Efficacy of 12 Weeks Versus 24 Weeks Treatment of Directly Acting Antiviral Therapy in Patients With Hepatitis C Related Chronic Liver Disease

Efficacy of 12 Weeks Versus 24 Weeks Treatment of Directly Acting Antiviral Therapy in Patients With Hepatitis C Related Chronic Liver Disease

This randomized controlled trial proposes to compare the treatment outcomes of 12 weeks versus 24 weeks of direct-acting antiviral (DAA) therapy in patients with HCV-related chronic liver disease, addressing the ongoing debate over the ideal treatment duration. To be conducted at the Department of Gastroenterology, Indus Hospital Health Network over nine months, the study will enroll 192 treatment-naive patients (96 per group) aged over 16 with chronic HCV, while excluding those with hepatocellular carcinoma, decompensated cirrhosis, other liver diseases, prior treatment failure, HBV/HIV co-infection, or various exclusionary lab parameters. Using consecutive sampling and draw randomization, Group A will receive 12 weeks and Group B will receive 24 weeks of a regimen comprising sofosbuvir, daclatasvir, and ribavirin, with all patients followed for 12 weeks post-treatment to assess the primary outcome of sustained virologic response (SVR, defined as HCV RNA <25 IU/ml). Data will be analyzed in SPSS v25 using t-tests and chi-square tests, with a p-value ≤0.05 considered significant, ultimately aiming to determine whether 12 weeks of therapy is sufficient or whether extending to 24 weeks offers meaningful benefit.

INTRODUCTION: Hepatitis C virus (HCV) infection can cause liver inflammation and fibrosis, may precede the development of cirrhosis and hepatocellular carcinoma (HCC).1 It has become a substantial public health problem, with approximately 185 million people infected worldwide. According to the World Health Organization more than 71 million people have chronic hepatitis C (CHC) worldwide, and an estimated 350,000 patients with CHC die each year, most because of liver cirrhosis and HCC.2,3 All-oral, interferon (IFN)-free direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection has allowed successful treatment of patients with advanced liver disease. Worldwide, large numbers of HCV-infected patients with decompensated cirrhosis have received antiviral therapy and although sustained virological response (SVR) rates are slightly reduced compared to patients with compensated disease, over 80% of treated patients still achieve viral clearance. Early analysis of patients who responded to therapy showed associated improvements in MELD and Child-Pugh scores,4,5 although some concerns have been expressed that the rate of malignancy may not change or may, paradoxically, increase.6,7 The standard of care for patients with chronic HCV infection has evolved. The ongoing development of direct-acting antivirals has delivered improvements in both efficacy outcomes and tolerability. Following the recent approval of sofosbuvir, the recommended treatment in the US for infection with genotypes 2 and 3 has been updated to 12 weeks or 24 weeks, respectively, of sofosbuvir in combination with ribavirin (RBV).8 Lawitz et al. conducted a study on comparison of outcomes of 12-week of DAAs treatment with 24 weeks DAAs, the authors reported sustained virologic response (SVR) at 12 weeks in 67% patients in 12 weeks groups and in 67% patients in 24 weeks group. While relapse occurred in 29% patients in 12-week group and in 20% patients in 24 weeks group.9 While a study by Dore et al. reported significantly lower relapse rate using 24 weeks therapy group; 11.1% versus in 26.9% patients in 12 weeks therapy group.10 The aim of the proposed study is to determine the treatment outcomes of 12 weeks DAAs therapy with 24 weeks DAAs in patients of HCV related chronic liver disease. This study is important because there is still a debate on ideal treatment duration of DAAs in HCV patients. The results of this study will help us to decide either 12 weeks DAAs therapy is sufficient, or we should continue to 24 weeks of DAAs for treating these patients. OBJECTIVE: To compare the outcomes 12 weeks versus 24 weeks (DAAs) Directly acting antiviral agents in the treatment of HCV related chronic liver disease. OPERATIONAL DEFINITIONS: Outcome 1-Sustained Virologic Response (SVR): Patients having HCV RNA <25 IU/ml after 12 weeks end of treatment will be labelled as having SVR. . Study Design: - Randomized control trial Study setting: Department of Gastroenterology, Indus Hospital Health Network. Duration of Study: 09 months after approval of synopsis. Sampling technique: Non-probability consecutive sampling. Sample Size: Sample size is calculated by using WHO sample size calculator. Following parameters were used to calculate the sample size; Frequency of relapse in 12 weeks treatment group: 26.9%10 Frequency of relapse in 24 weeks treatment group: 11.1%10 Power: 80% Level of Significance: 05% Sample Size: 192 (96 in each group) SAMPLE SELECTION: Inclusion Criteria: • Patients of chronic liver disease associated with HCV. • HCV treatment Naive • Both male and female patients. • Age > 16years Exclusion Criteria: • History or evidence of hepatocellular carcinoma • Decompensated cirrhosis • Chronic liver disease other than hepatitis C • HCV treatment failure or HCV Relapse • chronic HBV or HIV infection • presence of any other medical, psychiatric and/or social reason that would render the patient inappropriate for study participation; • Exclusionary laboratory parameters included o alanine aminotransferase (ALT) ≥ 5 x upper limit of normal; o total bilirubin ≥ 2 mg/dL; o international normalized ratio ≥ 1.7; o albumin ≤ 3.5 g/dL; o hemoglobin ≤ 12 g/dL (females) or ≤ 13 g/dL (males); o absolute neutrophil count ≤ 1.5 x 109 cells/L (≤ 1.2 x 109 cells/L for patients of black race); o platelets ≤ 90 x 109 cells/L; o creatinine clearance ≤ 50 mL/min o alpha fetoprotein > 100 ng/mL DATA COLLECTION PROCEDURE: Data collection will be started, after ERC approval. All patients in Gastroenterology clinic, who will be planned for HCV treatment having chronic liver disease using DAAs (Directly acting antiviral agents) fulfilling the inclusion criteria of the study will be included. Written consent will be obtained from each patient. The patients will be divided into two equal groups using draw randomization. In group A patients, DAAs therapy will be given for 12 weeks and in patients in group B, DAAs therapy will be given for 24 weeks. The treatment regimen will consist of Sofosbuvir 400mg OD, Daclatasvir 60mg OD, Ribavirin 400mg BD. All patients will be followed for 12 weeks after end of treatment to determine SVR as per-operational definition. This methodology ensures a robust randomized controlled trial design, facilitating the evaluation of the efficacy of different treatment durations. DATA ANALYSIS PROCEDURE: The data analysis will be analyzed using SPSS v25. Descriptive statistics like mean and standard deviation for normally distributed quantitative variables like age, or median (IQR) will be reported based on non-normal variables. Frequency and percentage will be reported for qualitative variables like gender, SRV and relapse rate. Base line characteristics between the groups will be compared by t-test for continuous data and chi-square test for categorical values A P-value ≤0.05 will be taken as significant difference with a confidence interval of 95%.

To include the patients in the study, we screened the high-risk population which included IV drug abusers, positive family history, history of blood transfusions and tooth extraction. We excluded the patients who had HCC, decompensated cirrhosis, CLD other than HCV, HCV treatment failure or HCV Relapse, chronic HBV or HIV infection, alanine aminotransferase (ALT) ≥ 5 x upper limit of normal, total bilirubin ≥ 2 mg/dL, international normalized ratio ≥ 1.7, albumin ≤ 3.5 g/dL, hemoglobin ≤ 12 g/dL (females) or ≤ 13 g/dL (males), absolute neutrophil count ≤ 1.5 x 109 cells/L (≤ 1.2 x 109 cells/L for patients of black race); platelets ≤ 90 x 109 cells/L, creatinine clearance ≤ 50 mL/min, alpha fetoprotein > 100 ng/mL