THE EFFICACY OF DIRECT-ACTING ANTIVIRAL THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C

assessment of hepatitis C and genotype, as well as the degree of hepatic fibrosis by Fibroscan, biochemical and complete blood count indices carried out. Results. The study results showed high efficacy of the generic DAAs treatment in patients with chronic HCV over 12 weeks. The SVR rate made up 90.3% in Sofosbuvir + Ledipasvir therapy and


INTRODUCTION
Viral hepatitis C is a significant global health problem. According to the World Health Organization data, 71 million people with hepatitis C virus are estimated worldwide, accounting for 1.2% of the world population. Approximately 399 000 people die annually from HCV-related complications, which include cirrhosis, hepatocellular carcinoma and liver failure (1). Annually, 3-4 million new cases of HCV occur, including 1300-1400 cases in the Republic of Moldova. The prevalence of HCV infection considerably ranges from a very low level (0.05-0.1%) in the UK and Scandinavian countries, to the highest level in Asia and Egypt (˃5-10%) (2,3). The HCV incidence in the Republic of Moldova was estimated at 4.5-5.0% in the overall population with the prevalence of genotype 1b, accounting for 98% (4,5). People aged between 30-49 are predominantly affected, men being more common than women. The risk of chronic HCV infection is very high. Untreated acute hepatitis C can develop into a chronic form in up to 80% of people, of whom 10-20% develop liver cirrhosis over 20 years, followed by decompensated liver disease, hepatocellular carcinoma and even death (6). Once the onset of chronic infection occurs, the rate of spontaneous recovery is significantly reduced. Chronic HCV in most patients develops asymptomatically or nonspecifically, as long as no cirrhosis is present (7,8,9). As a result, HVC is often diagnosed accidentally or remains undiagnosed. It has been estimated that only 30-50% of HCV people are aware of their disease. Therefore, the lack of an effective vaccine, that would contribute to a decrease in HCV morbidity rate and subsequent consequences, requires the development of early diagnostic measures and treatment in order to eradicate the infection. Once HCV is identified, the assessment of the therapeutic success is possible by dosing the amount of RNA-HCV and the sustained virologic response. Over time, the SVR rate increased from 5-20% in interferon monotherapy, to 40-50% in combined IFN + Ribavirin treatment. Currently, the SVR rate accounts for 95-100% in cases treated with DAAs (10). The major advantage in the treatment of chronic HVC is the opportunity to administer DAAs -NS3/4A protease inhibitors, NS5B polymerases and NS5A replication complex.
These drugs require oral short-term administration, having a high SVR rate and minimal side effects. The purpose of antiviral treatment is to definitely eliminate the virus and get negative RNA-HCV at a 6-month interval after treatment completion by obtaining a SVR. The literature data confirm that over 99% of patients who have obtained a SVR remain HCV-negative over 4-5 years after the treatment was discontinued, with no signs of hepatitis. The long-term SVR showed a 75% reduction of hepatocellular carcinoma cases, decompensated and compensated cirrhosis and death over the next 15 years (11). It has recently been shown that patients with SVR have a similar quality-of-life status as the overall population (7), whereas those with compensated and decompensated cirrhosis do not require liver transplant (9,12).

MATERIAL AND METHODS
The purpose of the research: to study the effectiveness of Interferon-free treatment in patients with chronic HCV infection.
The research objectives: to assess the efficacy of the DAAs therapy: Sofosbuvir + Ledipasvir and Sofosbuvir + Daclatasvir in patients with chronic HCV infection. To study the evolution of clinical, biochemical, virological and paraclinical indices in patients with chronic HCV infection both at the beginning and end of treatment, as well as over 24 weeks after treatment. To analyze the adverse reactions and complications that can occur after the DAAs treatment.
The research hypothesis: the emergence of new therapeutic opportunities allows each patient diagnosed with chronic HCV infection to receive antiviral treatment. DAAs have shown a higher efficacy and tolerability, as well as shorter treatment duration compared to interferon therapy. A combination of at least two of the three major classes of drugs results in SVR≥95% in just 8-12 weeks of treatment. Patients who were treated for HCV infection exhibited a better quality of life, as well as a reduced risk of developing liver cirrhosis, hepatocellular carcinoma and death related to liver and extrahepatic diseases.
The study was conducted on 206 adult patients with chronic HCV who initiated DAAs treatment within the PHMI Toma Ciorba Clinical Hospital of Infectious Diseases during 2017-2018.
The inclusion criteria were as follows: patients ≥18 years of age, with chronic HCV confirmed by anti-HCV, anti-HCV IgM, RNA-HCV>25 IU/mL, with F0-F3 fibrosis of all genotypes, naive patients or patients subjected to a previous unsuccessful antiviral treatment.
The exclusion criteria were as follows: pregnant and nursing patients, HIV-HBV-HVD co-infection, liver cirrhosis, F4 fibrosis, hepatocellular carcinoma or other malignancies.
The patients included in the study were randomly divided into two groups of 103 patients each. The study groups were comparable in terms of age and gender. The degree of liver fibrosis was assessed via Fibroscan. Patients with F0, F1, F2 and F3 fibrosis were selected. Chronic HCV patients were initially diagnosed by detecting anti-HCV via the immuno-enzymatic assay and confirmed by ARN-HCV testing. Serum levels of ARN-HCV were determined by real-time polymerase chain reaction (PCR) with a low detection limit <25 IU/mL. Prior to treatment initiation, the HCV genotype was assessed (1a, 1b, 2, 3 and 4). Anamnestic, epidemiological, clinical, biochemical, serological and molecular biology data were collected in all patients at the beginning, over 4 and 12 weeks of treatment, as well as over 24 weeks after the antiviral treatment completion.
All patients signed an informed consent. The study protocol was positively endorsed by the Research Ethics Committee of Nicolae Testemitanu SUMPh (meeting no. 75 of 26.04.2017).
At least one gastrointestinal disease, such as chronic pancreatitis, chronic cholecystitis or chronic gastroduodenopathy was found in 64 (62.1%) patients from group I and in 60 (58.2%) patients from group II.
Patients with extrahepatic manifestations were older (55.86±0.97 years) than those without manifestations (45.08±1.07 years) (p<0.001). Patients without extrahepatic manifestations exhibited a short-term disease from the time of detection (9.52±0.58 years), compared to those who had extrahepatic manifestations (11.54± 0.63 years), (p<0.05). There were no contraindications for DAAs, compared to Interferon treatment, in 9 (8.73%) patients from group I and in 6 (5.82%) patients from group II, who exhibited extrahepatic manifestations, as well as cancer remission.   The analysis of the SVR-related predictive factors in DAAs treatment (tab. 4, tab. 5), revealed that SVR was mostly found in patients with high cytolytic activity compared to those who had serum aminotransferase level within normal range. Young patients showed a more frequent SVR than those over 60, although the differences were not statistically significant. At the same time, patients with SVR showed a higher initial level of ALAT (117.75±10.69 IU/L), compared to those in whom virologic failure was recorded (79.68±11.88 IU/L), (p<0.05). The obtained data help to conclude that age, gender, level of viremia, liver fibrosis stage and genotype are not predictive factors of SVR in DAAs treatment.

DISCUSSIONS
The implementation of the National Program of combating viral hepatitis B, C and D over 2017 and 2021 has as an overall purpose to further reduce the morbidity rate of acute and chronic hepatitis B, C and D viral infections and cirrhosis, as well as minimize their socioeconomic consequences. Access to modern DAAs schemes leads to the disappearance of HCV RNA over four weeks after treatment initiation, as well as to virus elimination in about 90% of cases. Reactivation of HCV over 24 weeks after DAAs treatment completion is rare, although reinfection should not be excluded. About 99% of patients who exhibited SVR had a negative ARN-HCV after treatment, thus the progression of liver cirrhosis and hepatocellular carcinoma being stopped (8,9). Our study results have proved a high efficacy of generic antiviral agents administered over 12 weeks in patients with chronic HCV, thus a sustained virologic response was recorded over 24 weeks after treatment in 90.3% of patients undergoing Sofosbuvir + Ledipasvir and 86.4% patients receiving Sofosbuvir+Daclatasvir.
The treatment was effective in both naî� ve patients and those who underwent a previous unsuccessful treatment with PEG-INF, RBV, Boceprevir or Telaprevir.

CONCLUSIONS
1. The generic direct-acting antiviral agents showed a high efficacy, having a sustained virologic response in approximately 90% of patients treated with both treatment schemes.
2. The sustained virologic response was similar in both naî� ve patients and in those who underwent a previous unsuccessful antiviral treatment.
3. Generic antiviral agents have been well tolerated by most patients, whereas minor side effects did not require treatment discontinuation.