Chronic viral hepatitis c. Get treatment in Korea, Israel, Germany, USA

Hepatitis C is an inflammatory liver disease that develops under the influence of the hepatitis C virus. An effective vaccine that could protect against this virus simply does not exist in nature yet, and it will not appear soon.

It comes in two types – acute and chronic. In 20% of cases, people with acute hepatitis have a good chance of recovery, and in 80%, the patient’s body is not able to overcome the virus itself and the disease becomes chronic.

Transmission of the virus occurs through infection through blood. Today, there are 150 million people in the world who are carriers of chronic hepatitis C, and every year hepatitis ends in death in 350 thousand patients.

Basically, the first symptoms of hepatitis C appear 30-90 days after infection. That is why if you feel unwell, apathy, fatigue and other phenomena that are unusual for your body, then it is better for you to consult a doctor. This is necessary for the doctor to make an accurate diagnosis and, based on it, choose the most effective treatment.

How is hepatitis C transmitted?

What it is? Infection occurs mainly through contact with the blood of an infected person. Hepatitis C is also transmitted during medical procedures: blood collection and transfusion, surgical operations, and dental procedures.

The source of infection can be manicure instruments, tattoo devices, needles, scissors, razors, etc. If the skin or mucous membranes are broken, contact with the blood of an infected person can cause infection.

In rare cases, hepatitis C is transmitted through sexual contact. Infected pregnant women have a risk that their baby will also become infected with the virus at birth.

The most severe cases of the virus are:

• persons who abuse alcohol.
• persons suffering from other chronic liver diseases, including others.
• older people and children.

Hepatitis C disease is not transmitted through household contacts through hugs or handshakes; with this disease, you can share dishes and towels, but you cannot share personal hygiene items (razors, nail scissors, toothbrushes). The mechanism of transmission of the disease is only hematogenous.

Symptoms of hepatitis C

In most situations, viral hepatitis C proceeds slowly, without pronounced symptoms, remaining undiagnosed for years and manifesting itself after significant destruction of liver tissue. Often, patients are first diagnosed with hepatitis C when they already have hepatocellular liver cancer.

The incubation period of hepatitis lasts from 1 to 3 months. Even after this period ends, the virus may not manifest itself until liver damage becomes too obvious.

After infection, 10-15% of patients undergo self-healing, the remaining 85-90% develop primary chronic hepatitis C without any specific symptoms (such as pain, jaundice, etc.). And only in rare cases do patients develop an acute form with jaundice and severe clinical manifestations, which, with adequate therapy, leads to a complete cure of the patient from hepatitis C.

The first signs of hepatitis C in women and men

For a long time, symptoms practically do not bother patients. In the acute period, the disease manifests itself only as weakness, fatigue, and sometimes occurs under the guise of a respiratory viral infection with pain in the muscles and joints. These may be the first signs of hepatitis C in women or men.

Jaundice and any clinical manifestations of hepatitis develop in a very small percentage of infected people (the so-called icteric form of the disease). And this is actually great - patients immediately turn to specialists, and the disease is cured.

However, the majority of infected people suffer from hepatitis C on their feet: in the anicteric form, they either do not notice anything at all, or attribute the malaise to a cold.

Chronic hepatitis

The peculiarity of chronic hepatitis C is a latent or asymptomatic course for many years, usually without jaundice. , detection of anti-HCV and HCV RNA in the blood serum for at least 6 months are the main signs of chronic hepatitis C. Most often, this category of patients is discovered by chance, during examination before surgery, during medical examination, etc.

The course of chronic hepatitis C can be accompanied by such immune-mediated extrahepatic manifestations as mixed cryoglobulinemia, mesangiocapillary glomerulonephritis, porphyria cutanea tarda, etc.

Photo

The photo shows liver damage due to long-term hepatitis.

Forms

According to the presence of jaundice in the acute phase of the disease:

1. Icteric.
2. Anicteric.

According to the duration of the flow.

1. Acute (up to 3 months).
2. Protracted (more than 3 months).
3. Chronic (more than 6 months).

By gravity.

1. Easy.
2. Medium-heavy.
3. Heavy.
4. Fulminant.

Complications.

1. Hepatic coma.

1. Recovery.
2. Chronic hepatitis C.
3. Cirrhosis of the liver.
4. Hepatocellular carcinoma.

Based on the nature of the clinical manifestations of the acute phase of the disease, typical and atypical hepatitis C are distinguished. Typical include all cases of the disease accompanied by clinically visible jaundice, and atypical include anicteric and subclinical forms.

Stages

The disease is divided into several stages, depending on which treatment is prescribed.

1. Acute – it is characterized by an asymptomatic course. A person often does not even suspect that he is a carrier of the virus and a source of infection.
2. Chronic - in the vast majority of cases (about 85%), following the acute stage, the chronic course of the disease begins.
3. Liver cirrhosis develops with further progression of the pathology. This is a serious disease that threatens the patient’s life both in itself and because its presence significantly increases the risk of developing other complications - in particular, liver cancer.

A distinctive feature of the virus is its ability to undergo genetic mutations, due to which approximately 40 subspecies of HCV (within one genotype) can be simultaneously detected in the human body.

Virus genotypes

The severity and course of the disease depend on the genotype of hepatitis C infecting the body. Currently, six genotypes with several subtypes are known. Most often, viruses of genotypes 1, 2 and 3 are found in the blood of patients. They are the ones that cause the most pronounced manifestations of the disease.

In Russia, the most common genotype is 1b. Less often – 3, 2 and 1a. Hepatitis C, caused by genotype 1b virus, is characterized by a more severe course.

Diagnosis of hepatitis

The main method for diagnosing hepatitis is to determine the presence of antibodies to the hepatitis C virus (anti-HCV) and HCV RNA. Positive results from both tests confirm the presence of infection. The presence of IgM class antibodies (anti-HCV IgM) makes it possible to distinguish active hepatitis from carriage (when there are no IgM antibodies and ALT is normal).

A PCR test for hepatitis C (polymerase chain reaction) allows you to determine the presence of hepatitis C RNA in the patient’s blood. PCR testing is mandatory for all patients with suspected viral hepatitis. This method is effective from the first days of infection and plays an important role in early diagnosis.

When is hepatitis C more difficult to treat?

According to statistics, hepatitis C is more difficult to treat in men, people over 40 years of age, in patients with normal transaminase activity, with a high viral load, and in those with genotype 1 b of the virus. Of course, the presence of liver cirrhosis at the time of treatment worsens the prognosis.

The effectiveness of antiviral treatment depends on many factors. With a long course of hepatitis C, it is not easy to achieve complete eradication of the virus. The main task is to slow down the process of active reproduction of viruses.

This is possible in most cases using modern antiviral therapy regimens. In the absence of active reproduction of viruses in the liver, the severity of inflammation significantly decreases and fibrosis does not progress.

Treatment of hepatitis C

In the case of hepatitis C, combination therapy with interferon-alpha and ribavirin is considered the standard of treatment. The first drug is available as a solution for subcutaneous injection under the trademarks Pegasys® and PegIntron®. Peginterferons are taken once a week. Ribavirin is available under different brand names and is taken as tablets twice daily.

1. Interferon-alpha is a protein that the body synthesizes independently in response to a viral infection, i.e. it is actually a component of natural antiviral defense. In addition, interferon-alpha has antitumor activity.
2. Ribavirin as a stand-alone treatment is low in effectiveness, but when combined with interferon it significantly increases its effectiveness.

The duration of therapy can range from 16 to 72 weeks, depending on the genotype of the hepatitis C virus and the response to treatment, which is largely associated with the individual characteristics of the patient, which are determined by his genome.

A course of antiviral therapy using the “gold standard” can cost a patient from $5,000 to $30,000, depending on the choice of drugs and treatment regimen. The main costs are for interferon drugs. Foreign-made pegylated interferons are more expensive than conventional interferons from any manufacturer.

In most regions of Russia, treatment is not covered by compulsory medical insurance and is provided through regional programs. For example, in Moscow alone, up to 2,000,000,000 rubles are spent annually on treating people with hepatitis C, treating up to 1,500 patients per year. At the same time, 70,000 patients are officially registered in Moscow alone. It turns out that it will take 50 years to cure them all.

In addition to standard therapy, in 2018, for patients with chronic hepatitis C who are not at high risk of death from other causes, interferon-free therapy with direct-acting antivirals (DAAs) is recommended for a period of 8 to 24 weeks. Patients at high risk of complications (assessed by the degree of liver damage) should be considered first. Currently, interferon-free AVT regimens use inhibitors of the replication of three non-structural HCV proteins: NS3/4A protease, NS5A interferon-resistant protein, and NS5B polymerase.

The effectiveness of hepatitis C treatment is assessed by biochemical blood parameters (decreased transaminase activity) and the presence of HCV-RNA, and a decrease in the level of viral load.

New in hepatitis treatment

Although AbbVie Inc.'s second-generation NS3 and NS5A viral protein inhibitors glezaprevir/pibrentasvir received FDA registration on August 3, 2017, final phase 3 clinical trials of individual Maviret-based regimens are still ongoing and will continue until 2019. In particular, the optimal duration of therapy with glezaprevir/pibrentasvir for acute hepatitis C is being established, and the combination of glezaprevir/pibrentasvir and sofosbuvir is being studied as a “last resort” therapy for people with multidrug resistance.

The first pangenotypic representatives of the class of non-nucleoside NS5B polymerase inhibitors GSK2878175 and CC-31244 are undergoing phase I-II clinical trials. Both inhibitors can potentially be used in combination therapy with both other classes of DAAs and indirect-acting antiviral drugs.

Maviret was officially registered with the Ministry of Health of the Russian Federation on April 13, 2018, after which it appeared in pharmacies. The average cost of a Mavyret package exceeds 350 thousand rubles, and the price of a standard 8-week course of treatment reaches 600-700 thousand rubles or more.

It is worth noting that treatment standards for people with hepatitis C are changing rapidly. Sofosbuvir, daclatasvir and the sofosbuvir/ledipasvir combination are among the preferred treatment regimens in WHO guidelines and can achieve cure rates of 95%.

Side effects of antiviral therapy

If treatment with interferons is indicated, side effects cannot be avoided, but they are predictable.

After the first interferon injections, most people experience the syndrome. After 2-3 hours, the temperature increases to 38-39 0 C, there may be chills, pain in muscles and joints, and noticeable weakness. The duration of this condition can be from several hours to 2-3 days. Within 30 days, the body is able to get used to the administration of interferon, so by this time the flu-like syndrome disappears. Weakness and fatigue persist, but we have to put up with it.

As for Ribavirin, it is usually well tolerated. But quite often, a general blood test reveals mild hemolytic anemia. Mild dyspepsia, rarely headache, increased levels of uric acid in the blood may occur, and very rarely intolerance to the drug is observed.

How long can people live with hepatitis C if left untreated?

It is very difficult to say unambiguously how many people live with hepatitis C, just like with HIV infection. In the average number of patients, cirrhosis can develop in approximately 20 to 30 years.

In percentage, depending on the age of the person, cirrhosis develops:

• in 2% of patients infected before 20 years of age;
• 6% of those who received the virus aged 21–30 years;
• in 10% of those infected at 31–40 years of age;
• in 37% of cases aged 41–50 years;
• 63% of those infected are over 50 years of age.

Also, most studies have proven that the development of fibrosis also depends on gender. In men, this pathology develops much faster and in a more severe form, even if treated.

For quotation: Nadinskaya M.Yu. Treatment of chronic viral hepatitis // Breast cancer. 1999. No. 6. S. 4

Treatment of viral hepatitis, taking into account the level of morbidity, frequency of disability and mortality, is of great medical and socio-economic importance. Today, hepatitis B, C and D viruses are the most common causes of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). The goal of therapy for chronic viral hepatitis is to eradicate the virus, slow the progression of the disease and reduce the risk of developing HCC. The only drug with proven effectiveness in the treatment of chronic viral hepatitis is interferon-a. With its use, a stable response is achieved in 25 - 40% of patients with chronic hepatitis B, 9 - 25% with chronic hepatitis D and 10 - 25% with chronic hepatitis C. A new direction in the treatment of chronic viral hepatitis is the use of nucleoside analogues: lamivudine and famciclovir in the treatment chronic hepatitis B and ribavirin in combination with interferon in the treatment of chronic hepatitis C.

Interferon. Interferons (IFNs) are glycoprotein cytokines that have antiviral, immunomodulatory and antiproliferative activities. These cytokines are produced by immune cells in response to viral antigens. Interferons inhibit viral replication, increase the expression of HLA class I antigens (major histocompatibility complex) on the cell surface, stimulate the maturation of cytotoxic T cells and enhance the activity of NK cells (natural killer cells). These mechanisms ensure the clearance of infected cells from the virus. In addition, recently there is evidence that IFN slows down fibrogenesis in the liver. This is due to both a decrease in the activity of the inflammatory process in the liver as a result of the eradication of a viral infection, and with the direct effect of IFN on collagen synthesis.
There are two types of IFN. Type I includes IFN- a and IFN-b , to the second - IFN- g. IFN-a has shown the greatest effectiveness in the treatment of chronic viral hepatitis . Both leukocyte (natural) and recombinant preparations of IFN- a. The latter are most widespread. INF-a drugs are used parenterally - subcutaneously or intramuscularly, but the advantages of any of these two methods of administration have not been established.

Response to IFN therapy

The main indicators of the effectiveness of IFN-a therapy are: disappearance of viral replication markers and normalization of alanine transaminase (ALT) levels. Depending on these indicators, by the end of treatment and 6 months after its completion, several types of response are distinguished:
1. Lasting response. It is characterized by the disappearance of viral replication markers and normalization of ALT levels during treatment and for 6 months after the end of the course of therapy.
2. Unstable (transient) response. During treatment, replication markers disappear and ALT levels normalize, but a relapse develops within 6 months after stopping treatment.
3. Partial answer. During treatment, ALT levels decrease or normalize, while markers remain replication.
4. No response. Virus replication and elevated ALT levels persist.
The magnitude of the sustained response reflects the effectiveness of interferon therapy. If a relapse has not occurred 6 months after completion of treatment, then the likelihood that it will occur in the future is low.
In cases where a stable response is not achieved and a relapse develops, a second course of treatment is carried out.
If the response is incomplete or absent, the dose of IFN is adjusted or combined treatment regimens are used.
Contraindications for treatment with IFN- a chronic viral hepatitis:
1. Decompensated cirrhosis of the liver.
2. Severe somatic diseases.
3. Thrombocytopenia< 100 000/мл.
4. Leukopenia< 3000/мл.
5. Continued use of drugs or alcohol.
6. A history of mental illness (especially severe depression).
Given the high risk of developing HCC, patients with cirrhosis should be considered candidates for IFN-a therapy. Interferon therapy is carried out in these patients if the synthetic function of the liver is preserved, the number of platelets is more than 100,000/ml, leukocytes are more than 3000/ml, there is no history of complications of cirrhosis (bleeding from esophageal varices, ascites, hepatic encephalopathy) and there is no significant increase in the level of a-fetoprotein.

Side effects during treatment with IFN-a

The most common side effect during treatment with IFN-a There is a so-called flu-like syndrome, which develops 3 to 5 hours after administration of the drug and is characterized by fever, myalgia, arthralgia, and headache. This syndrome is most severe after the first injection and usually decreases significantly during the 1st and 2nd weeks of treatment. The severity of the syndrome can be significantly reduced by using IFN before bedtime and by administering paracetamol and/or non-steroidal anti-inflammatory drugs during IFN administration and the next morning.
Frequent side complications include a decrease in platelets and leukocytes, which most pronounced in patients with liver cirrhosis and usually develops in the 2nd to 4th month of treatment. If severe thrombocytopenia and/or leukopenia occurs, reduce the dose of IFN.
Rare side effects are decreased appetite and weight loss during treatment, which do not require discontinuation of treatment. Rare adverse reactions also include depression, which more often develops in patients with a severe mental history. If depression develops, treatment should be stopped. Therefore, patients with a history of depression should be evaluated by a psychiatrist before starting treatment.
Autoimmune complications when using INF-a develop rarely, but their occurrence requires discontinuation of treatment.

Treatment of chronic hepatitis C

Hepatitis C virus is the leading cause of chronic hepatitis and HCC, and, leading to the development of decompensated cirrhosis, is the most common indication for liver transplantation. According to WHO, about 1% of the world's population is infected with the hepatitis C virus. In the Russian Federation, the incidence of hepatitis C has been registered since 1994, and its significant increase has been noted (from 1994 to 1997, the increase in incidence was 180%). The highest incidence is observed in adolescents and young adults.
In works that have studied natural evolution of hepatitis C viral infection, it has been shown that the time from the onset of infection to the development of clinically significant hepatitis averages 10 - 20 years, to the development of liver cirrhosis - more than 20 years, and to the development of HCC - about 30 years. These data, as well as the increase in infection with the hepatitis C virus and the lack of effective immunoprophylaxis, suggest a continued increase in morbidity and mortality from liver cirrhosis caused by this virus in the next 10 to 20 years.
The purpose of treatment patients with chronic hepatitis C is eradication of the virus, slowing the progression of the disease and reducing the risk of developing HCC.
Indications for INF- therapya patients with chronic hepatitis C: detection of HCV RNA in the blood and increased ALT levels.
Factors predicting a good response to IFN therapy a : short period of disease, young age, absence of cirrhosis, low level of HCV RNA (< 10 5 k/ml), HCV genotype 2 - 6, HIV negative, female gender.
The most important factor in response is the genotype of the virus. The least effective treatment is achieved in patients infected with genotype 1b. This genotype in the Russian Federation accounts for about 70% of all cases of infection. With long-term treatment, some patients with genotype 1b can achieve a stable response.
The most widespread is the following treatment regimen: 3 IU 3 times a week for 6 months. Monitoring of patients, including clinical analysis (number of leukocytes and platelets) and biochemical studies (transminases) are carried out on the 1st, 2nd and 4th weeks of treatment, then every 4 weeks until the end of the course of therapy.
When applying the described treatment regimen, eradication of HCV RNA and normalization of ALT by the end of the course of treatment is achieved in 30 - 40% of patients, however, most of them develop a relapse over the next 6 months and the magnitude of the persistent response is 10 - 20%. An increase in sustained response can be achieved by increasing the duration of interferon therapy from 6 to 12 months or increasing the doses of IFN- a in the first 3 months of treatment up to 6 IU 3 times a week.
The first assessment of the effectiveness of treatment is carried out 3 months from the start of IFN- a . This is due to the fact that in 70% of patients who achieve a sustained response, HCV RNA disappears from the blood within the first 3 months of therapy. Although some patients may clear HCV RNA during the follow-up period (between 4 and 6 months of treatment), they are unlikely to achieve a sustained response.
Recent published studies indicate that interferon therapy may slow the progression of liver cirrhosis and prevent or delay the development of HCC in patients with chronic hepatitis. Therefore, with a high degree of hepatitis activity, when the goal of interferon therapy is to slow the progression of the disease, continued therapy with IFN- a.
There is controversial evidence regarding the need to treat patients with normal or slightly elevated ALT levels. According to modern concepts, treatment in these patients should be carried out when a high concentration of HCV RNA is detected in the blood or the presence of high inflammatory activity in the liver.
Patients who have developed a relapse are given a second course of therapy with the same IFN-a in higher doses (6 IU 3 times a week) or recombinant IFN-a is replaced with leukocyte one. Treatment is carried out for 12 months. A durable response is achieved in 30 - 40% of patients.
An alternative regimen for patients who relapse or do not respond to treatment is the use of IFN-a in combination with ribavirin.
Ribavirin is an analogue of purine nucleoses and has a wide spectrum of antiviral activity against RNA and DNA viruses. The mechanism of its action has not been fully studied. It is assumed to have a damaging effect on viral RNA and the synthesis of viral proteins.
When ribavirin is used as monotherapy, there is no reduction in HCV RNA concentrations, although ALT levels are significantly reduced. When used in combination with IFN- a the magnitude of the sustained response increases to 49% compared with the use of IFN alone. This occurs by reducing the frequency of relapses. Ribavirin doses range from 600 to 1200 mg per day.
The most common side effect of ribavirin treatment is hemolytic anemia. The average decrease in hemoglobin is 3 g/dl,although there have been cases of decreases of more than 5 - 6 g/dl. A decrease in hemoglobin to a level of 8.5 g/dL requires discontinuation of treatment. Other common side effects include rash and nausea. It should be taken into account that ribavirin is a teratogenic drug, therefore, women of reproductive age receiving ribavirin treatment should use contraception. The duration of teratogenic risk after discontinuation of ribavirin therapy is not clearly defined.
In the treatment of chronic hepatitis C, other drugs are also used as monotherapy or in combination with IFN-a . These include: antiviral drugs - amantidine; cytokines - granulocyte-macrophage stimulating factor and thymosin a1; ursodeoxycholic acid. Phlebotomies are used to reduce iron levels. But none of these agents showed a significant effect on either the titer of HCV RNA in the blood or slowing the progression of the disease.
Approaches to the treatment of chronic hepatitis C with coinfection with the hepatitis G virus do not differ significantly from those for chronic hepatitis C without coinfection.
Further directions towards increasing the effectiveness of treatment of chronic hepatitis C include the study of HCV-specific protease inhibitors - helicases, as well as the study of modification of IFN- a with long chain polyethylene glycol attached to it. This modification increases the half-life of interferon from 6 hours to 5 days, which allows this drug to be administered once a week. Clinical studies are currently underway.
The development of decompensated liver cirrhosis in patients with chronic hepatitis C is an indication for liver transplantation. In most countries, 20 to 30% of all liver transplants are performed for this reason. After transplantation, most patients develop recurrent HCV infection in the donor liver. However, this does not affect the rate of graft rejection and survival compared with transplants performed for other reasons. In the post-transplant period for the treatment of viral hepatitis C IFN-a alone or in combination with ribavirin has limited value.
There is currently no specific prevention of chronic hepatitis C. The large genetic heterogeneity of the virus genome and the high frequency of mutations introduce significant difficulties in creating a vaccine.

Treatment of chronic hepatitis B

The frequency of HBsAg infection in the population is subject to significant fluctuations depending on the geographical area and averages 1 - 2%. In the Russian Federation in recent years there has been a tendency to increase the incidence of hepatitis B.
Goal of therapy chronic hepatitis B - achieving seroconversion and elimination of HBsAg, slowing the progression of the disease and reducing the risk of developing HCC.
Indications for interferon therapy: detection of HBV replication markers - HBeAg, HBcAb IgM, HBVDNA and elevated ALT levels.
: ALT level exceeding the norm by 2 times or more (compared to the normal ALT level, the value increases 2 times), short medical history, low level of HBV DNA (level less than 200 pg/ml increases the response 4 times), absence of history of indications for taking immunosuppressants, the presence of histological signs of activity, HIV negativity.
The first assessment of the effectiveness of treatment is assessed by the onset of seroconversion - elimination of HBeAg and the appearance of anti-HBe. Almost simultaneously with HBeAg, HBV DNA disappears. During the onset of seroconversion (2nd - 3rd month of treatment), the level of transaminases increases by 2 - 4 times relative to the initial level, which reflects the immunologically determined elimination of HBV. Increased cytolytic syndrome is usually asymptomatic, but in some patients clinical deterioration occurs with the development of jaundice and, in some cases, hepatic encephalopathy.
The most commonly used is the following IFN-treatment regimena : 5 IU daily or 10 IU 3 times a week. Duration of therapy is 16 - 24 weeks. Patients are monitored weekly for the first 4 weeks of treatment, then every 2 weeks for 8 weeks and then once every 4 weeks. The clinical condition, the number of blood cells and the level of transaminases are monitored.
When using the above treatment regimens, a transient response is achieved in 30 - 56% of patients. A persistent response was observed in 30 - 40% of patients. The disappearance of HBsAg is achieved in 7 - 11%. The magnitude of the persistent response decreases during infection with a mutant strain of HBV (when HBeAg is not detected), as well as in patients with liver cirrhosis and with low initial biochemical activity.
Treatment of patients with liver cirrhosis caused by HBV is carried out with lower doses of IFN-a (3 IU 3 times a week), for a long period - 6 - 18 months.
There is no clear opinion regarding the use of prednisolone to increase the effectiveness of treatment in patients with initially low ALT levels. Use of a preliminary course of treatment with prednisolone (scheme: 2 weeks at a daily dose of 0.6 mg/kg, 1 week at a dose of 0.45 mg/kg, 1 week at a dose of 0.25 mg/kg, then discontinuation and after 2 weeks IFN-a ) showed an increase in treatment effectiveness. However, in 10-15% of patients, its use leads to the development of decompensation of the disease and the impossibility of further interferon therapy.
If seroconversion does not occur within the first 4 months of treatment or patients with a complete initial response develop a relapse, then it becomes necessary to adjust the treatment regimen or conduct a repeat course of therapy. For this purpose, lamivudine or famciclovir is used. These drugs are used either alone or in combination with IFN-a.
Lamivudine and famciclovir are drugs with antiviral activity and are second generation nucleoside analogues. They only act on DNA viruses. Their advantage over IFN-a is ease of use (the drugs are administered orally) and the presence of significantly fewer side effects (weakness, headache, myalgia, abdominal pain, nausea, diarrhea).
There is limited data on the use of these drugs in the treatment of chronic hepatitis B. During the first course of treatment with lamivudine, its effectiveness is similar to that of IFN-a. When carrying out repeated courses of treatment, the use of lamivudine in combination with IFN-a leads to seroconversion in only 20% of patients.
In the treatment of chronic hepatitis B, other drugs are also used, such as levamisole, thymosin-a 1, and a complex of cytokines. Of this group of drugs, the most widely used is thymosin-a 1, a polypeptide of thymic origin. It has 35% homology with the C-terminal region of IFN-a , which is considered as an important component responsible for the antiviral effect. In preliminary studies, recombinant thymosin- a 1 showed similar efficacy to that of IFN-a in achieving a lasting response.
In patients with decompensated HBV cirrhosis, the only effective treatment is liver transplantation. In this case, it is necessary to take into account the high risk of developing viral hepatitis B in the donor liver in the post-transplantation period.
Specific prevention of chronic hepatitis B includes the use of a vaccine.

Treatment of chronic hepatitis D

The detection rate of hepatitis D virus in patients with positive HBsAg is approximately 5 to 10%. The possibility of developing hepatitis D should be considered in all patients with chronic HBV infection.
Goal of therapy- elimination of HDV RNA and HBsAg, reduction of disease progression.
Indications for IFN-therapya: presence of anti-HDV and HDV RNA in patients with compensated liver disease and signs of biochemical activity. Along with HDV RNA, a confirmatory test for CGD is the detection of HDAg in liver tissue.
Factors predicting durable response, not installed. Preliminary studies have shown that in HIV-infected patients the effectiveness of treatment for chronic hepatitis D corresponds to that in patients without HIV infection.
The following IFN-a treatment regimens are commonly used: : 5 IU daily or 9 IU 3 times a week. The duration of therapy is 6-12 months. Other treatment regimens for IFN- a : first 6 months 10 IU 3 times a week, then 6 months 6 IU 3 times a week. Monitoring of patients is carried out according to the scheme of chronic hepatitis B.
A transient response is achieved in 40 - 50% of patients. It is characterized by the disappearance of HDV RNA and normalization of ALT by the end of the course of therapy. With further follow-up, 25% develop a relapse. A persistent response is observed in 9 - 25% of patients. However, only in a small proportion of these patients (up to 10%) HBsAg disappears.
Research on the use of nucleoside analogues in the treatment of chronic hepatitis D has not been completed.
Prevention and the role of liver transplantation in the treatment of chronic hepatitis D are the same as for chronic hepatitis B.

Literature:

1. Poynard T, Bedossa P, Opolon P, et al. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR and DOSVIRC groups // Lancet 1997;349 (9055):825-32.
2. Data from the Federal Center for State Sanitary and Epidemiological Surveillance of the Ministry of Health of the Russian Federation, 1998.
3. Lvov D.K., Samokhvalov E.I., Mishiro S. et al. Patterns of spread of the hepatitis C virus and its genotypes in Russia and the CIS countries // Questions of Virology 1997;4:157-61.
4. Ouzan D, Babany G, Valla D. Comparison of initial and fixed-dose regimens of interferon-alpha2a in chronic hepatitis C: a randomized controlled trial. French Multicenter Interferon Study Group // J Viral Hepat. 1998;5(1):53-9.
5. Shiffman ML. Management of hepatitis C // Clinical perspectives in gastroenterology 1998;6-19.
6. Reichard O, Schvarcz R, Weiland O. Therapy of hepatitis C: alpha interferon and ribavirin // Hepatology 1997;26 (3) Suppl 1: 108-11.
7. Malaguarnera M, Restuccia S, Motta M et al. Interferon, cortisone, and antivirals in the treatment of chronic viral hepatitis: a review of 30 years of therapy// Pharmacotherapy 1997;17(5):998-1005.
8. Krogsgaard K, Marcellin P, Trepo C, et al. Pretreatment with prednisolone enhances the effect of human lymphoblastoid interferon in chronic hepatitis B// Ugeskr Laeger 1998 (Sep 21);160 (39):5657-61.
9. Mutimer D, Naoumov N, Honkoop P, et al. Combination alpha-interferon and lamivudine therapy for alpha-interferon-resistant cronic hepatitis B infection: results of a pilot study // J Hepatol 1998;28 (6):923-9.
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11. Farci P, Mandas H, Coiana A, et al. Treatment of chromic hepatitis D with interferon-2 a// N Engl J Med 1994;330:88-94.

How to kill the hepatitis C virus is a pressing issue due to the spread of infection and its ability to lead to serious complications. There are dozens of traditional and non-traditional therapies. There are experimental and classical schemes to combat the disease. Cases of self-healing from hepatitis C have been recorded. Doctors recommend a treatment regimen. But the last “word” always belongs to the patient. What to trust and how to treat?

When hepatitis C is diagnosed, antiviral treatment does not always need to be started immediately. In approximately 5-20% of patients, the body is able to kill the viral hepatitis infection on its own. How? The immune system is triggered. If it is strong, the patient is young and does not suffer from anything other than hepatitis, the doctor may postpone the therapeutic course. At the same time, attention is paid not only to the age of the infected person, but also:

• genotype of the identified virus;
• duration of infection;
• virological load;
• the patient's tendency to develop cirrhosis.

When choosing treatments for a disease, doctors pay special attention to the last factor. To determine how likely a patient is to have cirrhosis, the doctor conducts a study to identify specific immunogenetic markers.

Questioning the patient is also important. The tendency to develop liver cirrhosis is genetically determined.

If the risk of developing a complication is high, treatment begins immediately, even with other prerequisites for self-recovery. Cirrhosis is an irreversible process. The replacement of most normal hepatocytes with nonfunctional fibrous tissue is the reason for organ transplantation. And this threatens the patient's life. Firstly, the liver may not take root. Secondly, selecting a donor organ is difficult.

The main goal of therapy is eradication of the virus, that is, its removal from the body. If this is not possible, the course of treatment is aimed at slowing the progression of inflammation in the liver. This prevents the infection from progressing to cancer or cirrhosis.

The effectiveness of therapy depends on the following factors:

1. The patient's age and initial health.
2. Liver conditions at the time of hepatitis diagnosis.
3. Viral load, that is, the amount of detected pathogen in the blood.
4. Forms of hepatitis. It can be acute or chronic.

Drug treatment is based on the use of antiviral drugs. Direct-acting drugs are prescribed that attack the protein compounds of the hepatitis causative agent. The pathogen cannot reproduce further.

Until recently, the combination of Ribavirin and Interferon was considered the gold standard for hepatitis C therapy. However, this treatment was not safe. In addition, the effectiveness of therapy did not exceed 50%. Now there are more effective and safe drugs that can completely eliminate the virus. Among them are Ledipasvir, Sofosbuvir, Daclinase.

Antiviral therapy has contraindications. Among them:

• intolerance to individual components of the drug;
• unsuccessful treatment with similar drugs in the past.

In addition, new generation products are expensive. Every month you have to spend from 500 to 2500 dollars. Therefore, new products are available to a limited number of patients. Doctors are forced to prescribe the old treatment regimen.

Auxiliaries are mandatory when treating with both new generation drugs and Interferon. The main ones are hepatoprotectors. They protect liver cells and support their performance. Doctors often prescribe Essentiale and Silimar.

The choice of therapy is always individual and based on the results of the examination. Duration of use of medications is at least 3 months. In some cases, the patient has to take medications for years.

Research results have shown that the hepatitis C virus is highly resistant. It can remain active in dried blood for approximately 6 weeks. The lifespan of a virus in the air directly depends on temperature:

1. If the atmosphere is heated within +2-22 degrees, the pathogen can remain active for up to 7 days.
2. When the air temperature changes in one direction, the activity of the virus decreases.

It turns out that if the task is to kill a pathogen in the external environment, it is necessary to create conditions unfavorable for it. Cold will not destroy the pathogen, it will only reduce its activity. But boiling kills the virus.

If the hepatitis C virus is exposed to ultraviolet light, the pathogen dies instantly.

After the virus enters the body, a person may feel well for a long time, without even suspecting that he is infected. In this case, the causative agent of hepatitis can be released into the external environment along with saliva, blood and other biological fluids.

The following may be dangerous:

• blood dried on the surface of instruments (cosmetic and medical), razors and other objects;
• contaminated blood, semen and saliva that have come into contact with damaged skin or mucous membranes of a healthy person.

Outside the human body, at room temperature, the virus that causes hepatitis C can remain active for at least 16 hours. In some cases, the pathogen remains viable for up to 4 days.

It is worth remembering that you cannot become infected through airborne droplets or contact (shaking hands, hugging).

The infection can persist for a long time in donated blood. The pathogen survives in a reservoir for about 10 months.

The virus that causes hepatitis C is not resistant to various disinfectants. However, simply washing your hands after visiting public places may not be enough.

To quickly eliminate the viral agent, it is necessary to disinfect the damaged skin surface with any antiseptic. The pathogen can be destroyed by:

• boric, hydrochloric or phosphoric acid;
• hydrogen peroxide;
• Miramistin or Chlorhexidine.

During surgical operations, an iodine solution is used to treat the intervention area. This helps prevent the virus from entering an open wound.

What to do with surgical instruments? They are always sterilized in special devices where the equipment is exposed to high temperatures or ultraviolet rays.

In beauty salons, alcohol-containing liquids can be used for disinfection. For example, ethyl alcohol is a powerful antiseptic. In it, the virus dies within the second minute. Ethyl helps destroy the protein structure of the hepatitis C pathogen.

When treating a potentially contaminated item with alcohol, do not allow it to evaporate for several minutes. Otherwise, disinfection is not effective.

You can get rid of infection on things by boiling them. If the water temperature is above 50 degrees, the pathogen will die in half an hour. When the temperature reaches 100 degrees, the virus is destroyed in the second minute.

Therefore, simply washing items with dried blood at 40-60 degrees may not be enough.

If infected blood comes into contact with your skin, you should:

1. Use bleach. To do this, the powder is dissolved in water in a ratio of 1 to 100. The solution is effective against hepatitis and tuberculosis viruses.
2. If the skin is damaged by a sharp object, it is necessary to compress the wound, trying to squeeze out the blood from it. After this, the cut site must be treated with soapy water and lubricated with ethyl alcohol or iodine.
3. If infected blood gets into the eyes, they should be rinsed well with a 1% boric acid solution.
4. If there is a possibility of the virus getting into the mouth, it is necessary to spit out as much saliva as possible and rinse the cavity with a 70% alcohol solution or manganese solution.
5. If the virus gets into the nasal passages, you need to drip a silver solution. In pharmacies it is called Protargol.

In most cases, after performing the steps described above, the hepatitis C virus dies. To verify this, you need to undergo a comprehensive examination. It is carried out at 1, 4 and 12 weeks after the suspected infection.

Since effective treatment of hepatitis C requires significant financial costs, non-traditional treatment regimens are gaining wide popularity. One of them is the method of Professor Neumyvakin, based on the use of hydrogen peroxide.

The drug should be used as follows:

• on the first day, take 2-3 drops of peroxide dissolved in a tablespoon of water three times a day;
• daily the amount of peroxide is increased by 1 drop;
• when the dosage reaches 10 drops, stop increasing the dose and take the medicine for another 10 days.

Another question is the effect of the drug on the body.

Neumyvakin emphasizes that serious ailments are possible:

• vomit;
• diarrhea;
• dizziness;
• weakness.

Therefore, before starting therapy using the Neumyvakin method, it is important to consult with your doctor. A history of organ transplantation may be a contraindication to the use of the experimental regimen.

Traditional methods of fighting the virus

If a patient has contraindications to drug treatment for hepatitis C, you can use the practices of herbalists. They advise using medicinal herbs that have anti-inflammatory, immunostimulating, analgesic and antispasmodic effects.

Herbal therapy is aimed at the body’s synthesis of interferon. Human cells are capable of producing it themselves. Interferon has an inhibitory effect on the virus and prevents the development of complications of hepatitis.

For this use:

• a decoction made from milk thistle seeds;
• alcohol tincture of milk thistle seeds;
• powder made from dried dandelion root;
• a decoction made from unpeeled oats;
• product based on Caucasian hellebore;
• infusion made from corn silk;
• black radish juice mixed with natural honey;
• water tincture of perennial daisy;
• tincture of lovage (seeds and leaves).

In addition, natural juices of lemon, blueberries, carrots and cabbage can be used. Your doctor will tell you how much to take and according to what regimen.

Doctors have proven that the human body is able to get rid of the virus that causes hepatitis C on its own. This is possible if a person has a strong immune defense. The state of immunity also plays an important role in the standard treatment of the disease. To reduce the time of treatment, as well as to avoid the dangerous consequences of hepatitis, you should follow a certain diet and give up bad habits.

Additionally required:

1. Maintain a drinking regime, drinking at least 7-8 glasses of clean still water per day.
2. Avoid eating fatty, fried and spicy foods, chocolate, baked goods and smoked meats.
3. Avoid alcohol.
4. Provide yourself with a nutritious diet rich in plant foods.
5. Avoid prolonged fasting.
6. Eat small meals. It is advisable to have meals 5-6 times per day, preparing 200-gram portions.
7. Limit your sugar intake.

Which virus genotype is more difficult to kill?

In total, doctors were able to identify 11 different genotypes of this virus, but only six are recognized by the World Health Organization:

• the first is divided into 3 subtypes: a, b, c;
• the second a, b, c and d quasitypes;
• the third genotype is divided into a, b, c, d, e, f subtypes;
• the fourth strain also has quasitype g;
• The fifth and sixth genotypes of hepatitis C have only one a-strain.

The most common is genotype 1. It infects about 46% of all patients with hepatitis C. Less commonly, in about 30% of cases, a 3rd strain of the pathogen is diagnosed.

The traditional treatment regimen based on the use of Interferon is the most responsive to genotype 1b. Since interferon-free treatment regimens have been developed, it is possible to get rid of this type of infection.

Treatment for hepatitis C is long and expensive. Therefore, doctors recommend taking preventive measures to prevent infection. If this fails, treatment should be prescribed by a doctor. If drug therapy is not possible for any reason, the doctor may recommend unconventional methods.

Optimal combinations of oral agents for eradication of hepatitis C virus: the role of ribavirin

1 Department of Hepatology and Gastroenterology, Hopital Henri Mondor, AP-HP, Universite Paris-Est, INSERM U955, Creteil, France; 2 Department of Hepatology and Gastroenterology, Center Hospitalier Universitaire de Nancy, Universite de Lorraine, INSERM U954, Vandoeuvre-les-Nancy, France

Essay

Modern all-oral interferon-free regimens achieve sustained virological response (SVR) in 90% of cases and can reduce treatment duration to 12 weeks. in most patients with chronic hepatitis C, including patients with and without cirrhosis, previously untreated and already treated. There are many combinations of direct acting antiviral drugs (DAAs) that can be used to achieve an optimal balance between the effectiveness and safety of therapy. Each of these regimens can be modified in various ways, including the use of ribavirin (RBV). When using sofosbuvir-based combinations (SOF), the use of RBV is appropriate in the following situations: in patients infected with hepatitis C virus (HCV) genotype 1, previously treated and with cirrhosis or decompensated cirrhosis, and in patients infected with HCV genotype 3, with cirrhosis of the liver. In these situations, the addition of RBV can reduce the duration of treatment to 12 weeks. in most cases, which leads to a decrease in its value. The need to use RBV in patients with cirrhosis treated with SOF and simeprevir remains to be determined. RBV is recommended for the treatment of all patients infected with HCV genotype 1a receiving a combination of three DAAs: paritaprevir/ritonavir, ombitasvir, dasabuvir. In general, adding RBV to various DAA combinations slightly increases the risk of anemia. However, severe anemia is rare and responds well to RBV dose reduction without affecting SVR.

In practice, because RBV is an inexpensive drug that is well tolerated when combined with interferon-free regimens, it remains an effective tool for improving hepatitis C treatment regimens and optimizing their results.

© 2015 European Association for the Study of the Liver.

Key words: ribavirin, direct-acting antiviral drugs, interferon-free, sofosbuvir.

Abbreviations: ASV - asunaprevir; APRI - aspartate aminotransferase/platelet index; DCV - daclatasvir; HCV - hepatitis C virus; IFN - interferon; LDV - ledipasvir; PegIFN - peginterferon; RBV - ribavirin; SMV - simeprevir; SOF - sofosbuvir; GPT - guanosine triphosphate; IMPDH - inosine monophosphate dehydrogenase; DAAs - direct acting antiviral drugs; SVR - sustained virological response; CHC - chronic hepatitis C.

Introduction

Chronic hepatitis C (CHC) occurs with progressive liver damage, which can lead to the development of cirrhosis and hepatocellular cancer. According to modern estimates, CHC affects about 130–150 million people, and its mortality rate is 350,000 cases per year. Today, 7 genotypes of hepatitis C virus (HCV) have been identified, of which genotype 1 is the most common worldwide.

The current treatment for CHC is sofosbuvir (SOF), a uridine nucleotide analogue that inhibits nonstructural protein polymerase 5B (NS5B) and is used in combination with other drugs, including pegylated interferon (PegIFN), ribavirin (RBV), and direct-acting antivirals ( DPP). The use of SOF-based interferon-free regimens leads to an increase in the sustained virological response (SVR) rate of more than 90% while reducing the duration of treatment (≤12 weeks). Approval of other interferon-free regimens is expected based on results from phase III studies that found them to be as effective as interferon-free regimens containing SOF.

Combination therapy with RBV significantly increased response rates to PegIFN by preventing relapses. RBV has been an important component of PegIFN-based regimens that included first-generation protease inhibitors used to prevent virologic breakthrough or relapse, but results from phase II studies examining interferon-free DAA-based regimens suggest that inclusion of RBV in the regimen is not required. Always . Although RBV is less toxic in the absence of PegIFN, it is teratogenic and causes hemolytic anemia. Therefore, the purpose of this review was to identify patient populations for which recommendations for the use of RBV remain in the various DAA regimens currently approved or expected to be approved in the near future.

Mechanism of action of ribavirin

The disappearance (cure) of infected cells (the second phase of the curve) during antiviral therapy occurs under the influence of many parameters, some of which can be modified to optimize the response to treatment. These include the antiviral efficacy of the drug combination, duration of treatment, and use of RBV. Thus, patients with a slow decline in the curve in the second phase (such as patients with an unfavorable IL28B genotype, cirrhosis, HCV genotype 3 or 1a, etc.) require the use of a regimen with more pronounced antiviral efficacy for an appropriate period of time. In addition, RBV may be effective in both shortening treatment duration and increasing SVR rates for a given treatment duration. This is due to the acceleration of the second phase of viral load reduction by RBV through as yet unidentified mechanisms in patients who have achieved effective suppression of viral production using interferon-free regimens.

RBV has been found to produce strong, moderate, or transient antiviral effects in a significant proportion of patients receiving it as monotherapy. Moreover, during RBV monotherapy, a decrease in serum alanine aminotransferase levels was observed, which was independent of the antiviral activity of the drug. A number of possible mechanisms of direct inhibition of viral RNA polymerase by the drug are suggested. However, the modest antiviral effect of RBV monotherapy in vivo makes this hypothesis (direct inhibition of RNA polymerase) unlikely. It has been suggested that the antiviral activity of RBV is due to depletion of intracellular guanosine triphosphate caused by inhibition of inosine monophosphate dehydrogenase (IMPDH) by the drug. However, other potent specific inhibitors of IMPDH, used alone or in combination with RBV or IFN, do not have a significant effect on HCV replication in patients with CHC. This suggests that IMPDH inhibition is not related to the antiviral activity of RBV. In HCV-infected patients receiving RBV, the concept of the mutagenic properties of RBV leading to the development of an “error catastrophe”, i.e., disruption of the distribution of mutant variants in quasispecies and the emergence of a generation of non-viable viral populations, has also been studied. However, conflicting results were obtained. However, a recent study was performed in which the analysis of RBV-induced mutations was carried out using a highly sensitive deep sequencing method. This study found that RBV is mutagenic against HCV by inducing nucleotide substitution, which may explain the antiviral activity of RBV. But RBV-induced mutagenesis does not explain the development of the biochemical response. Finally, the hypothesis that RBV may act as a factor that stimulates the IFN signaling pathway by enhancing the induction of IFN-stimulated genes has not been confirmed in vivo. Thus, the discrepancy between the antiviral and biochemical responses to RBV suggests that RBV may act through different mechanisms. At the same time, the direct antiviral effect of the drug is partly explained by its mutagenic properties, and the indirect biochemical effect is realized through an as yet unknown mechanism.

Effect of RBV on treatment efficacy in patients without cirrhosis infected with HCV genotype 1

Sofosbuvir-based regimens

In vitro, strong pangenotypic activity of SOF against HCV (genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a and 6a) was demonstrated at concentrations that inhibited viral replication by 50%, equal to 0.014–0.11 μM. In vitro studies using drug combinations have demonstrated additive interactions between SOF and IFN. Only minor synergism was found for the combination of SOF and RBV. However, in the phase II ELECTRON study, all 10 treatment-naive patients infected with HCV genotypes 2 and 3 who received SOF + RBV therapy for 12 weeks achieved SVR at week 24 (SVR24). Another 10 treatment-naive patients infected with HCV genotypes 2 and 3 received SOF monotherapy for 12 weeks, and only 6 of them achieved SVR24. In this group, all 10 patients had a rapid response and had undetectable HCV RNA levels by week 4 of treatment, which persisted throughout the remainder of the treatment period. 4 patients developed a relapse after completion of treatment. Although the study's statistical power is limited due to the small sample size, the findings highlight the important role of RBV in preventing relapse and maintaining the antiviral response.

Sofosbuvir and ribavirin

An independent study evaluated the effectiveness of SOF in combination with RBV for 24 weeks. in treatment-naive patients infected with HCV genotype 1. In the second part of the study, 50 patients were randomized to receive SOF in combination with RBV, which was given either based on body weight or at a low dose of 600 mg/day . The SVR24 rate was 68% in patients given weight-based RBV and only 48% in patients given low-dose RBV. However, given the low effectiveness/cost ratio, the use of this strategy in patients infected with HCV genotype 1 is not recommended.

Sofosbuvir and ledipasvir

3 phase III studies evaluated the combination of SOF with ledipasvir (LDV) (an NS5A inhibitor) with and without RBV (1000 mg/day in patients weighing less than 75 kg and 1200 mg/day in patients weighing 75 kg or more ) in different groups of patients infected with HCV genotype 1 (Table 1). It is important to note that these studies were not sufficiently powered to compare responses to regimens with and without RBV or treatment efficacy at 12 and 24 weeks. In treatment-naïve patients without cirrhosis infected with HCV genotype 1, SOF + LDV for 8 weeks. was as effective as SOF + LDV with RBV for 8 weeks. and SOF + LDV regimen for 12 weeks. The SVR rate was 94 vs 93 vs 95%, respectively. In treatment-naïve patients with or without cirrhosis infected with HCV genotype 1, SOF + LDV for 12 weeks. was as effective as SOF + LDV with RBV for 12 weeks. and SOF + LDV or SOF + LDV + RBV regimen for 24 weeks. (99 vs 97 vs 98 vs 99% respectively). In patients without cirrhosis, the addition of RBV had no effect on SVR. The third study evaluated the same regimens as the first 2 studies but in previously treated patients with or without cirrhosis. SVR rates were similar between regimens with RBV (96 and 99% for 12 and 24 weeks, respectively) and without (94 and 99% for 12 and 24 weeks, respectively). In patients without cirrhosis, use of RBV had no effect on SVR. Based on the above, SOF and LDV without RBV can be used in patients without cirrhosis infected with HCV genotype 1.

Sofosbuvir and daclatasvir

Daclatasvir (DCV) is a potent pan-genotypic NS5A inhibitor with antiviral activity against HCV genotypes 1–6, which is used in combination with SOF for the treatment of CHC. The effectiveness of this combination (SOF + DCV) with and without RBV (1000 mg/day in patients weighing less than 75 kg and 1200 mg/day in patients weighing 75 kg or more) was studied primarily in patients without cirrhosis, infected genotype 1 virus. Patients were randomly assigned to groups receiving SOF + DCV with and without RBV for 12 weeks. (82 previously untreated patients) or 24 weeks. (41 patients who had previously experienced treatment failure with telaprevir or boceprevir in combination with IFN and RBV). In treatment-naïve patients, SVR12 rates were 100% and 95% in the SOF + DCV and SOF + DCV + RBV groups, respectively. In patients with prior virologic failure on protease inhibitor therapy, SVR12 rates were 100% and 95% in the SOF + DCV and SOF + DCV + RBV groups, respectively. In an uncontrolled cohort of patients in real-world clinical practice, the SVR4 rate was 100% in 20 patients with severe fibrosis (but without cirrhosis, fibrosis stage based on non-invasive markers) infected with HCV genotype 1 who received SOF + DCV without RBV for 12 weeks. . Due to the small number of patients receiving this regimen, no definitive conclusions can be drawn regarding the effectiveness of the addition of RBV. However, these preliminary results suggest that the addition of RBV to this combination is not necessary.

Sofosbuvir and simeprevir

In the COSMOS study, the combination of SOF and simeprevir (SMV), a protease inhibitor, with or without RBV for 12 or 24 weeks was effective. was evaluated in patients without severe fibrosis who were infected with HCV genotype 1 and were treatment-naïve or had not responded to previous therapy. SVR12 was achieved in 98 (91%) of 108 patients who received RBV and in 56 (95%) of 59 patients who did not receive RBV. SVR12 rates were similar regardless of prior therapy status (38 of 40 treatment-naive patients vs 116 of 127 treatment-naïve patients) and treatment duration (77 of 82 patients after 12 weeks of therapy vs 77 of 85 patients after 24 weeks of therapy). weeks of therapy). Neither RBV nor duration of therapy had a clear effect on SVR rates in patients infected with HCV with the Gln80Lys polymorphism at baseline. There was a high SVR rate in patients infected with HCV genotype 1a, regardless of the presence of the Gln80Lys polymorphism at baseline, and in patients infected with HCV genotype 1b. These results were confirmed in a phase III clinical trial that included patients without cirrhosis. Thus, the addition of RBV does not appear to improve treatment efficacy in patients without severe fibrosis, regardless of prior therapy status or HCV subtype. This combination can be recommended as an RBV-free regimen for all patients infected with HCV genotype 1, especially for patients without cirrhosis.

Paritaprevir-based regimens

The AbbVie regimen includes a fixed-dose combination of paritaprevir (formerly ABT-450)/ritonavir with ombitasvir (formerly ABT-267) in a single dosage form and dasabuvir (formerly ABT-333) (3-DAA) with weight-based RBV body (1000 mg/day in patients weighing less than 75 kg and 1200 mg/day in patients weighing 75 kg or more), or without it. Paritaprevir, an HCV NS3/4A protease inhibitor with potency at nanomolar concentrations in vitro, is coadministered with low-dose ritonavir (paritaprevir/ritonavir), a CYP3A4 inhibitor that does not itself have antiviral activity. Ombitasvir is an inhibitor of HCV NS5A with potency at picomolar concentrations in vitro, and dasabuvir is an inhibitor of HCV NS5B RNA polymerase with potency at nanomolar concentrations in vitro. Four phase III studies examined the effectiveness of the 3-DAA regimen in different groups of patients infected with HCV genotype 1, including patients without cirrhosis who had not previously received treatment and patients without cirrhosis who had previously received PegIFN and RBV therapy (Table 2). It is important to note that these studies were not sufficiently powered to compare responses to therapy with and without RBV.

The placebo-controlled study included 631 patients without cirrhosis who were infected with HCV genotype 1 and had not previously received treatment. In this study, during therapy with a 3-DAA + RBV regimen for 12 weeks. there was a high SVR12 rate of 96.2% (455 of 473). This rate was almost the same in patients infected with HCV genotypes 1a (95.3%; 307 of 322) and 1b (98%; 148 of 151). Based on these data, 2 large phase III studies were designed to evaluate the effect of RBV in combination with a 3-DAA administered for 12 weeks. on the effectiveness and safety of therapy in patients without cirrhosis of the liver infected with HCV genotype 1a or 1b who have not previously received treatment. These studies reported high SVR12 rates of 99.5 (209 of 210) and 99.0% (207 of 209) in patients infected with HCV genotype 1b with and without RBV supplementation, respectively. This suggests that RBV does not improve response rates in patients with HCV genotype 1b infection, allowing the use of an RBV-free regimen in these patients. In patients infected with HCV genotype 1a, high rates of SVR were observed both with and without RBV (97%; 97 of 100) use (90.2%; 185 of 205). There was a higher rate of virological failure (7.8 vs 2.0%) in the non-RBV group. The difference between the groups suggests that RBV improves the effectiveness of treatment in patients infected with HCV genotype 1a, which allows us to recommend the 3-DAA + RBV regimen as the optimal treatment method for these patients.

In a placebo-controlled study of treatment-experienced patients assigned to 3-DAA + RBV for 12 weeks, the SVR12 rate was 96.3% (286 of 297). The rate of virological failure was almost the same among patients infected with HCV genotypes 1a and 1b: 2.9 (5 of 173) and 1.6% (2 of 123), respectively. SVR12 rates were similar regardless of prior therapy status: 95.3 (82 of 86), 100 (65 of 65), and 95.2% (139 of 146) in patients who relapsed, those who achieved a partial response, and those who did not. reaching the answer, respectively. Based on these data, the benefit of including RBV in a 3-DAA regimen was assessed exclusively in HCV genotype 1b-infected patients without cirrhosis who had previously received PegIFN and RBV therapy. These patients were randomized to receive 3-DAA treatment for 12 weeks. with or without RBV. In the group not receiving RBV, the SVR12 rate was 100% (91 of 91), which was no less than that in the group receiving RBV (97%; 85 of 88). There were no virological failures recorded during treatment. Regimen with 3-DAA for 12 weeks. is sufficient to achieve an optimal response to treatment in HCV genotype 1b-infected patients without cirrhosis who have previously received PegIFN and RBV therapy. Based on the above, a regimen with 3-DAA without RBV for 12 weeks. is the optimal treatment for patients infected with HCV genotype 1b. Its use is accompanied by a high rate of HCV eradication. Patients infected with HCV genotype 1a require a full dose of RBV to maximize the chances of eradicating the virus.

Daclatasvir-based regimens

For the treatment of chronic hepatitis C, DCV has been prescribed with SOF and in combination with other DAAs. A randomized, open-label, phase II trial evaluated the efficacy of 12- and 24-week regimens consisting of low-dose DCV (30 mg/day) + SMV (NS3 protease inhibitor, 150 mg/day) with or without RBV (1000 mg/day in patients with a body weight of less than 75 kg and 1200 mg/day in patients with a body weight of 75 kg or more), in patients with chronic HCV infection genotype 1, who generally did not have cirrhosis. Of patients with HCV genotype 1b, 84.9 and 74.5% of treatment-naïve patients and 69.6 and 95.0% of treatment-unresponsive patients achieved SVR12 with DCV + SMV without RBV and with RBV accordingly. The duration of the response did not have a significant effect on its frequency. The addition of RBV to the DCV + SMV regimen also had little effect on SVR12 rates: in treatment-naïve patients, there was no increase in SVR12 rates with RBV, while in a smaller subgroup of patients who did not respond to previous therapy, SVR12 rates were found to be background RBV was higher. Among patients with HCV genotype 1a, the use of the DCV + SMV with RBV regimen resulted in a response in 66.7% of cases in patients who had not previously received treatment, and was ineffective in patients who had not achieved a response to previous therapy.

Asunaprevir (ASV) is an NS3 protease inhibitor active against genotypes 1, 4, 5 and 6 in vitro. Preliminary clinical evaluation of the DCV + ASV combination showed high SVR rates in patients infected with HCV genotype 1b. However, effectiveness against genotype 1a was limited. Therefore, a large phase III clinical trial examined the safety and efficacy of the oral combination of DCV + ASV without RBV for 24 weeks. in patients infected with HCV genotype 1b (including patients with cirrhosis of the liver), who have not previously received treatment, have not achieved a response to previous therapy with PegIFN + RBV, or have medical contraindications to the use of PegIFN + RBV, and/or are poorly tolerated this diagram earlier. SVR rates in this study ranged from 82% in previously unresponsive patients to 91% in treatment-naïve patients. One limitation of this study is the lack of a group in which RBV was added to the treatment regimen. It is possible that the addition of RBV could improve treatment efficacy in subgroups of patients with the lowest SVR rates with this two-drug regimen. It is interesting to note that administration of DCV and ASV with PegIFN and RBV at 24 weeks. was accompanied by a high SVR12 rate (98.9%) in patients infected with HCV genotype 1b who had not responded to previous therapy. This indicates the benefit of additional treatment in this group of patients who are difficult to respond to treatment.

Combining three antiviral drugs with different mechanisms of action also improves the resistance barrier and may increase treatment efficacy. Therefore, an all-oral combination of DCV, ASV and beclabuvir (BMS-791325), a non-nucleoside thumb polymerase inhibitor, was successfully tested (SVR12 rate 92%) in a phase II trial. Based on these results, a phase III study was designed to evaluate the efficacy of this all-oral, RBV-free combination in treatment-naïve and treatment-experienced patients without cirrhosis infected with HCV genotype 1. Overall, SVR12 was achieved in 91% of patients. However, a higher SVR rate was observed in patients infected with HCV genotype 1a compared to genotype 1b (100 vs 85–90%), indicating the need to study the effectiveness of an RBV-containing regimen in patients infected with HCV genotype 1a. However, due to safety concerns, Bristol-Myers Squibb recently decided not to register this combination with the American (FDA) and European (EMEA) Medicines Administrations.

Effect of RBV on treatment efficacy in patients with liver cirrhosis infected with HCV genotype 1

Sofosbuvir-based regimens

Sofosbuvir and ledipasvir

The effectiveness of the SOF + LDV regimen with or without RBV (1000 mg/day in patients weighing less than 75 kg and 1200 mg/day in patients weighing 75 kg or more) for 12 or 24 weeks. was evaluated in treatment-naive patients infected with HCV genotype 1, with or without cirrhosis. In patients with cirrhosis (METAVIR stage F4 or Ishak score 5–6; FibroScan score > 12.5 kPa or Fibrotest score > 0.75 and APRI > 2), the SVR12 rate was 100% with the SOF + LDV regimen with RBV for 12 or 24 weeks. and 94% during treatment with SOF + LDV for 12 or 24 weeks. This indicates the positive effect of RBV, and also that the SOF + LDV + RBV regimen for 12 weeks. is optimal for patients with liver cirrhosis infected with HCV genotype 1 who have not previously received treatment (see Table 1). Another study evaluated these same 4 groups with the same definition of cirrhosis as the previous study, but in treatment-experienced patients with and without cirrhosis. The SVR rate was almost the same in all groups. However, it was slightly lower in patients with cirrhosis who received treatment for 12 weeks. with the addition of RBV (82%) and without (86%), compared with patients treated for 24 weeks. with and without the use of RBV (100% in both groups) (see Table 1). The results of an analysis of data obtained from 513 patients with cirrhosis included in different phase II-III studies that assessed the effectiveness of the combination of SOF + LDV indicate that the use of SOF + LDV for 12 weeks. may be sufficient for the treatment of patients infected with HCV genotype 1 who have not previously received treatment. On the other hand, the SVR12 rate with SOF + LDV for 12 weeks. in patients with cirrhosis who had already received previous treatment was 90% compared with 96% during treatment with SOF + LDV + RBV for 12 weeks. and 98–100% with SOF + LDV for 24 weeks, with or without RBV. Thus, SOF + LDV + RBV for 12 weeks may be the most effective and cost-effective therapy in previously treated patients with cirrhosis infected with HCV genotype 1. This assumption is also supported by the results of the SIRIUS trial, which compared effectiveness of the SOF + LDV + RBV regimen for 12 weeks. and SOF + LDV combinations for 24 weeks. in patients with liver cirrhosis infected with HCV genotype 1 who have not previously achieved a response to therapy with first-generation protease inhibitors (in both groups the SVR12 rate was 95%). Unfortunately, this study did not evaluate the efficacy of SOF + LDV with RBV for 12 weeks. Rate of SVR12 in 20 HCV genotype 1-infected patients with cirrhosis (Child-Pugh stage B) treated with SOF + LDV for 12 weeks. was only 65%. Another study showed the effectiveness of SOF + LDV with RBV for 12 weeks. was compared with the effectiveness of the same regimen over 24 weeks. in patients infected with HCV genotype 1 with cirrhosis (Child-Pugh stages B and C). Recent evidence from an uncontrolled real-world cohort suggests that this regimen for 12 weeks. with RBV (164 patients) and without RBV (21 patients) in patients with decompensated liver cirrhosis infected with HCV genotype 1, led to the achievement of SVR in 86 and 81% of cases, respectively. The slight increase in efficacy in the RBV group may support its use in patients with HCV genotype 1. Thus, the use of RBV may reduce the duration of therapy to 12 weeks. in patients with liver cirrhosis who have already received previous treatment. Its use is recommended in patients with decompensated cirrhosis. Perhaps the overall conclusion is that adding RBV to a 12-week SOF + LDV regimen improves SVR rates.

Sofosbuvir and daclatasvir

In the phase II clinical trial, the number of patients with cirrhosis was extremely limited, and the effectiveness of a shorter course of therapy (12 weeks) was not assessed in patients who had previously failed with protease inhibitors. This indicates that the potential role of RBV is not clearly established and more data from clinical trials or real-world cohorts are required. The effectiveness of the SOF + DCV regimen for 12 and 24 weeks. with or without RBV was studied based on data from a large real-world cohort of patients with cirrhosis (diagnosed by non-invasive markers) infected with HCV genotype 1. This study was not controlled and the choice of treatment regimen was based on at the discretion of the doctor. Therefore, it is difficult to draw definitive conclusions regarding the use of RBV and the optimal duration of treatment in this population. However, SVR4 rates were 76.5 (26 of 34), 100 (9 of 9), 94 (203 of 216), and 98.3% (59 of 60) in patients treated with this regimen with and without RBV. it for 12 weeks, and in patients receiving the same therapy for 24 weeks, respectively. Based on preliminary data, it can be concluded that RBV may reduce the duration of treatment to 12 weeks. in this population. However, additional data are required in patients receiving SOF + DCV with RBV for 12 weeks. The efficacy of this regimen was evaluated in 45 patients with decompensated cirrhosis infected with HCV genotype 1 enrolled in an uncontrolled phase III trial. The initial dose of RBV was 600 mg per day. This dose was increased to 1000 mg per day taking into account hemoglobin levels and renal function. The overall SVR12 rate was 82%. Treatment was not equally effective in patients with stage A and B cirrhosis (>90%) and in patients with stage C cirrhosis (< 60 %) по шкале Чайлда-Пью. Это позволяет предположить, что применение схемы SOF + DCV с RBV (с повышением дозы) в течение 12 нед. является оптимальным методом лечения больных с декомпенсированным циррозом печени в стадиях A и B по шкале Чайлда-Пью, инфицированных HCV генотипа 1 . Комбинация SOF + DCV с RBV (45 пациентов) и без него (5 пациентов) назначалась на 12 нед. больным с циррозом печени, инфицированным HCV генотипа 1, вошедших в реальную неконтролируемую когорту. Частота УВО равнялась 82 и 60 % на фоне применения RBV и без него соответственно . Небольшой выбор участников, а также то, что выбор терапии проводился по усмотрению врача, не позволяют убедительно подтвердить эффективность применения RBV у этих больных. Из вышесказанного следует, что применение комбинации SOF + DCV с RBV в течение 12 нед. можно рекомендовать пациентам, инфицированным HCV генотипа 1, с декомпенсированным циррозом печени стадии B по шкале Чайлда-Пью. Необходимы дополнительные данные относительно пациентов с более тяжелым поражением печени (стадия C по шкале Чайлда-Пью).

Sofosbuvir and simeprevir

Efficacy of SOF + SMV regimen without RBV for 12 weeks. was studied in a phase III clinical trial in patients infected with HCV genotype 1 with compensated cirrhosis (FibroScan density greater than 12.5 kPa). SVR rates were lower than expected: 88 (44 of 50), 79 (42 of 53), 83 (60 of 72), and 84% (26 of 31) in treatment-naïve, treatment-experienced, patients infected with HCV genotypes 1a and 1b, respectively. Unfortunately, the effectiveness of the SOF + SMV regimen with weight-based RBV for 12 weeks. was not assessed in this study. Data from other combinations with SOF without IFN suggest that the addition of weight-based RBV (1000 or 1200 mg in patients with weight< 75 и? 75 кг соответственно), к SOF и SMV можно рекомендовать у пациентов с компенсированным циррозом, инфицированных HCV генотипа 1. Эффективность и безопасность применения SOF + SMV в течение 12 или 24 нед. с RBV или без него у больных с декомпенсированным циррозом, инфицированных HCV генотипа 1, оценивались в нескольких реальных когортах . Результаты этих исследований свидетельствуют о том, что добавление RBV может повысить частоту УВО12 в этой популяции .

Paritaprevir-based regimens

Large randomized phase III clinical trials examined the efficacy and safety of a 3-DAA regimen with RBV (1000 or 1200 mg/day depending on body weight) given for 12 or 24 weeks. in 380 HCV genotype 1 infected patients with compensated liver cirrhosis (METAVIR score > F3, or Ishak score > 4, or FibroScan results ≥ 14.6 kPa). In subgroup analyses, the difference in SVR12 rates between the subgroups receiving 12 and 24 weeks of therapy was found to be primarily due to differential response in patients with genotype 1a who had not previously responded to treatment. These data are supported by the fact that both viral subtype and lack of response to previous therapy were identified as predictors of SVR12. Patients with liver cirrhosis who had not previously responded to therapy achieved SVR12 in 86.7 and 95.2% of cases when treated for 12 and 24 weeks. respectively. Thus, in patients with genotype 1a who had not previously responded to treatment, the SVR12 rate was 80% (40 out of 50) when treated for 12 weeks. and 93% (39 of 42) when treated for 24 weeks. In all other subgroups of genotype 1a patients, including treatment-naïve patients and patients with partial response and relapse after prior therapy, response rates ranged from 92% to 100% for 12 and 24 weeks of treatment. Among patients with genotype 1b, all but one patient achieved SVR12 when treated for both 12 and 24 weeks. . Given these data, as well as the results obtained in patients without cirrhosis (see Table 2), it is clear that there is no need to evaluate the effectiveness of an RBV-free regimen in patients infected with HCV genotype 1a. However, the role of RBV and the need for its inclusion to maximize response rates in HCV genotype 1b patients with compensated cirrhosis remained incompletely established in this clinical trial. Therefore, the effectiveness of the RBV-free 3-DAA regimen in this patient population was evaluated. SVR12 was achieved in all 60 patients infected with HCV genotype 1b with compensated cirrhosis (METAVIR score > F3, or Ishak score > 4, or FibroScan ≥ 12.5 kPa), including treatment-naïve or treatment-experienced patients PegIFN and RBV patients. This indicates that there is no need to add RBV in these patients (see Table 2).

Daclatasvir-based regimens

The efficacy of the combination of DCV + SMV with or without RBV has been studied in patients with cirrhosis infected with HCV genotype 1b. Its use was accompanied by a lower SVR12 rate (69.2%) compared to patients without cirrhosis (82.6%). However, the small number of patients with cirrhosis may have contributed to interpatient variability. The effect of RBV on the effectiveness of therapy in patients with cirrhosis could not be analyzed in the present study due to the small number of studies.

In patients infected with HCV genotype 1 with compensated liver cirrhosis (METAVIR F4 score, or FibroScan results ≥ 14.6 kPa, or Fibrotest ≥ 0.75 and APRI > 2) after 12 weeks. Using 3-DAA with fixed doses of DCV, ASV, beclabuvir with or without RBV (1000–1200 mg/day), the overall SVR12 rate was 93%. In patients infected with HCV genotype 1a, with the addition of RBV, this figure was higher by 7% in patients who had not previously received treatment, and by 5% in patients who had already received previous therapy. In contrast, RBV had no effect on achieving response in patients with HCV genotype 1b; Overall, 51 of 52 patients infected with HCV genotype 1b achieved SVR12. Although the difference in SVR12 associated with the use of RBV in patients infected with HCV genotype 1a was modest, it suggests that the inclusion of RBV may improve the effectiveness of therapy in patients with cirrhosis. The role of RBV is more difficult to determine because the study was not sufficiently powered to statistically assess the contribution of RBV to efficacy outcomes. As of today, development of this combination has been discontinued. Therefore, DCV-based regimens with or without RBV will not be used in patients with cirrhosis infected with HCV genotype 1.

Effect of RBV on the effectiveness of therapy in patients infected with HCV genotypes 2, 3 and 4

Sofosbuvir-based regimens

Genotype 2

4 phase III studies showed that when using the combination of SOF + RBV (1000 or 1200 mg in patients with body weight< 75 и? 75 кг соответственно) в течение 12 нед. частота УВО превышает 90 % у большинства пациентов, инфицированных HCV генотипа 2. Исключение составляют больные с циррозом печени, уже получавшие ранее лечение, у которых, по-видимому, эффективна более продолжительная терапия. У этих больных частота УВО12 после 12 и 16 нед. лечения SOF + RBV составила 60 (6 из 10) и 78 % (7 из 9) соответственно . Позднее в другом исследовании частота УВО12 равнялась 87 (13 из 15) и 100 % (17 из 17) после 16 и 24 нед. соответственно . Эти результаты свидетельствуют о том, что терапия по схеме SOF + RBV (назначаемым в зависимости от массы тела) является стандартным методом лечения для всех пациентов, инфицированных HCV генотипа 2, за исключением больных с циррозом печени, у которых продолжительность лечения рекомендуется увеличить до 24 нед.

Genotype 3

In patients infected with HCV genotype 3, the SVR rate was lower than in patients with HCV genotype 2. A more pronounced effect was found in them with increasing duration of SOF + RBV therapy (1000 or 1200 mg in patients with body weight< 75 и? 75 кг соответственно) до 24 нед. Частота УВО у пациентов, инфицированных HCV генотипа 3, варьировала в зависимости от проведения и эффективности предшествовавшей терапии и наличия цирроза печени (на основании результатов биопсии печени, или результатов FibroScan >12.5 kPa, or Fibrotest > 0.75 and APRI > 2). Among treatment-naive patients, the SVR12 rate was 92% in patients with cirrhosis and 95% in those without. However, among previously treated patients with HCV genotype 3, the SVR rate was lower: 62% in patients with cirrhosis and 87% in patients without cirrhosis. Thus, in the future, it is necessary to search for more effective combinations and evaluate the impact on the effectiveness of treatment in patients infected with HCV genotype 3.

The effectiveness of the combination of SOF with or without an NS5A inhibitor and RBV (1000 or 1200 mg/day depending on body weight) has been evaluated in several open-label studies. When using a combination of SOF + DCV with or without RBV for 24 weeks. SVR12 was achieved in a total of 89% of 18 patients without cirrhosis infected with HCV genotype 3. More interestingly, the use of a combination of SOF + DCV without RBV for 12 weeks. was evaluated in 152 HCV genotype 3-infected, treatment-naïve and treatment-experienced patients without cirrhosis and with compensated cirrhosis (METAVIR F4, or FibroScan > 14.6 kPa, or Fibrotest ≥ 0.75 and APRI > 2). SVR12 rates were 97 (73 of 75) and 94% (32 of 34) in treatment-naïve and treatment-experienced patients without cirrhosis, respectively. However, in patients with cirrhosis (63%), this figure was lower: 58 (11 of 19) and 69% (9 of 13) in patients who had not received and had previously received treatment, respectively. An uncontrolled cohort study in real clinical practice confirmed the effectiveness of SOF + DCV therapy for 12 weeks. in patients infected with HCV genotype 3 without severe liver fibrosis. These results suggest that SOF + DCV for 12 weeks can be used in patients with HCV genotype 3 without cirrhosis. without RBV. In contrast, the potential beneficial effects of RBV in patients with cirrhosis need to be assessed. In patients with decompensated cirrhosis enrolled in a health care access program, SVR12 rates were similar between those receiving SOF + DCV with and without RBV (70% and 71%, respectively). However, no definitive conclusions can be drawn from the results obtained in this cohort (addition of RBV was at the discretion of the treating physician and only 7 patients were included in the no-RBV group). Efficacy of the SOF + DCV combination with and without RBV (prescribed according to body weight) for 12 and 16 weeks. is currently being studied in patients infected with HCV genotype 3 with severe fibrosis or compensated cirrhosis (ClinicalTrials.gov, no. NTC02319031). Optimizing treatment outcomes in patients with cirrhosis may include increasing the duration of treatment (up to 24 weeks) with or without the addition of RBV. Preliminary data from a real-world, uncontrolled cohort appear to show improved treatment response (SVR4 88%) in patients with cirrhosis when treatment duration is extended to 24 weeks. It is currently impossible to assess the potential role of RBV in this population at this treatment duration. The optimal regimen combining SOF + DCV and the need for the addition of RBV in patients with cirrhosis infected with HCV genotype 3 require further study.

Efficacy of SOF + LDV combination with and without RBV for 12 weeks. was evaluated in 51 treatment-naïve patients infected with HCV genotype 3. A higher SVR12 rate was observed in patients receiving RBV compared to patients in whom RBV was not added to the treatment regimen (100 vs 64%, respectively). However, it was found that the presence of cirrhosis may reduce the rate of SVR in patients with HCV genotype 3 receiving SOF + LDV with RBV for 12 weeks. Thus, the SVR12 rate was 73% in 22 previously treated patients with cirrhosis, compared with 89% in 28 previously treated patients without cirrhosis. Efficacy of the SOF + LDV regimen over 12 weeks. increased with the addition of RBV in patients with decompensated cirrhosis, but remained significantly lower than the effectiveness of the SOF + DCV regimen with or without RBV. Similarly, the addition of RBV increased the SVR12 rate in HCV genotype 3-infected, previously treated cirrhotic patients treated with SOF + GS-5816 (a second-generation NS5A inhibitor) for 12 weeks. (88 vs 96%). Based on the above, the use of RBV appears to be mandatory in patients with cirrhosis of the liver infected with HCV genotype 3 receiving a short course of therapy with a combination of DAAs.

Genotype 4

In an open-label study of 21 HCV genotype 4-infected patients with and without cirrhosis, treatment-naïve and treatment-experienced, the SVR12 rate was 95% after 12 weeks. therapy according to the SOF + LDV regimen. This appears to indicate that there is no need to add RBV in this group of patients. However, further results from clinical trials and real-world cohorts are required to draw definitive conclusions. When combining the results with data obtained from patients infected with HCV genotype 1, evaluation of the role of RBV in the SOF + LDV regimen remains necessary, especially in patients with cirrhosis infected with HCV genotype 4.

Paritaprevir/ritonavir and ombitasvir (2-DAA regimen) also have antiviral effects against HCV genotype 4. Efficacy of a 2-DAA regimen with or without RBV (based on body weight) for 12 weeks. was studied in a phase II study in patients infected with HCV genotype 4 who did not have cirrhosis and had not previously received treatment. SVR12 was achieved by all patients receiving RBV (42 of 42) and 90.9% of patients (40 of 44) in whom RBV was not added. Failures were primarily due to virologic reasons (1 breakthrough, 2 relapses, and 1 loss to follow-up), indicating that RBV increases the likelihood of achieving SVR in this population. Based on these data, a 2-DAA regimen with RBV (based on body weight) for 12 weeks. was used in patients without cirrhosis infected with HCV genotype 4 who had already received previous therapy. All patients (42 of 42) achieved SVR12, indicating that the 2-DAA regimen with RBV for 12 weeks. is the optimal treatment for all non-cirrhotic patients infected with HCV genotype 4. The efficacy of the 2-DAA regimen with RBV is currently being evaluated in patients with compensated cirrhosis (ClinicalTrials.gov, no. NCT02265237).

Impact of RBV on treatment safety

In table Table 3 summarizes the most common adverse events that occurred during the use of SOF/LDV for 12 weeks. with or without the addition of RBV (1000 or 1200 mg/day depending on body weight). The addition of RBV resulted in an increased risk of fatigue, insomnia, irritability, and anemia. However, no severe cases of anemia (hemoglobin less than 85 g/l) were reported. The anemia was easily corrected by reducing the RBV dose without affecting the achievement of SVR. The SIRIUS study was designed to allow informal comparisons of adverse event rates between patients with cirrhosis receiving placebo, SOF + LDV + RBV (based on body weight), and SOF + LDV. Overall, the incidence of adverse events was high (>80%) and similar in all three groups. In the SOF + LDV + RBV group, the incidence of headache was lower than in the placebo group, and the incidence of fatigue was lower than in the SOF + LDV group. Most pathological changes in laboratory parameters of grade III–IV were observed during the use of placebo. 1 (1%) patient developed anemia (hemoglobin less than 85 g/l) during the period of active treatment, which required a blood transfusion. None of the patients were prescribed erythropoiesis-stimulating agents. On the other hand, the pooled results of 3 phase III clinical trials suggest that the SOF + LDV-based regimen resulted in improved quality of life and other patient-rated outcomes, regardless of stage of liver disease, and that the most significant reduction in quality of life was associated with using RBV. Overall, the addition of weight-based RBV to a sofosbuvir-containing regimen in patients with cirrhosis is safe and well tolerated.

In table Table 4 presents the adverse events that most often occur during the use of the 3-DAA regimen. The majority of patients experienced at least one adverse event, but in most cases these events were of mild severity. The incidence of serious adverse events and events leading to treatment interruption was low in the studies, but was numerically higher in patients with cirrhosis. Adverse events occurring in 5% or less of the 3-DAA and RBV regimen (based on body weight) compared with placebo were considered antiviral-related. These events included fatigue, nausea, itching, insomnia, asthenia and anemia. The incidence of these adverse events was generally lower in the group not receiving RBV. Overall, the incidence of adverse events was similar in patients with and without cirrhosis. The transient increase in total bilirubin (mainly due to indirect bilirubin) was due to the suppression of OATP1B1 (organic anion transport polypeptide 1B1) and OATPB3 (organic anion transport polypeptide 1B3) by paritoprevir, as well as RBV-induced hemolysis. Hyperbilirubinemia was observed less frequently in patients treated with the 3-DAA regimen without RBV compared with patients in whom RBV was added to this regimen, suggesting that it was related to the use of RBV. Grade II anemia (hemoglobin less than 100 g/L) was reported in 6% of patients without cirrhosis treated with the 3-DAA regimen with RBV for 12 weeks, and in 7 and 11% of patients with cirrhosis treated with the regimen 3-DAA for 12 and 24 weeks. respectively . Grade III anemia (hemoglobin less than 80 g/l) rarely developed. The decrease in hemoglobin levels was corrected primarily by reducing the RBV dose, which did not affect the achievement of SVR. Cases of anemia reported during clinical trials were primarily considered to be associated with RBV use, as no anemia was observed with the 3-DAA regimen without RBV.

Use of RBV: risk-benefit ratio

The decision to add RBV should be made on a patient-by-patient basis, taking into account the risk-benefit balance: some increase in efficacy and reduction in treatment duration versus a decrease in safety profile and quality of life, mainly due to the development of anemia. Most patients are overtreated by the addition of RBV because it is not possible to select patients who absolutely require this drug based on varying background data. The severity of liver damage may play a role. A relationship has also been suggested between FibroScan test results and treatment effectiveness. Another factor may be the initial presence of viral strains resistant to NS5A inhibitors. In patients with cirrhosis treated with SOF + LDV, it was found that in the presence of these options, the addition of RBV resulted in higher SVR rates than treatment without RBV, but in the absence of these options, SVR rates with RBV were the same. as without him. Unfortunately, resistance testing cannot be performed and recommended for all patients with cirrhosis. One way to improve the risk-benefit ratio may be to more carefully determine the optimal dose of RBV when combined with a 3-DAA. Typically, the dose of RBV used in this case is calculated for use as part of the PegIFN + RBV regimen. Use of a SOF-containing regimen or a 2-DAA or 3-DAA regimen with low doses of RBV (600 or 800 mg per day) may increase SVR rates compared with regimens without RBV. This will minimize the incidence of toxicities associated with the use of RBV (prescribed based on body weight). In practice, it is recommended to start treatment with RBV according to body weight, and then adjust the dose based on hemoglobin levels and renal function. Finally, the use of RBV is problematic in a number of groups, such as patients on hemodialysis and patients who are planning or have undergone organ transplantation. In these conditions, an individual approach to choosing the dose of the drug is necessary. A better understanding of the drug's mechanism of action may enable selective use of RBV in the DAA era.

Conclusion

Modern completely oral treatment regimens that do not contain IFN allow achieving SVR in more than 90% of cases, as well as reducing the duration of treatment in the majority of patients with CHC, including in patients with cirrhosis and those who have already received previous therapy. This fact, along with a more favorable safety profile, contributes to increased treatment efficacy compared to IFN-based regimens. There are many combinations of DAAs that can be used to achieve an optimal balance between the effectiveness and safety of therapy. Each of these schemes can be modified in various ways, including the use of RBV. In table Table 5 shows indications for adding RBV to primary regimens according to patient and virus characteristics. When using SOF-based combinations, the use of RBV is appropriate in the following situations: in patients infected with HCV genotype 1, previously treated and with cirrhosis or decompensated cirrhosis, and in patients infected with HCV genotype 3 with cirrhosis. As in many similar situations, the difference was not statistically significant in patients with HCV genotype 1, and the question of whether RBV is necessary in patients with HCV genotype 3 with cirrhosis receiving SOF + DCV remains to be studied. In these situations, the addition of RBV can reduce the duration of treatment to 12 weeks. in most cases, which leads to a decrease in its value. The need for RBV use in patients with cirrhosis treated with SOF and SMV should be clarified. Inclusion of RBV is recommended in the treatment of all patients infected with HCV genotypes 1a and 4 receiving combinations of 3-DAA and 2-DAA, respectively. Because RBV is an inexpensive drug that is well tolerated when combined with IFN-free regimens, it remains an effective tool for improving treatment regimens for CHC and optimizing their outcome.

Conflicts of interest

Hezode has worked as a speaker and consultant for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme and Roche.

Jean-Pierre Bronowicki has worked as a clinical researcher, speaker and/or consultant for Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme, Novartis and Roche.

Authors' contributions

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RCHR (Republican Center for Health Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical protocols of the Ministry of Health of the Republic of Kazakhstan - 2015

Chronic viral hepatitis C (B18.2)

Gastroenterology

general information

Short description

Recommended
Expert advice
RSE at the RVC "Republican Center"
healthcare development"
Ministry of Health
and social development
Republic of Kazakhstan
dated December 10, 2015
Protocol No. 19

Chronic hepatitis C- liver disease caused by the hepatitis C virus, lasting 6 months or more. In 10 - 40% of cases, chronic hepatitis C progresses to liver cirrhosis, and in 5% of cases to hepatocellular carcinoma (more often in patients with cirrhosis or severe fibrosis)

Protocol code:

ICD-10 codes:
B18 Chronic viral hepatitis
B18.2 Chronic viral hepatitis C

Abbreviations used in the protocol
ANA- antinuclear antibodies
AMA- antimitochondrial antibodies
anti-HBc - antibodies to HBcAg
anti-HBe - antibodies to HBeAg
anti-HBs - antibodies to HBsAg
anti-HCV- antibodies to hepatitis C virus
anti-HDV- antibodies to hepatitis D virus
anti-HIV - antibodies to HIV
HBeAg- hepatitis B virus internal antigen
HBsAg - hepatitis B virus surface antigen
HCV RNA - HCV RNA
IgG - immunoglobulins class G
IQR - interquartile coefficient
LBx - liver biopsy
ALT - alanine aminotransferase
ART - antiretroviral therapy
AST - aspartate aminotransferase
AFP - alpha fetoprotein
APTT - activated partial thromboplastin time
HAART - highly active antiretroviral therapy
VGA - viral hepatitis A
HBV - viral hepatitis B
HEV - viral hepatitis E
VGN - upper limit of normal
HCV - viral hepatitis C
HIV - AIDS virus
VN
VRV - varicose veins
GGTP - gamma-glutamyl transpeptidase
GCC - hepatocellular carcinoma
D+OPR - combination of dasabuvir with ombitasvir, paritaprevir, ritonavir
IL28B - interleukin 28B
BMI - body mass index
IR - insulin resistance
ELISA - linked immunosorbent assay
IHA - immunochemical analysis
CT - CT scan
INN - international nonproprietary name
INR - international normalized ratio
MRI - Magnetic resonance imaging
UAC - general blood analysis
OAM - general urine analysis
OBP - abdominal organs
OGS - acute hepatitis C
OST - opioid substitution therapy
PV - prothrombin time
HTP - antiviral therapy
PegIFN - pegylated interferon
PI - prothrombin index
PIN - injecting drug users
PCR - polymerase chain reaction
RBV - ribavirin
RVO - early virological response
RNA - ribonucleic acid
DM - diabetes mellitus
SMV - simeprevir
ESR - erythrocyte sedimentation rate
AIDS - acquired immunodeficiency syndrome
CVD - cardiovascular diseases
TV - thrombin time
TP - liver transplantation
TSH - thyroid-stimulating hormone
UVO - sustained virological response
Ultrasound - ultrasonography
FPP - liver function tests
HG - chronic hepatitis
CHC - chronic hepatitis C
LC - liver cirrhosis
alkaline phosphate - alkaline phosphatase
EGDS - esophagogastroduodenoscopy
ECG - electrocardiogram

Date of protocol development: year 2014.

Date of protocol revision: 2015

Protocol users: gastroenterologists, infectious disease specialists, therapists, general practitioners, as well as doctors of related specialties who manage and treat patients with hepatitis C at different stages of the disease.

Methodology: The protocol was developed based on the Clinical Guidelines of leading international societies (WHO, EASL, AASLD, CASL, SASL, FASL, EACS, ROPIP) and adapted taking into account the diagnostic and treatment methods used in Kazakhstan. The classification of recommendations used in this protocol is presented in Table 1.

Classification

Clinical classification:
There is no generally accepted classification of CHC.
When making a diagnosis, it is necessary to indicate the virological status (genotype and viral load), activity (biochemical and/or histological), as well as the stage of the disease (according to indirect elastography or morphological studies)

Clinical picture

Symptoms, course

Diagnostic criteria:
The main criterion for the diagnosis of chronic hepatitis C is the presence of HCV RNA in the blood for more than 6 months.

Complaints and anamnesis:
Chronic hepatitis C is asymptomatic or minimally symptomatic and may be accompanied by such nonspecific symptoms as:
· fatigue;
· flu-like symptoms;
· joint pain;
· itching;
sleep and appetite disturbances;
· nausea;
Depression (assessed in all patients using the Beck scale).

Chronic hepatitis C may be associated with extrahepatic manifestations, such as:
Depression (assessed in all patients using the Beck scale);
· cryoglobulinemia;
· B-cell lymphoproliferative diseases;
· porphyria cutanea tarda;
· vasculitis;
· lichen planus;
· Sjögren's syndrome;
· glomerulonephritis;
· diabetes mellitus type 2.
When collecting anamnesis, one should take into account indications of blood transfusions, organ and tissue transplantation, unsafe invasive (non-medical) manipulations, membership in risk groups (drug users, people with promiscuous sex, patients on chronic hemodialysis, patients with oncohematological diseases, people living with HIV and other parenteral infections, sexual partners of persons with HCV, medical workers, children born to HCV-infected mothers, persons with altered liver function tests). Persons with these risk factors require preventive screening for the presence of HCV (anti-HCV)

Physical examination:

During physical examination at the initial stage of CHC, no pathology is detected, with the exception of minor hepatomegaly. As the disease progresses, the liver may become enlarged and hardened. Splenomegaly and other stigmata of chronic liver disease may appear in later stages.
Viral hepatitis C is predominantly asymptomatic. During the transition of chronic hepatitis C to cirrhosis, in 6.4% of cases, symptoms caused by liver dysfunction and portal hypertension are noted:
· peripheral edema;
· ascites;
· jaundice;
· bruises and bleeding;
· stellate hemangiomas (telangiectasia);
· hair loss on the skin of the chest and abdomen (in men);
· gynecomastia;
· varicose veins of the esophagus and stomach;
· cognitive impairment associated with hepatic encephalopathy.
In some cases, HCV is detected in patients with HCC, which, as a rule, is asymptomatic, except in cases of an advanced stage, when the tumor reaches a significant size, causing deterioration of liver function (jaundice, ascites, hepatic encephalopathy), pain in the upper right quadrant, asthenia and weight loss.

Diagnostics

List of basic and additional diagnostic measures

Basic (mandatory) diagnostic examinations performed on an outpatient basis: are listed in Table 2.

Additional diagnostic examinations performed on an outpatient basis: are listed in Table 2.

The minimum list of examinations that must be carried out when referred for planned hospitalization: in accordance with the internal regulations of the hospital, taking into account the current order of the authorized body in the field of healthcare.

Basic (mandatory) diagnostic examinations carried out at the inpatient level correspond to those at the outpatient level and are presented in Table 2.

Additional diagnostic examinations carried out at the hospital level correspond to those at the outpatient level and are presented in Table 2.

Instrumental studies

Radiological examination
Radiological examination of the liver (primarily ultrasound) makes it possible to identify signs of steatosis, severe fibrosis and transition to cirrhosis of the liver (rounding of the contours of the liver, uneven surface and coarse-grained liver parenchyma), signs of portal hypertension and thrombosis (increase in diameter, cavernous transformation, the presence of portal and splenic veins, ascites, splenomegaly), as well as the presence of space-occupying lesions (HCC). Other imaging technologies (CT, MRI) may also be used.

Endoscopic examination
Allows you to identify such signs of portal hypertension as varicose veins (esophagus and stomach) and portal gastropathy in patients with liver cirrhosis as a result of CHC.

Study of fibrosis stage
An assessment of the severity of liver disease should be carried out before AVT. Identification of patients with liver cirrhosis is of particular importance, since the effectiveness of AVT is inversely proportional to the stage of fibrosis. The absence of pronounced fibrosis is important when deciding on the time to start AVT. Patients with clear clinical signs of cirrhosis do not require a liver biopsy to assess the stage of fibrosis. Patients with evidence of cirrhosis should be evaluated for HCC. Severe fibrosis can occur in patients with normal ALT activity, so the severity of the disease should be assessed independently of ALT levels. Needle biopsy remains the reference method for assessing the stage of liver fibrosis. The risk of severe complications with biopsy is very low (1/4000 to 1/10000). In patients with bleeding disorders, transjugular liver biopsy with simultaneous assessment of portal venous pressure can be used.
For CHC, alternative, non-invasive methods (indirect elastography and biomarkers) can be used instead of biopsy.
Indirect elastography can be used to assess the stage of liver fibrosis in patients with CHC, but it is necessary to take into account factors that may affect the reliability of the results, for example, severe disease activity, obesity.
Both methods (indirect elastography and biomarkers) are accurate in assessing cirrhosis and null fibrosis, but are less accurate in intermediate stages of fibrosis. Combining biomarkers and indirect elastography improves the accuracy of fibrosis stage assessment and reduces the need for needle biopsy. In case of conflicting results of biomarkers and indirect elastography, a needle biopsy of the liver can be used. Histologic evaluation is also necessary for mixed etiologies (eg, HCV with HBV, metabolic syndrome, alcoholism, or autoimmune diseases)

Liver puncture biopsy (LBP)- a relatively safe method for assessing morphological changes in the liver in patients with CHC. PBP allows you to assess the severity of the fibrotic process and necroinflammatory changes. PBP results are easy to interpret and can be semi-quantitatively assessed. LBP is carried out over time to assess the progression of liver damage in CHC. PBP is the only available method that allows us to assess the contribution of concomitant diseases (steatohepatitis, hemochromatosis, autoimmune hepatitis, etc.) in the pathological process and their impact on the course and effectiveness of treatment of CHC. It must be remembered that PBP has a number of limitations. In particular, the experience of the doctor performing the puncture and the morphologist assessing morphological changes is important; small volume of liver tissue samples; invasiveness and discomfort for patients; risk of complications. PBP requires strict adherence to the rules for its implementation in specialized departments and the presence of qualified morphologists. The rules for performing a puncture biopsy of the liver are presented in Appendix 1, and the interpretation of the results is in Tables 4 and 5.

Table 4. Morphological diagnosis of the degree of necroinflammatory activity of hepatitis

Laboratory diagnostics

Laboratory research:

Tests required for all patients with HCV:
CBC with platelet count. Anemia (as a result of hypersplenism, bleeding from varicose veins), leukopenia, thrombocytopenia (as a result of hypersplenism and the direct myelosuppressive effect of HCV), acceleration of ESR (with infectious complications) can be detected.
Biochemical profile includes the determination of ALT, AST, GGTP, albumin, bilirubin, alkaline phosphatase, INR or PT, as well as routine (glucose, creatinine, cholesterol) and some specific indicators, such as gamma globulins, IgG (autoimmune hepatitis screening), serum iron and ferritin (screening for hemochromatosis and secondary iron overload), ceruloplasmin (screening for Wilson-Konovalov disease), AFP (screening for HCC). ALT and AST activity may be minimal (< ВГН), слабовыраженной (< 5 ВГН), умеренной (5-10 ВГН), выраженной (>10 ULN) and does not always correlate with histological activity. Bilirubin levels in CHC are usually normal. Its increase may be observed in acute hepatitis or indicate deterioration of liver function at a late stage of the disease, which is also accompanied by a decrease in albumin levels and an increase in INR or PT. Alkaline phosphatase and GGTP levels may increase in acute hepatitis and remain at normal levels in chronic hepatitis.
The clinical laboratory examination plan also includes OAM and coprogram.
Serological studies (ICA/ELISA) include the determination of anti-HCV, markers of other parenteral infections such as HBV (HBsAg, HBeAg, anti-HBs, anti-HBe, anti-HBc total/IgM), HDV (anti-HDV in HBsAg carriers), HIV (anti-HIV) , as well as (if acute hepatitis is suspected) HAV (anti-HAV) and HEV (anti-HEV)
Molecular diagnostics includes qualitative determination of HCV RNA using highly sensitive real-time PCR with a lower detection limit of 15 IU/ml on closed-type automatic analyzers. In general, virological diagnosis is carried out based on the following principles:
· determination of anti-HCV is the first line of diagnosis of HCV (recommendation A1);
· In cases of suspected acute HCV or in immunosuppressed patients, determination of HCV RNA is necessary (recommendation A1);
· if the test for anti-HCV is positive, it is necessary to determine HCV RNA using a sensitive molecular method (recommendation A1);
· patients with a positive anti-HCV test and a negative molecular test for HCV RNA should be tested for HCV RNA after 3 months to confirm viral clearance (recommendation A1).
Interpretation of the results of ICA/ELISA and PCR is carried out according to Table 3.

Table 3. Interpretation of ICA/ELISA and PCR results

In recent years, the feasibility of studying IL28B gene polymorphism as a predictor of achieving SVR has been proven both in the case of dual therapy with PegINF and during triple therapy with the inclusion of protease inhibitors in patients with HCV genotype 1. The IL28B gene, encoding lambda type 3 interferon, is located on the 19th chromosome. Single nucleotide polymorphism of the C (cytosine) or T (thymine) alleles at position rs12979860 has a high predictive value for achieving SVR. The CC genotype is approximately 2 times more common in patients with spontaneous clearance of HCV during acute hepatitis C compared to those in whom the infection has become chronic. Among patients with CHC genotype 1 of the Caucasian race, treated with PegINF and having genotypes CC, CT and TT, a sustained virological response is achieved in 69%, 33% and 27%, respectively. The predictive value of determining the polymorphism of the IL28B gene regarding the achievement of SVR at the stage of planning AVT is higher than the predictive value of the level of viral load, stage of fibrosis, age and gender of the patient.

Differential diagnosis

Differential diagnosis:
Carried out with other hepatitis (Table 9)

Table 9. Differential diagnosis of CHC

Treatment abroad

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Treatment

Treatment Goals
HCV eradication to prevent cirrhosis, HCC, and death (recommendation A1)
· In patients with liver cirrhosis, a reduction in the incidence of decompensation and the risk of HCC (for this group of patients, HCC screening should be continued) (recommendation A1)
The end point of therapy is sustained virological response (SVR) - undetectable level of HCV RNA (<15 МЕ/мл) на 24 неделе после окончания терапии (рекомендация A1)

Treatment tactics:

Non-drug treatment:
· Protective regime (avoid insolation, overheating of the body, in advanced stages of the disease and portal hypertension - limit physical activity, ease the work schedule)
Drink plenty of water up to 2-3 liters per day
· Minimization of risk factors for progression (exclusion of alcohol, tobacco, marijuana, hepatotoxic drugs, including dietary supplements, normalization of body weight, etc.)

Drug treatment:
The basis of treatment for CHC is AVT based on a combination of pegylated interferons, ribavirin, and direct antiviral agents. The list of essential drugs approved for the treatment of CHC in the Republic of Kazakhstan is presented in Table 10. After approval of other antiviral drugs in the Republic of Kazakhstan, they should be used in accordance with officially approved instructions.

Table 10. List of drugs approved for the treatment of CHC in the Republic of Kazakhstan