The influence of Interferon based antiviral therapy in combination with Atorvastatin 20 mg on sustained virological response and metabolic alterations at patients with chronic hepatitis C

Abstract

Introduction: Chronic hepatitis C virus infection represents more frequent cause of liver cirrhosis and hepatocellular carcinoma. The severity of the disease and its progression depends on factors related to the virus and factors associated with the host, among which metabolic abnormalities are listed, such as: changes occurring in the metabolism of fats, sugars, vitamin D, iron, the presence of fatty liver, obesity and others. Statins, inhibit HCV replication in vitro, enhances the antiviral effect of the already known antiviral drugs and reduce their resistance. Objectives of the study: Primary objective: To determine the impact of additional therapy (treatment with Atorvastatin 20 mg) to the standard antiviral therapy (pegylated interferon alpha (peg-IFN α) and ribavirin) on achieving sustained virological response (SVR). Secondary objectives: to determine the presence of metabolic alterations in patients with chronic hepatitis C, their impact on achieving SVR, to determine the impact of antiviral therapy on metabolic abnormalities, to determine the influence of genotype on the incidence of metabolic alterations and achieving SVR and to analyze the connection of metabolic alterations with the level of stetatotic, necro-inflammatory and fibrotic changes in the liver, with the gender, age and viral load, aiming to determine their mutual correlation. Material and Methods: In the study which is comparative, open label, prospective - retrospective, 70 patients diagnosed with chronic hepatitis C virus infection who met criteria for treatment with standard antiviral therapy combined with anti-lipemic therapy (Atorvastatin 20 mg) were included. Patients in the study were divided into two groups: one group of 35 patients receiving combination therapy (Atorvastatin + Pegylated alpha interferon + Ribavirin) and another group of 35 patients received only standard antiviral therapy. For the realization of secondary objectives, the patients were divided in accordance to the achieved virological response to group with SVR and group non virologic response (NVR). Those parameters were followed in all patients: genotyping, quantification of the virus, histological assessment of liver inflammation and fibrosis degree (before starting treatment), the presence of steatosis, laboratory analysis: hematology, liver, lipid and carbohydrate status, HbA1c, insulin blood level (the calculation of HOMA-IR), vitamin D3, serum iron, ferritin and body mass index (BMI) calculation. Overall treatment of the patients depends from the virus genotype, thus, patients with genotype 1 and 4 received 48 weeks standard antiviral therapy, but patients with genotypes 2 and 3 received 24 weeks of antiviral therapy. SVR was considered an undetectable levels of HCV RNA levels 24 weeks after completion of antiviral therapy. The results were statistically analyzed, and all results for p <0.05 were considered statistically significant. Results: Combination therapy leads to a slightly higher percentage of SVR (85.71%) in patients with chronic hepatitis C versus standard therapy (74.29%) and in patients with genotype 3 this rate of SVR amounting to 95.83%. Combination therapy leads to significant improvement of lipid and glucose status after treatment, and in terms of side effects, there was no appearance of serious adverse events that would be a reason for discontinuation. Presence of insulin resistance (IR> 2) in 48.6% of patients, low (insufficient) levels of vitamin D of 26.94 ± 14.7, which has not affected significantly the achieved virological response, a high percentage of steatosis (total 54.3% of which 48.6% have mild degree of steatosis and 5.7 have severe steatosis) and increased body mass (55.7% total), of which 40% were overweight and 15.7% obese, were detected in all tested group. Patients who achieved SVR had a slightly higher baseline values of TG, total cholesterol and LDL, as well as slightly lower values for HDL, and significantly lower HOMA IR at the beginning of the treatment apart from the group who did not achieve SVR (p = 0.028). Patients without virological response had significantly higher BMI than those with SVR, p = 0.014. Univariable Logistic Regression Analysis as factors that are significantly associated with achieving SVR has confirmed the following parameters: the age of patients, HCV genotype 3, BMI and HOMA-IR prior to therapy. Multivariable Logistic Regression analysis, as independent significant predictors of achieving SVR pointed only the age, HCV genotype and HOMA-IR. Antiviral therapy that led to achieved SVR, significantly affected the increasing of TG serum levels, total cholesterol and LDL 24 weeks after completion of the treatment compared from their basic level, as well as significant reduction of ferritin 24 weeks after completed treatment, compared to those who did not achieve SVR (Z = 2.06 p = 0.039). Although, the antiviral therapy slightly improved steatosis among patients who achieved SVR (p = 0.06). Early virological response, response at the end of treatment and SVR, significantly more frequently encountered in patients with genotype 3. Genotype 1 patients had significantly higher BMI, higher glucose and insignificantly higher HOMA-IR, compared to patients with genotype 3. Values of cholesterol and its fractions, LDL and HDL were lower in the group with genotype 3, with significant difference for HDL. The presence of steatosis was associated with BMI, with insulin blood level and HOMA-IR. There was a negative correlation between inflammatory changes in the liver and HDL, while Knodell score positively correlated with glucose, insulin blood level, HOMA-IR index, ferritin and serum iron. The presence of fibrotic changes and cirrhosis of the liver were correlated with higher values of LDL, glucose and ferritin. From the metabolic parameters only glucose, serum iron and ferritin values prior treatment were significantly dependent on the gender of the subjects, with significantly higher values in male patients. Positive correlations was detected between the age of the patients and the BMI, serum ferritin and iron. The level of viremia is positively correlated with the degree of steatosis and serum iron levels before the treatment. Conclusion: Combination therapy Atorvastatin + pegylated interferon alpha + Ribavirin leads to high rate of SVR of 95.83% in patients with chronic hepatitis C, genotype 3. Statins can be used safely in patients with chronic hepatitis C. Determined independent significant predictors for achieving SVR were: age (by increasing the age for 1 year, the chance of achieving SVR is reduced by 10.2%), HCV genotype (patients with HCV genotype 3 have about 8,112 times higher chance to achieve SVR, compared with patients with genotype 1) and HOMA-IR (increased HOMA-IR value for one unit before starting the therapy, reduces the chance of achieving SVR for 18.5%), confirmed by Multivariable Logistic Regression Analysis.