Efficacy of Generic Oral Directly Acting Agents in Patients With Hepatitis C Virus Infection

S. Gupta; G. Rout; A. H. Patel; M. Mahanta; N. Kalra; P. Sahu; R. Sethia; A. Agarwal; G. Ranjan; S. Kedia; S. K. Acharya; B. Nayak; Shalimar


J Viral Hepat. 2018;25(7):771-778. 

In This Article

Patients and Methods

Inclusion and Exclusion Criteria

In this prospective study, all consecutive HCV–positive patients evaluated in the Department of Gastroenterology at the All India Institute of Medical Sciences (AIIMS), in New Delhi, India between May 2015 and January 2017 were included. Written informed consent was obtained from all patients. The study was approved by the institute's ethics committee. Patients with co–infection with hepatitis B virus (HBV) and human immunodeficiency virus (HIV), hepatocellular carcinoma (HCC), pregnancy and lactation, active tuberculosis, malignancy, Wilson's disease, chronic kidney disease and those not willing to consent were excluded from the study. All demographic, virological and SVR12 data were collected from a prospectively maintained database.

Patient Evaluation

All patients underwent a complete blood count (CBC), liver function tests (LFT), kidney function tests, fasting blood sugar and an abdominal ultrasound. Upper gastrointestinal endoscopy and triple phase CT of the abdomen were performed in patients with concern for cirrhosis and hepatocellular carcinoma. In patients with suspected autoimmune liver disease and Wilson's disease workup was performed as per the standard guidelines.[10,11] Serological testing of all patients for HBV surface antigen, anti–HCV antibody and HIV–1 and 2 was carried out using commercial ELISA. For HCV genotyping and quantitation, viral nucleic acid was extracted using an automated nucleic acid isolation system (Qiasymphony, Qiagen). The HCV genotyping was carried out using the AmpliSensò HCV–genotype–FRT PCR kit which can detect genotypes 1–6.

High viral load was defined as ≥600 000 IU/mL, and low viral load was defined as <600 000 IU/mL. HCV RNA quantification was performed at baseline, end of therapy and 12 weeks post–treatment (SVR12). SVR12 was achieved if HCV RNA was negative/below detectable limit. While all patients had HCV RNA levels checked at baseline, end of treatment and SVR12, several patients had HCV viral loads checked at additional intervals. The diagnosis of cirrhosis was based on histologic findings on liver biopsy, fibroscan showing a liver stiffness ≥12.5 KPa (Echosens, France) or a combination of conventional endoscopic (varices, gastric antral vascular ectasia or portal hypertensive gastropathy on esophagogastroduodenoscopy) and imaging criteria (CT scan or ultrasound findings concerning for cirrhosis). Decompensated cirrhosis was defined as the presence of jaundice, ascites, variceal haemorrhage or hepatic encephalopathy. The model for end–stage liver disease (MELD) score[12] was calculated at baseline and after 12 weeks of completion of treatment. Patients were classified as being either "treatment naïve" with no prior treatment given or "treatment experienced" if they had attempted a prior regimen including peginterferon and ribavirin. Breakthrough was defined as undetectable HCV RNA during treatment followed by the appearance of HCV RNA, despite continued treatment. All patients who were included in the study had a fibroscan performed prior to initiation of DAAs, as per our institutional protocol.

Management Protocol

The management protocol of chronic hepatitis C (CHC) patients was as per the American Association for the Study of Liver Diseases (AASLD) practice guidelines for management of HCV infection.[3] Sofosbuvir remained the backbone of all combination therapies. Initially, when sofosbuvir alone was available, a combination of sofosbuvir with ribavirin alone or in combination with peginterferon was used for both HCV genotypes 1 and 3. Later, as other DAAs became commercially available in India, sofosbuvir was used in combination with daclatasvir (for genotypes 2, 3, 5 and those with genotype not available) and ledipasvir (for genotype 1 and 4). The use of ribavirin was considered in patients who previously relapsed or did not respond to interferon–based regimens, and in patients with cirrhosis; the duration of therapy in these patients was 24 weeks as combination therapy with sofosbuvir. Patients were followed until the end of therapy and then had follow–up studies for a further 12 weeks. Various DAA combination drugs were purchased by patients with prescriptions. Many patients (n = 220) were not able to afford the medications and received the generic drugs (sofosbuvir and ribavirin, with or without peginterferon) free of cost from Cadila Zydus Ltd. and Cipla Ltd., at the request of the treating physicians. HCV genotyping and viral load estimation was performed free of cost for all patients.

Statistical Analysis

The normally distributed variables were expressed as mean ± standard deviation (SD) and continuous variables with skewed distribution as median (inter–quartile range). Categorical data are presented as frequency and percentage. Univariate analysis was performed to assess the factors associated with SVR12 using an independent t test or Mann–Whitney U test for continuous variables. The chi–square test or Fisher's exact test for categorical variables was used whenever applicable. The continuous variables were dichotomized to assess the effect on SVR. A P value of .05 was considered as statistically significant. Data were analysed using IBM SPSS Statistics software (version 20.0, Chicago, IL, USA).