Chronic hepatitis C: treatment

Chronic hepatitis C treatment requires long-term and complex treatment. However, unfortunately, the treatment cannot be considered satisfactory. Normalization of serum transaminase activity during treatment is observed in 50% of patients; at the same time, 50% of them subsequently experience exacerbations, so that a stable effect can be achieved only in 25% of patients. If the HCV-RNA level in the serum is used for monitoring, the effectiveness of chronic hepatitis C treatment 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. Determination of HCV-RNA in dynamics is of great importance. Liver biopsy before treatment allows to verify the diagnosis. Treatment of chronic hepatitis C should not be started in patients in whom liver biopsy reveals minimal damage, and HCV-RNA is absent in the PCR study. In patients with liver cirrhosis, the probability of achieving improvement with treatment is extremely low.

Selection of patients for treatment of chronic hepatitis C is very complex and requires consideration of many factors. Favorable patient-related factors include female gender, absence of obesity and normal serum GGT activity, short duration of infection and absence of histological signs of cirrhosis. Favorable virus-related factors include low viremia, genotype II or III and homogeneity of the viral population.

Unsatisfactory results associated with genotype 1b are attributed to mutations in the N55A gene.

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Drug treatment of chronic hepatitis C

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Interferon-a

The accepted treatment regimen for chronic hepatitis C with interferon-a involves injections of 3 million IU 3 times a week for 6 months. It is still unclear 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 non-A, non-B hepatitis received an initial course of interferon at 3 million IU 3 times a week for 6 months. They were divided into 3 groups: in the 1st group, therapy was continued for another 6 months, in the 2nd the drug was used at a lower dose for 12 months, and in the 3rd, placebo was prescribed. Observation was carried out for 19-42 months. A significant proportion of patients who received 3 million IU 3 times a week for 12 months showed normalization of ALT activity, serum became HCV RNA negative, and the histological picture improved.

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

Patient-Related Factors

• Age under 45 years
• Female gender
• No obesity for 5 years
• The infection has been going on for less than
• No HBV co-infection
• Absence of immunosuppression
• Absence of alcoholism
• Moderate increase in ALT activity
• Normal GGT activity
• Liver biopsy: low activity of the process
• Absence of cirrhosis

Factors associated with the virus

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

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

Treatment tactics	Normalization of ALT, %	Improvement in histological examination, %	HCV-RNA disappearance, %
Additional treatment for 6 months with the initial dose	22.3	69	65
1 million IU 3 times a week for 12 months	9.9	47	27
Termination of treatment	9.1	38	31

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

The results of a randomized study conducted in Italy showed that a stable effect is more often observed in patients treated with IFN, administered at 6 million units 3 times a week for 6 months with subsequent dose adjustment depending on the activity of ALT and continuation of treatment for up to 12 months. Almost half of the patients showed stable normalization of ALT activity, disappearance of HCV-RNA from the serum, and improvement of the histological picture of the liver. However, the patients were distinguished by a relatively young age, short duration of HCV infection, and a low incidence of cirrhosis. The good results obtained cannot reflect the overall picture.

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

In children receiving 5 million U/ ^m2 for 12 months, persistent normalization of ALT activity and disappearance of HCV-RNA can be achieved in 43% of cases.

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

The presence of thyroid microsome antibodies before the start of interferon therapy is a risk factor for the subsequent development of thyroid dysfunction. In the absence of antithyroid antibodies, the risk of developing thyroid dysfunction is significantly lower.

In anti-LKM-positive patients with chronic hepatitis C, the risk of developing adverse reactions from the liver increases during the treatment of chronic hepatitis C with interferon. However, this risk is minimal compared to the expected effect. However, careful monitoring of liver function is necessary in such patients.

Treatment of chronic hepatitis C in patients who have had an exacerbation or no effect after a course of interferon treatment appears to be difficult. In some patients, improvement can be achieved by increasing the dose of interferon to 6 million units 3 times a week. In others, combination therapy with interferon and ribavirin should be considered. In many cases, psychological support and regular monitoring are sufficient.

Combination of interferon with ribavirin

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

Changing the regimen of further IFN treatment after 2 months from its start (3 million IU 3 times a week) depending on the activity of ALT

ALT activity	Treatment tactics
Normal	Continued at a dose of 3 million IU
Partial reduction	Increase to 6 million units
It is not decreasing	Termination of treatment

The advantage of ribavirin is that it is administered orally; side effects are minimal and include minor abdominal discomfort, hemolysis (serum hemoglobin and bilirubin levels should be monitored during treatment of chronic hepatitis C), and hyperuricemia. Hemolysis may lead to increased iron deposition in the liver.

Studies suggest that the use of ribavirin in combination with interferon enhances the antiviral effect, especially in patients who failed to achieve a stable effect with interferon alone. Ribavirin is prescribed at a dose of 1000-1200 mg/day in 2 doses. The dose of interferon is 3 million IU 3 times a week. Both drugs are prescribed for 24 weeks. Treatment of chronic hepatitis C is accompanied by a decrease in ALT activity, 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 data. The combination of these drugs also proved effective in relapses after a course of interferon treatment in patients without cirrhosis. Comparison of the results of treatment with interferon alone, ribavirin alone, and their combination shows that ribavirin produces a transient effect, while when a combination of drugs is prescribed, a full and lasting effect can be achieved more often than with interferon alone. In another study, 6-month treatment of chronic hepatitis C with interferon and ribavirin led to normalization of serum transaminase activity in 78% of patients, which persisted for 5 months after treatment. When treated with interferon alone, normalization of transaminase activity was achieved in 33%, while transaminase activity did not normalize with ribavirin monotherapy.

The studies mentioned were performed in a small number of patients. Multicenter studies are currently being organized to include patients receiving interferon for the first time, patients in whom interferon was ineffective, and patients who developed an exacerbation after a course of interferon treatment. It remains to be seen whether the expensive combination of interferon and ribavirin is effective in the treatment of chronic hepatitis C and whether it is superior to currently available agents.

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Ursodeoxycholic acid

Ursodeoxycholic acid can improve liver function in patients with chronic hepatitis. Its effect is especially favorable with respect to the "biliary" component: there is a decrease in the activity of serum transaminases and GGT, the degree of ductular metaplasia, bile duct damage and cytoskeletal changes.

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 of iron from the liver

Chronic hepatitis C, the treatment of which has proven effective with the use of interferon, the concentration of iron in the liver is lower than in patients who have not responded to this treatment. Increased iron content can affect the state of oxidative processes and makes the cell vulnerable. Bloodletting to remove iron in combination with the administration of interferon can increase the effectiveness of treatment (as can be judged by the activity of ALT and the level of HCV-RNA in the serum) and reduce the likelihood of exacerbations.

New antiviral agents

The development of new antiviral agents and vaccines has been hampered by the failure to obtain suitable cell culture for HCV. However, knowledge of the molecular biology of HCV has led to the identification of specific functions associated with certain regions of the virus. These include a putative ribosomal entry site in the 5' noncoding region, sites of protease and helicase activity in the NS3 region, and an NS5-associated RNA-dependent RNA polymerase. As techniques for investigating these functions become available, it will be possible to investigate the specific inhibitory activity of new compounds.