Efectividad y seguridad de los antivirales de acción directa frente al virus de la hepatitis Cfoco en subpoblaciones especiales

Abstract

The hepatitis C virus is a single chain ribonucleic acid virus identified as the etiologic agent of hepatitis C. It´s main target organ is the liver, developing acute and/or chronic hepatitis, which can cause long-term hepatic fibrosis, hepatic cirrhosis, hepatocellular carcinoma and finally death. Six main hepatitis C virus genotypes have been isolated, with uneven distribution worldwide and a seventh genotype in some individuals. This genetic heterogeneity has important implications at the level of the evolution of the liver disease of the infected patient and in the selection and effectiveness of antiviral treatment in actual clinical practice. In particular, chronic infection with genotype 3 has a faster progression in all stages of liver disease and a worse response to available antiviral treatments. The goal of antiviral treatment against hepatitis C virus is to cure this viral infection, to prevent liver complications and related extrahepatic diseases (liver necroinflammation , fibrosis, cirrhosis, decompensation of cirrhosis, hepatocellular carcinoma, severe extrahepatic manifestations and death), improve quality of life , eliminate stigma and avoid subsequent transmission of hepatitis C virus. According to the reference scientific societies in our field, all patients with HCC, monoinfected or coinfected with human immunodeficiency virus, naïve or previously treated with therapeutic failure, and without contraindications to treatment, should be considered candidates for antiviral treatment, regardless of their degree of fibrosis. The treatment of chronic hepatitis C virus infection has undergone a very important evolution, especially in the last two decades, as new, more effective and safer drugs have been authorized against this virus. The results of clinical trials have very recently positioned direct- acting antivirals as the drugs of choice in the treatment of chronic hepatitis C virus infection. There are three broad classes of direct- acting antivirals that act at different levels of the hepatitis C virus life cycle: NS3/4A protease inhibitors, NS5A replication complex inhibitors, and NS5B polymerase inhibitors, which are divided into nucleos(t)ide or non-nucleoside inhibitors. Antiviral treatment selection is independent of human inmmudeficiency virus coinfection and depends on three variables: hepatitis C virus genotype/subtype, severity of liver disease and/or previous treatments. Other variables depending on the virus, the patient or the basal treatment of the patient could condition the outcome of antiviral treatment against the hepatitis C virus in actual clinical practice. Therefore, it is important to know the effectiveness and safety in real clinical practice of direct-acting antivirals in patients diagnosed with chronic hepatitis C, especially in special subpopulations with characteristics that could condition the success of antiviral treatment. The present thesis summarizes five studies: - Study I. The objective of this study was to determine the effectiveness and safety of direct acting antivirals in clinical practice and analyze the influence of drug interactions on both variables and characterize interactions in patients with chronic hepatitis C. Direct antiviral agents were observed to achieve sustained viral responses in 97.3% of patients and to develop serious adverse events in less than 1.5% of them. Likewise, 24.5% of the patients diagnosed with chronic hepatitis C treated with direct-acting antivirals had clinically significant drug-drug interactions. Despite this, these interactions did not interfere with the effectiveness and safety of antiviral treatment in real clinical practice. Two variables independently associated with the presence of these interactions were identified: combinations of direct antiviral agents that include protease inhibitors and age equal to or greater than 65 years in the treated patients. - Study II. The objective of this study was to compare the incidence of liver-related events and mortality between patients younger than 65 years and patients aged ≥ 65 years with similar liver damage and similar treatment based on direct-acting antivirals. The incidence of liver-related events was 2.62/100 patient-years in patients ≥ 65 years and 1.41/100 patient-years in patients ˂ 65 years. All-cause mortality was 3.89 and 1.27/100 patient-years in patients older and younger than 65 years, respectively. In cirrhotic patients, all-cause mortality and liver-related mortality did not differ between groups. Therefore, no significant differences were detected regarding the incidence of liver-related events and all-cause mortality in patients receiving direct-acting antivirals aged less than or equal to/greater than 65 years. These results support the use of direct- acting antivirals in elderly patients. - Study III. The objective of this study was to analyze the effectiveness and safety of Daclatasvir plus Sofosbuvir with or without Ribavirin in patients infected with genotype 3 of the hepatitis C virus in actual clinical practice. The global sustained viral response at week 12 was 94.6%, being 100% in patients with low fibrosis (F0-2) compared to 90.8% in patients with advanced fibrosis (F3-4). In the subgroup of cirrhotic patients, the response was 100% or 40.0% depending on the addition or not of ribavirin (p=0.001). Only 4.5% of patients developed serious adverse events. Therefore, it is concluded that Daclatasvir+Sofosbuvir±Ribavirin showed high effectiveness and clinical safety in patients infected with the genotype 3 of the hepatitis C virus, which is lower in patients with advanced fibrosis. Also, we observed l to addition of ribavirin to Daclatasvir+Sofosbuvir, increases the effectiveness of the treatment while decreasing safety antiviral treatment. - Study IV. The objective of this study was to evaluate the effectiveness and safety of Sofosbuvir/Velpatasvir±Ribavirin compared to Glecaprevir/Pibrentasvir in routine clinical practice for the treatment of patients infected with genotype 3 of the hepatitis C virus. 95.7% of patients treated with Sofosbuvir/Velpatasvir±Ribavirin and 96.7% of those treated with Glecaprevir/Pibrentasvir, achieved a sustained virological response at week 12 (p = 0.7). Among patients with low grade liver fibrosis (F0-2) and advanced fibrosis (F3-4), the response was 100% and 85.7%, respectively (p = 0.03). During follow- up, 21.1% of patients experienced some adverse effect, of which 9.3% was of moderate degree. The incidence of any degree adverse events was 26.1% in patients who received Sofosbuvir/Velpatasvir±Ribavirin compared to 13.3% in patients receiving Glecaprevir/Pibrentasvir treatment (p=0.30). Therefore Sofosbuvir/Velpatasvir±Ribavirin or Glecaprevir/Pibrentasvir presents high effectiveness and safety in the treatment of patients infected with genotype 3 of the hepatitis C, with no significant difference between treatments. The effectiveness was lower in patients with advanced fibrosis, without significant differences between both treatments. - Study V. The main objective of this study was to analyze the effectiveness and safety of direct-acting antivirals in psychiatric patients with chronic hepatitis C, and the secondary objectives included evaluations of therapeutic adherence and drug-drug interactions. The sustained virological response week 12 by intention-to-treat in psychiatric vs. non-psychiatric patients was 92.6% vs. 96.2% (p=0.02). The sustained virological response week 12 by modified intention-to-treat in psychiatric vs. non- psychiatric patients was 97.8% vs 98.4% (p=0,74). The integrated analysis of the percentage of patients adhering to direct-acting antivirals did not show differences between both cohorts. 30.2% of psychiatric patients and 27.6% of non-psychiatric patients presented clinically significant drug-drug interactions; the concomitant changes in psychiatric treatment required by the presence of these interactions did not lead to loss of control of mental illness. 1.7% of psychiatric patients had serious adverse effects of any nature and there were no serious psychiatric adverse effects. In short, direct- acting antivirals showed very high effectiveness and safety in the treatment of psychiatric patients diagnosed with chronic hepatitis C, although this effectiveness was slightly lower than that observed in patients without mental illness. Furthermore, no clinically relevant differences in therapeutic adherence or drug-drug interactions with direct-acting antivirals were observed compared to non-psychiatric patients. Finally, the use of direct-acting antivirals did not significantly worsen psychiatric symptoms. In summary, the results obtained in the studies included in this doctoral thesis have allowed a detailed knowledge of the high effectiveness and safety in real clinical practice of direct-acting antivirals against the hepatitis C virus. Among the main findings found are note that proper management of drug-drug interactions does not condition the outcome of antiviral treatment; that advanced age should not limit patients' access to treatment with direct-acting antivirals; the high effectiveness and safety of Daclatasvir+Sofosbuvir±Ribavirin, Sofosbuvir/ Velpatasvir±Ribavirin and Glecaprevir/Pibrentasvir in the treatment of patients infected with genotype 3 of the hepatitis C virus, although less in patients with advanced fibrosis; the need for specific multidisciplinary clinical follow-ups of psychiatric patients to guarantee the same effectiveness of antiviral treatment as in patients without mental illness; and the high safety of these antivirals at the level of psychiatric symptoms