Some advances in the treatment of hepatitis C

The article was written by Dr. Bui Xuan Truong - Department of General Internal Medicine - Vinmec Times City International General Hospital.

Compared with some other hepatitis viruses, hepatitis C virus (HCV: hepatitis C virus) was discovered quite late, in 1989, about 150 - 170 million people worldwide are chronically infected with hepatitis C virus. Every year, about 500,000 patients die from diseases related to hepatitis C. Along with hepatitis B virus and alcohol, hepatitis C virus is one of the three leading causes of chronic hepatitis, cirrhosis and cancer. liver letter.

When infected with acute HCV, the rate of chronic HCV infection is quite high, about 55-85% and if not treated and controlled, after about 20 years, 15-30% of patients with chronic HCV infection will die. develop cirrhosis. On the background of cirrhosis caused by HCV, every year about 2-4% will develop liver cancer. In addition, HCV infection can cause a number of extrahepatic diseases, which are mainly the result of the body's immune response to HCV.
In terms of vaccine prevention, there are still many difficulties, because HCV has a very high genotype polymorphism (HCV has 07 genotypes and each genotype has many subgenotypes), besides HCV does not have a common antigenic determinant group like hepatitis B virus (HBV: hepatitis B virus), so medicine is currently unable to create a vaccine to vaccinate against all HCV strains worldwide. .
Although there are still many difficulties in creating a preventive vaccine and up to 55-85% of patients with acute HCV infection will develop chronic HCV infection. However, compared to hepatitis B, we can completely clear HCV from the body, and with recent progress in creating new drugs for the treatment of hepatitis C, some countries are trying to The fight sets out a roadmap towards eradicating hepatitis C.

Hepatitis C virus (HCV: hepatitis C virus) belongs to the group of Hepaciviruses of the Flaviviridea family (in the Flaviviridea family, there are two other groups, Flavivirus and Pestivirus) Flaviviruses of the Flavividea family have some basic structural similarities, however the viruses have different pathogenic sites and pathological characteristics.

Hepatitis C virus (HCV) has an outer shell of a lipid bilayer – penetrating this lipid bilayer are protein molecules (E) that look like anchor-shaped spikes that protrude outward. Virus Inside the lipid bilayer is the core membrane (nucleocapsid layer - Core protein) Inside the core membrane is a single-stranded RNA (containing the genetic information of the virus) The HCV RNA molecule (HCV-RNA) has about 9600 nt or 9.6 kb (nt stands for nucleotide and kb stands for kilobase) and encodes for about 3,300 amino acids (aa) – however with slight variation, the This variation depends on the genotype of HCV. The restriction of the HCV-RNA molecule is the 5'URT and 3'URT terminals. The 5'URT terminus is about 341 nt long and the 3'URT terminus is about 225 nt long, the 5'URT and 3'URT terminals are not directly involved in encoding amino acid molecules, However, many 5'URT terminals play an important role in the initiation of HCV-RNA messenger translation, and 3'URT participates in signaling effects for HCV-RNA replication.

The HCV-RNA molecule consists of only one frame containing the genetic information – sequentially decodes and translates genetic information (ORF), HCV-RNA encodes for about 11 HCV proteins. and is divided into two main parts, the part containing genetic information coding for HCV structural proteins (structural proteins) including: C (core protein), E1 (E1 protein) and E2 (E2 protein) , and contains the genetic information that encodes HCV non-structural proteins including: NS2 (NS2 protein), NS3 (NS3 protein), NS4A (NS4A protein), NS4B ( NS4B protein), NS5A (NS5A protein) and NS5B (NS5B protein). The P7 protein is not involved in the construction of HCV – although the function of the P7 protein is currently unknown, some studies suggest that the P7 protein acts as a calcium channel.

Until now, Medicine has made many advances, achieved many successes in studying the replication process of HCV in the human body, however, there are still many problems and mechanisms that we have not recognized and analyzed. . For the replication process to be completed, HCV requires interaction and support from a number of activities including on the surface and in the cytoplasm of hepatocytes. HCV must utilize a number of products within the hepatocytes, although many of the processes are intracytoplasmic but entirely extracellular, and HCV-RNA has no integration or interaction with cellular DNA. liver like hepatitis B virus.

(1).HCV approaches, attaches to the surface of the liver cell membrane and then the membrane fusion process.
(4).HCV-RNA molecules move to the endoplasmic reticulum system of hepatocytes – where the translation process and synthesis of HCV protein molecules take place.
(2).HCV corpuscles with nucleocapsid coat enter the cytoplasm of hepatocytes.
(5).Next is the process of replication and synthesis of new HCV-RNA molecules.
(3).The HCV-RNA molecule breaks out of the nucleocapsid.
(6).Finally is the encapsulation phase, forming complete HCV corpuscles and then exiting the hepatocytes.

1991: Intron A (Shering's Alpha Interferon) was approved by the US Food and Drug Administration (FDA) for the treatment of hepatitis C in clinical practice.
1996: Roferon A (Roche's Alpha Interferon) is approved by the FDA.
1997: Consnsus Interferon is approved by the FDA.
However, the application of alpha-interferon alone has a relatively low therapeutic effect (after 6 months), the response rate for HCV genotype 1 is only about 9-10% and for genotype 2 and 3 only about 20-30%. At the same time, alpha-interferon has quite a lot of side effects, many patients have had to give up the full course of treatment.
The nature of Interferon is a protein with immune function, belongs to the group of Cytokines, this is one of the groups of substances produced by our body, these substances participate in the process of immune regulation and response. immune response to eliminate pathogens, including viruses. Our body can make many different types of Interferon (type I – type II and type III) – in which the type of Interferon used in the treatment of hepatitis C is only Alpha-Interferon of type I and Alpha-Interferon itself. There are many different subgroups of which Alpha-Interferon-2a or 2b is just one (there are about 13 genes encoding alpha-interferon).
1998: FDA approved the combination of Ribavirin with Interferon in the treatment of hepatitis C.
With the combination regimen, the effectiveness of treatment has been significantly improved, the treatment response rate for HCV genotype 1 reached approx. 30% and for genotypes 2 and 3 it is about 60%.
Ribavirin is a broad-spectrum antiviral drug, initially expected to be developed to treat HIV-infected patients, however, the authors later found that Ribavirin was not capable of treating HIV-Aids patients, but vice versa. has quite good effect against viruses of the Flavivirus family, including hepatitis C virus.
2001: Peg-Intron (pegylated interferon alpha-2b) of Shering company is FDA approved.
2002: Roche's Pegasys (pegylated interferon alpha-2a) is FDA approved for the treatment of hepatitis C.
With the introduction of Peg-Interferon (Peg-Intron and Pegasys) there is a significant transformation. In the past, with traditional types of Interferong, patients needed to inject the drug 3 times a week, although many authors have tried to give different courses - but with different types. Traditional interferon is difficult to create a constant concentration of Interferong in the patient's body during treatment.
With the introduction of Peg-Interferon, patients only need to inject once a week - and at the same time achieve a constant concentration of Interferon in the patient's body during treatment.
The combination of Peg-Interferon with Ribavirin significantly changed the effectiveness of hepatitis C treatment, the sustained treatment response rate for HCV genotype 1 was increased by 40-45% and the rate of Treatment response for HCV genotypes 2 and 3 increases to about 75-85%, for genotypes 4, 5 and 6 to about 50-75%.
2007: This year marks the beginning of the birth of new generations of oral drugs, the first being VX-950 (Telaprevir), an oral tablet used to treat HCV genotype 1.
2010: Telaprevir and Boceprevir ended the phase III clinical trial and formally requested FDA approval to allow widespread clinical application of hepatitis C.
2011: Telaprevir and Boceprevir are officially approved by the FDA.
2013: Simeprevir and Sofosbuvir are licensed.
2014: Ledipasvir is licensed.
2015: Daclatasvir was licensed, this is also a turning point in the development of drugs, specific treatment regimens for each HCV genotype.
2016: Elbasvir and Grazoprevir are licensed.
Currently, along with the development of research and an increasingly detailed and synchronous understanding of the structure, function and pathogenesis of hepatitis C virus, more and more new generation oral drugs are being developed. successfully studied and allowed to apply in clinical treatment. This has allowed to reduce dependence or no longer have to depend on Interferong drugs in treatment, creating favorable conditions - easy to apply - minimizing side effects - easy to be accepted by patients and effective. high treatment.
In 2016 and in the future, many new drugs will be allowed to be applied in clinical practice – this is a very positive signal for patients and many countries hope to clear the pathology caused by hepatitis C virus. .

As shown above, HCV replication involves many steps and HCV-RNA molecule consists of only one translation frame (ORF), however from one translation frame this can be generated. should obtain a variety of HCV proteins, including both structural and non-structural HCV proteins. Current new generations of drugs mainly affect HCV non-structural proteins, but these proteins play an important role in the process of entry, replication, and maturation of HCV into fully pathogenic viruses. correction.
The new generation oral drugs mentioned in the article are drugs belonging to the group of DAAs (Direct-Acting Antivirals: direct antiviral effect).
Drugs that affect NS3/NS4A proteins: Boceprevir, Telaprevir, Simeprevir, Grazoprevir, Faldaprevir and Asunaprevir.........
NS3 both have the role of protease, NTPase/helicase and create complex with NS4A (where the NS4A protease is the binding factor that supports the NS3 protease). The primary protein molecule that HCV produces is a poly-protein, from which a single molecule of HCV protein is required, poly-protein cleavage is required. The NS3/NS4A protein complex has the function of lysis and cleavage of poly-protein molecules to produce single protein products, NS3, NS4A, NS5A and NS5B. If successful inhibition of the NS3/NS4A protease complex will stop this process and HCV single protein products will not be produced, thereby interrupting HCV replication. In addition, NS3/NS4A protease complex is also capable of inhibiting some immune response pathways of the body through signal chains of some Interferons, thus inhibiting NS3/NS4A protease is also releasing These signaling chains increase the body's immune response to HCV.
Drugs acting on NS5A protein: Daclatasvir, Ledipasvir, Obitasvir.........
Unlike NS3/NS4A protease complex, NS5A protein does not have a lysis role to cut poly molecule -proteins initially into single protein molecules, but NS5A participates in HCV-RNA replication and packaging to form complete HCV corpuscles. The NS5A protein has three main functional segments (domains I, II and III) in which domains I and II participate in the replication of HCV-RNA molecules and domain III participates in the packaging and release of subunits. HCV body from liver cells. Therefore, inhibiting NS5A can both inhibit HCV replication - and inhibit the packaging that makes perfect HCV corpuscles, and at the same time inhibit the release of HCV corpuscles from the cell. liver.
Drugs that act on NS5B proteins: Sofosbuvir, Dasabuvir.........
Synthetic replication of HCV-RNA molecules by RNA polymerase dependent RNA synthesis, not DNA polymerase dependent RNA process. The HCV NS5B protein molecule acts as an RNA polymerase, thus playing a key role in the synthesis of the (-) HCV-RNA (negative HCV-RNA strand) precursor and itself from this molecule. will synthesize (+) HCV-RNA molecules of the hepatitis C virus. Therefore, inhibiting NS5B will prevent the replication of HCV-RNA from taking place.

In order to achieve effective treatment and reduce the incidence of hepatitis C, it is necessary to do well in screening and managing HCV infected patients.

(first). Healthcare workers and social workers who have contact with medical waste and HCV-infected subjects.
(2). Smokers use injections, including inhaled drugs through the nose.
(3). Patients on hemodialysis.
(4). Patients with a history of blood transfusion and use of blood products, especially in patients who used it from an era when HCV screening with blood transfusion was not available.
(5). Organ transplant patient.
(6). Children born to mothers infected with HCV.
(7). HIV-infected people.
(8). People with liver dysfunction and no cause can be found.
(9). People who have unprotected sex, homosexuality.
(ten). People who have a habit of tattooing or sharing tools contaminated with blood and body fluids.

When you want advice on screening and treatment of hepatitis C, you should visit and consult at clinics or hospitals that specialize in Gastroenterology - Hepatology - Hepatitis, and Infectious Diseases. Currently, at many health facilities across the country, in addition to tests to assess liver disease, tests at the molecular level of HCV have also been deployed - helping to accurately assess the effectiveness of treatment.
You should not self-reference and self-medicate, because although medicine has made many advances in the treatment of hepatitis C, there are still many problems in the pathogenesis that have not been fully explained. There are still difficulties and challenges that Medicine needs to continue to research. Self-treatment or improper treatment counseling will increase resistance mutations.
Besides, you need to know that hepatitis C is a disease caused by a virus – so now for traditional medicine, these drugs can stabilize liver function, but there is no evidence that can ability to clear chronic HCV infection from the body.