determined by their affinity for mitochondrial and nuclear DNA. If the affinity for nuclear DNA is predominant, toxicity appears within a few weeks. However, if the affinity for mitochondrial DNA is predominant, toxicity symptoms appear only after several months of treatment. This can be explained by the large functional reserve of mitochondria and the large number of DNA copies per mitochondrion. Severe manifestations of toxic syndrome include myopathy, neuropathy, pancreatitis, liver dysfunction and lactic acidosis.

A preliminary study showed good results with fialuridine treatment, with significant reductions in HBV DNA levels. However, the long-term study was justifiably suspended due to the development of severe mitochondrial toxicity and fatal outcomes in volunteers.

Lamivudine inhibits reverse transcriptase, which is necessary for transcription of the HBV RNA pregenome into 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 possible mitochondrial toxicity. Discontinuation of the drug may be accompanied by exacerbation of hepatitis.

Lamivudine and famciclovir have been used to prevent reinfection after transplantation in HBV DNA-positive patients with liver cirrhosis.

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

Corticosteroids

Corticosteroids enhance viral replication, and after their withdrawal, an "immune rebound" is observed in the form of a decrease in the concentration of HBV DNA. After corticosteroids, a full course of interferon treatment is prescribed. However, it is not prescribed to seriously ill patients, since an increase in the immune response can lead to hepatocellular failure. Moreover, a controlled study comparing interferon monotherapy with prednisolone treatment followed by interferon did not reveal any advantages of combination therapy. However, in patients with initial serum transaminase activity less than 100 IU/L, the addition of prednisolone to treatment improved its results.

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

HBV mutations

Specific mutations in the core protein interfere with T cell function in later stages of chronic HBV infection and may reduce the effectiveness of interferon treatment. These mutations develop over the course of the disease and affect the ability of the host immune system to recognize the host. Some studies have found conflicting associations between mutations and poor interferon response and have not been confirmed by other studies. The emergence of pre-core mutants during therapy usually predicts failure to eradicate the virus, but changes in the core region do not affect the overall outcome of the disease. Pre-core mutants may cause severe relapses of HBV infection after liver transplantation.

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

• Favorable
  • Female gender
  • Heterosexuality
  • Adherence to treatment
  • Short history of infection
  • High serum transaminase activity
  • Presence of histological signs of activity
  • Low HBV DNA levels
• Unfavorable
  • Homosexuality
  • HIV infection
  • Long-standing infection
  • Eastern origin

In a 3-7 year follow-up of 23 patients who responded to interferon treatment, relapse 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 older age and a more advanced stage of liver disease. There is no specific treatment for this category of patients, it is mainly symptomatic and includes a full range of known agents. Ursodeoxycholic acid, a safe, non-toxic hydrophilic bile acid, reduces the effect of toxic bile acids retained in patients with hepatocellular damage. In a daily dose of 500 mg, it reduces the activity of serum transaminases in patients with chronic hepatitis. In some cases, anti-HBe are detected, but in the presence of HBV DNA in the serum.

Screening of patients for hepatocellular carcinoma

HBsAg-positive patients with chronic hepatitis or cirrhosis, especially men over 45 years of age, should undergo regular preventive examination for early detection of hepatocellular carcinoma, when liver resection is possible. Serum alpha-fetoprotein and ultrasound examination are performed at 6-month intervals.