Chronic hepatitis C: treatment

Chronic hepatitis C treatment involves a long and complex. However, unfortunately, the treatment can not be considered satisfactory. Normalization of serum transaminase activity during treatment is noted in 50% of patients; while 50% of them later exacerbated, so that a persistent effect can be achieved only in 25% of patients. If HCV-RNA is used for monitoring in serum, then the effectiveness of treatment for chronic hepatitis C will be lower.

The results can be assessed by determining the activity of ALT in dynamics. Unfortunately, this indicator does not accurately reflect the effect of treatment of chronic hepatitis C. The definition of HCV-RNA in dynamics is of great importance. A liver biopsy before the start of treatment allows you to verify the diagnosis. Do not start treatment for chronic hepatitis C in patients with a liver biopsy showing a minimal lesion, and HCV-RNA in the PCR test is not available. In patients with cirrhosis the likelihood of achieving improvement in treatment is extremely small.

The selection of patients for the treatment of chronic hepatitis C is very complicated and requires the consideration of many factors. The favorable factors associated with the patient include female sex, the lack of obesity and normal activity of GGTP serum, the low prescription of infection and the absence of histological signs of cirrhosis. Favorable factors associated with the virus are low levels of viremia, genotype II or III, and homogeneity of the viral population.

Unsatisfactory results associated with the genotype 1b, attributed to the mutations of the gene N55A.

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

Drug treatment for chronic hepatitis C

[7], [8], [9], [10], [11], [12], [13],

Interferon-a

The adopted scheme of treatment of chronic hepatitis C with interferon-a provides for injection of 3 million units 3 times a week for 6 months. Until now, it is not clear whether the results can be improved by changing the treatment regimen, for example by increasing the dose or duration of treatment. In a controlled study, patients with chronic hepatitis A or B received an initial interferon dose of 3 million units 3 times a week for 6 months. They were divided into 3 groups: in the 1st group, the therapy was continued for another 6 months, the second drug was used in a lower dose for 12 months and in the 3rd one was administered a placebo. The observation was carried out for 19-42 months. A significant proportion of patients who received 3 million units 3 times a week for 12 months normalized the activity of ALT, serum became HCV RNA negative and the histological picture improved.

Factors associated with the beneficial effect of antiviral treatment of chronic hepatitis C

Factors associated with the patient

• Age under 45 years
• Female
• Lack of obesity 5 years
• Infection durability is less than
• Absence of co-infection with HBV
• Absence of immunosuppression
• Absence of alcoholism
• Moderate increase in ALT activity
• Normal activity of GGTP
• Liver biopsy: low activity of the process
• Absence of cirrhosis

Factors associated with the virus

• Low serum HCV-RNA
• Genotype II or III
• Uniformity of the virus population
• Low iron content in the liver

Three regimens for the treatment of chronic hepatitis C with IFN-a (the initial dose of 3 million units 3 times a week for 6 months)

Tactics of treatment	Normalization of ALT,%	Improvement in histological examination,%	Disappearance of HCV-RNA,%
Additional treatment within 6 months of the initial dose	22.3	69	65
1 million units 3 times a week for 12 months	9.9	47	27th
Discontinuation of treatment	9.1	38	31

In another study, prolongation of therapy from 28 to 52 weeks increased the number of patients with a sustained improvement from 33.3 to 53.5%. However, 38% of patients were resistant to prolonged treatment of chronic hepatitis C with interferon. The extension of the treatment to 60 weeks also increased the proportion of patients with a persistent effect. Long-term treatment of chronic hepatitis C is indicated for patients with a high level of viremia in the period preceding treatment.

The results of a randomized study conducted in Italy showed that a persistent effect is more often observed in patients treated with IFN administered 6 million units 3 times a week for 6 months with a further dose adjustment depending on the activity of ALT and the continuation of treatment up to 12 months . Almost half of the patients had a stable normalization of ALT activity, disappeared from the serum of HCV-RNA and the histological picture of the liver improved. However, the patients differed by a relatively young age, a low prescription of HCV infection and a low incidence of cirrhosis. The good results obtained can not reflect the general picture.

The most effective dose of interferon and the duration of the course have not been finally established. A meta-analysis of 20 randomized trials showed that the best efficacy / risk ratio was obtained at a dose of 3 million units 3 times per week and a course duration of at least 12 months; The persistent effect of treatment persisted for 1 year. If there is no improvement within 2 months, treatment should not be continued. Several improved results are achieved with increasing doses.

In children receiving 5 million units / m ² for 12 months, persistent normalization of ALT activity and disappearance of HCV-RNA can be achieved in 43% of cases.

With the improvement of liver function in chronic hepatitis C and cirrhosis, the incidence of hepatocellular carcinoma decreases.

The presence of antibodies to the thyroid gland microsomes before initiating interferon therapy is a risk factor for the subsequent development of thyroid dysfunction. In the absence of antithyroid antibodies, the risk of thyroid dysfunction is significantly lower.

In anti-LKM-positive patients with chronic hepatitis C in the treatment of chronic hepatitis C, interferon increases the risk of developing side-effects from the liver. Nevertheless, this risk is minimal in comparison with the expected effect. However, such patients need careful monitoring of liver function.

Treatment of chronic hepatitis C in patients who experienced an exacerbation after the course of treatment with interferon or had no effect seems difficult. In some cases, improvement can be achieved by increasing the interferon dose to 6 million units 3 times a week. Others should consider combining therapy with interferon with ribavirin. In many cases, it is necessary to limit oneself to psychological support and regular supervision.

Combination of interferon with ribavirin

Ribavirin is an analogue of guanosine with a broad spectrum of activity against RNA and DNA containing viruses, including the family of flaviviruses. In patients with chronic HCV infection, it temporarily reduces ALT activity, but has little effect on the level of HCV-RNA, which may increase.

The change in the scheme for further treatment of IFN at 2 months from the beginning (3 million units 3 times a week), depending on the activity of ALT

ALT activity	Tactics of treatment
Normal	Continuation in a dose of 3 million units
Partial reduction	Increase to 6 million units
Does not decrease	Discontinuation of treatment

The advantage of ribavirin is oral administration; side effects are minimal and include minor discomfort in the abdomen, hemolysis (during the treatment of chronic hepatitis C should monitor hemoglobin and serum bilirubin levels) and hyperuricemia. Hemolysis can lead to an increase in iron deposition in the liver.

Studies suggest that the administration of ribavirin in combination with interferon enhances the antiviral effect, especially in those patients who have not been able to achieve a stable effect in the treatment with one interferon. Ribavirin is prescribed in a dose of 1000-1200 mg / day in 2 doses. The dose of interferon is 3 million units 3 times a week. Both drugs are prescribed for 24 weeks. Treatment of chronic hepatitis C is accompanied by a decrease in the activity of ALT, persistent disappearance of HCV-RNA in 40% of patients and a decrease in the activity of the inflammatory and necrotic process according to liver biopsy. The combination of these drugs was also effective in relapses after a course of interferon treatment in patients without cirrhosis. Comparison of the results of treatment with one interferon, one ribavirin and a combination of them shows that ribavirin gives a transient effect, and when a combination of drugs is prescribed, a full and persistent effect can be achieved more often than with treatment with one interferon. In another study, a 6-month treatment of chronic hepatitis C with interferon and ribavirin led to a normalization of serum transaminase activity in 78% of patients, which persisted for 5 months after treatment. In the treatment with interferon alone, normalization of transaminase activity was achieved in 33%, with ribavirin monotherapy, the activity of transaminases did not return to normal.

These studies were performed in a small number of patients. Currently, multicenter studies are being conducted with the inclusion of patients receiving interferon for the first time, patients whose interferon was ineffective, and patients who developed an exacerbation after interferon treatment. It is to be determined whether an expensive combination of interferon and ribavirin is effective in the treatment of chronic hepatitis C and whether it is more affordable than currently available.

[14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25],

Ursodeoxycholic acid

Ursodeoxycholic acid can improve liver function in patients with chronic hepatitis. Particularly favorable is its effect on the "biliary" component: a decrease in the activity of serum transaminases and GGTP, the degree of ductular metaplasia, damage to the bile ducts and changes in the cytoskeleton.

The addition of ursodeoxycholic acid to interferon therapy significantly increases the period during which ALT activity remains within normal limits. However, it does not lead to the disappearance of HCV-RNA from the blood and does not improve the histological picture in the liver.

Removal from the liver of iron

Chronic hepatitis C, whose treatment was effective with the use of interferon, the concentration of iron in the liver is lower than in patients who did not respond to this treatment. Increased iron content can be reflected in the state of oxidative processes and makes the cell easy to disintegrate. Bleeding for the removal of iron in combination with the use of interferon may improve the effectiveness of treatment (as judged by ALT activity and serum HCV-RNA level) and reduce the likelihood of exacerbations.

New antiviral agents

The development of new antiviral agents and vaccines is hampered by the failure to obtain a suitable cell culture for HCV. However, knowledge of the molecular biology of HCV led to the identification of specific functions associated with certain regions of the virus. The latter include the putative ribosomal entry site in the 5 'non-coding region, the centers of protease activity and helicase in the NS3 region and the RNA-dependent RNA polymerase bound to the NS5 region. As the methods for the study of these functions appear, it will also be possible to study the specific inhibitory activity of new compounds.