Combined treatment of chronic hepatitis C (genotype 3a) with Russian antiviral drugs (Reaferon, Interal, Vero-Ribavirin, Ribamidil): efficacy and safety

The dissertation is devoted to assessing the efficacy and safety of combination antiviral therapy of chronic hepatitis C (genotype 3a) in men using domestic drugs — reaferon and interal in combination with vero-ribavirin or ribamidil. The work is based on clinical examination and six-month treatment of patient groups with four combinations of Russian antiviral agents. The dynamics of clinical, biochemical and virological parameters are analyzed, along with the frequency of ALT activity normalization and virus elimination, and the frequency and character of adverse reactions and serious adverse events. The dependence of treatment outcomes on body weight, age, histological activity index and degree of fibrosis is examined, a comparative evaluation of the efficacy and cost of different therapeutic regimens is performed, and early criteria of antiviral treatment success are proposed.

The study was carried out at the Main Military Clinical Hospital and is aimed at substantiating the use of affordable Russian interferon alfa-2 and ribavirin in the treatment of chronic hepatitis C genotype 3a.

Relevance of the study. The leading cause of chronic liver disease worldwide is infection caused by the hepatitis C virus [53].

In Russia, the incidence of acute hepatitis C in 1994 did not exceed 3.2 per 100,000 population. In 2000 this figure reached 20.7 per 100,000 population. In recent years, following the introduction of screening of blood for antibodies to the hepatitis C virus and the attraction of broad public attention to HCV infection, the incidence of AHC has been declining. However, the number of patients in whom chronic hepatitis C is detected for the first time continues to rise (in 2004 compared with 2000 the increase was almost 1.5-fold) [35, 54, 55]. In the next 20–30 years a further increase in the number of patients with late sequelae of CHC will have to be reckoned with, unless effective and widely available methods of treatment are developed [13, 52]. Decompensated liver cirrhosis as a consequence of CHC serves as the principal indication for liver transplantation in most industrially developed countries [53, 93, 110].

The structure of hepatitis C virus genotypes has also changed. In 1995–1996 genotype 1b was detected in 67% and genotype 3a in only 11% of those infected with HCV [28]. In 2001–2004 a rise in the proportion of genotype 3a was noted. At present in the Novosibirsk Oblast the proportion of genotype 1b is 50% and that of genotype 3a is 46%, and in Saint Petersburg 25% and 57.9%, respectively [55]. This is related to the wide spread of intravenous drug use among young people in the mid-1990s.

The efforts of many investigators and gastroenterologists are directed toward the development of effective therapeutic agents for CHC. The principal method of etiotropic treatment of CHC, accepted worldwide as having proven efficacy, is interferon therapy combined with ribavirin [72, 104]. In the USA and the European Union, recombinant interferon alfa-2 and ribavirin produced by "Schering-Plough" and "Roche" are used for the treatment of hepatitis C; their price is extremely high, which makes CHC therapy one of the major problems of public health, since considerable financial resources are expended. The cost of a course of treatment for one CHC patient (genotype 3a) with intron and rebetol (ribavirin) ("Schering-Plough") amounts to 5 thousand US dollars, and with pegylated interferon (pegintron) to 12 thousand US dollars [25].

Russian interferon alfa-2 and ribavirin are considerably cheaper than their foreign counterparts [14, 50]. The small number of publications on the efficacy and safety of domestic interferons (reaferon, interal) in combination with vero-ribavirin or ribamidil, and their affordable cost, prompted us to undertake this study.

Aim of the study: to assess the efficacy and safety of various combinations of Russian antiviral drugs (interal, reaferon, vero-ribavirin, ribamidil) in the treatment of CHC (genotype 3a) in men.

Objectives of the study:

1. To determine the dynamics of clinical, biochemical and virological parameters during 6-month treatment of CHC patients (genotype 3a) with reaferon and vero-ribavirin.

2. To identify the dynamics of clinical, biochemical and virological parameters during 6-month treatment of CHC (genotype 3a) with reaferon and ribamidil.

3. To study the dynamics of clinical, biochemical and virological parameters during 6-month treatment of CHC (genotype 3a) with interal and vero-ribavirin.

4. To perform 6-month monitoring of clinical, biochemical and virological parameters during treatment of CHC (genotype 3a) with interal and ribamidil.

5. To compare the efficacy of combination treatment of CHC patients (genotype 3a) with vero-ribavirin together with reaferon or interal, as well as with ribamidil together with reaferon or interal.

6. To identify the dependence of the antiviral treatment effect on age, body weight, histological activity index (HAI) and degree of fibrosis (DF).

7. To determine the frequency of serious adverse events and adverse reactions in the combination treatment of CHC with Russian antiviral medicinal agents.

8. To evaluate the efficacy and costs of antiviral therapy of CHC using various combinations of domestic interferon alfa-2 and ribavirin.

9. To search for early criteria of antiviral therapy success.

Scientific novelty:

- the efficacy of treatment of CHC (genotype 3a) with combinations of Russian antiviral drugs (reaferon with vero-ribavirin or ribamidil, and interal with vero-ribavirin or ribamidil) in men, and the frequency of adverse reactions and serious adverse events, have been refined;

- the relationship between the degree of fibrosis, age, histological activity index, body weight and the efficacy of variants of antiviral treatment of CHC (genotype 3a) in men has been studied;

- criteria of therapy success at early stages have been identified;

- a comparative evaluation of the efficacy and costs of antiviral treatment of CHC with Russian drugs has been carried out with account for the degree of fibrosis;

Practical significance of the study is determined by the following clinical results:

- with the use of domestic antiviral drugs interferon alfa-2 and vero-ribavirin, a complete biochemical and virological response to treatment in men with CHC (genotype 3a) is achieved in 80%;

- with the use of domestic antiviral drugs interferon and ribamidil, a complete biochemical and virological response to treatment in men with CHC (genotype 3a) is achieved in 70%;

- the smallest number and severity of adverse reactions in CHC treatment is observed with the combination of interal and vero-ribavirin;

- the degree of fibrosis in CHC treatment (genotype 3a) determines the success of antiviral therapy. The higher the degree of fibrosis, the less frequently a biochemical and virological response can be achieved, especially with the combination of interferon alfa-2 and ribamidil.

Implementation into practice: the obtained results of the study are used in the City Gastroenterological Center of Samara (Medical Sanitary Unit No. 5), in the Samara Military Medical Institute, in the 3rd Central Military Clinical Hospital named after A. A. Vishnevsky, and in the State Institute for Advanced Medical Training of the Ministry of Defense of the Russian Federation.

Approval of the dissertation

The main materials of the dissertation were reported and discussed at scientific conferences of the Main Military Clinical Hospital named after N. N. Burdenko (Moscow, 2003) and the 3rd Central Military Clinical Hospital named after A. Vishnevsky (Krasnogorsk, 2003); the 9th Russian Conference "Hepatology Today" (Moscow, 2004); the 10th Russian Gastroenterological Week (Moscow, 2004); the 10th Russian Conference "Hepatology Today" (Moscow, 2005); the 6th All-Russian Scientific and Practical Conference "Viral Hepatitis — Problems of Epidemiology, Treatment and Prevention" (Moscow, 2005).

On the topic of the dissertation 20 printed works have been published, of which 19 in central press.

The dissertation was approved on 18 May 2005 at the Academic Council of the Main Military Clinical Hospital named after N. N. Burdenko.

Volume and structure of the dissertation:

The dissertation is presented on 142 pages of typewritten text and consists of an introduction, 6 chapters, a conclusion, findings, practical recommendations, a list of references comprising 125 titles: 57 domestic and 68 foreign, and is illustrated with 14 figures and 61 tables.