Generic Sofosbuvir-based Direct-acting Antivirals in Hepatitis C Virus-infected Patients With Chronic Kidney Disease

Manoj Kumar; Suman L. Nayak; Ekta Gupta; Ashish Kataria; Shiv K. Sarin

Disclosures

Liver International. 2018;38(12):2137-2148. 

In This Article

Methods

Patients

Patients with CKD including patients with advanced CKD (CKD stage 4 or 5 with an e-GFR <30 mL/min or those on dialysis) and having HCV infection, who fulfilled the following inclusion criteria were enrolled in this study: (i) Age 18 years or older; (ii) HCV RNA positive.

Patients who were started on treatment between 26 September 2015 and 15 February 2017 were included in the study. The last follow-up date was fixed at 25 February 2018 for the purpose of data analysis.

All patients consented to the off-label use of sofosbuvir, understanding that safety and efficacy under such circumstances is unknown and lacks substantial clinical data.

Treatment Schedule and Follow-up

As part of the pretreatment evaluation, each patient's medication list as well as baseline symptoms were carefully reviewed and recorded. Close attention was paid to pretreatment presence and severity of symptoms such as nausea, fatigue, headache, pruritus and insomnia, as these are typically seen in patients with end stage renal diseases (ESRD) or advanced renal disease, but have also been described as common side effects of sofosbuvir.

The study was started in September 2015. From September 2015 to December 2015, sofosbuvir plus ribavirin for 24 weeks was used for all genotypes. From January 2016, sofosbuvir plus ledipasvir for 12 weeks (for genotype 1) and sofosbuvir plus daclatasvir for 12 weeks (for genotype 3) were used.

All patients were started on sofosbuvir 400 mg daily (given 1 hour prior to dialysis on days of scheduled dialysis sessions, on other days at around the same time). Ribavirin was started at 200 mg daily and dose was increased weekly as per tolerated by the patients. Full-dose sofosbuvir and ledipasvir combination (400 mg + 90 mg) and daclatasvir (60 mg) was used.

Generic versions of sofosbuvir, ribavirin, sofosbuvir plus ledipasvir combination and daclatasvir were used.

Treatment-induced anaemia was managed with iron use as needed, erythropoietin use (either starting of erythropoietin or increasing the dose if already on erythropoietin), reducing the dose of ribavirin and blood transfusion (as needed).

Laboratory tests (including a complete blood count, hepatic profile, thyroid hormone, iron kinetics and α-foetoprotein) and ultrasound liver were done at baseline. All patients underwent serological tests for hepatitis B virus infection (HBsAg, anti-HBs titres) and human immunodeficiency virus (HIV) infection (HIV antibodies for HIV1 and 2). Genotyping of HCV and HCV RNA quantification were determined in all patients before treatment.

During treatment, a complete blood count was performed weekly during the first 8 weeks, and every 4 weeks thereafter or as needed. Liver function tests were evaluated every 4 weeks.

Quantitative HCV RNA testing was done after 4 weeks, at end of treatment and then 12 weeks, 24 weeks, 48 weeks and 72 weeks after end of therapy.

Drug concentrations in blood and pharmacokinetic analysis were not obtained during the treatment period, as the infrastructure for this type of analysis was not available at the centre.

Study Assessments

HCV RNA assay. HCV RNA quantification was done by Abbott Real Time HCV quantitative assay (Abbott, Wiesbaden, Germany). The lower limit of detection and lower limit of quantification of this assay is similar, ie, 12 IU/ml and linear range of the assay is from 12 to 108 IU/mL.

HCV genotyping. NS5B region of the virus was used for genotyping and subtyping. HCV RNA isolation was done using High pure viral nucleic acid kit (Roche Diagnostics, GmbH, Mannheim, Germany) according to the manufacturer's instructions.

End Points

The primary efficacy end point was the rate of sustained virological response, which was defined as an HCV RNA level of less than 12 IU per millilitre at 12 weeks after the end of treatment.

Secondary end points included virological response at week 4 of starting treatment, sustained virological response at 24 weeks, 48 weeks and 72 weeks after end of therapy, the rate of adverse events and treatment discontinuations because of adverse events.

Definitions

Cirrhosis: Liver biopsy was not done in any of the patients. In the absence of liver biopsy, any 2 of the following criteria were taken as indicative of cirrhosis: platelets count <140 000 per μL, presence of oesophageal varices, evidence of cirrhosis and/or portal hypertension and/or ascites by imaging studies (Ascites should have high serum ascites albumin gradient on biochemical analysis).

Chronic kidney disease (CKD) Staging: The e-GFR was estimated using the equation for modification of diet in renal disease. The stages of CKD were classified according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines.[21]

Serious adverse event: An adverse event that required hospitalization,

Anaemia: Defined as the presence of at least one of the following: (i) a haemoglobin <10 g/dL or >2 g/dL drop if baseline haemoglobin was <10 g/dL; (ii) new administration or increasing the dose of erythropoiesis stimulating agents (if already on such drugs before start of therapy) or (iii) need for blood transfusion.

Study Oversight

The study was approved by the Institutional Review Board of the Institute of Liver and Biliary Sciences, New Delhi, India, where the study was conducted [Institutional ethical committee number: F.25/5/80/ILBS/AC/2015/629 and ClinicalTrials.gov identifier number: NCT02563665].

Statistical Analysis

Statistical analysis was performed using the Statistical Package for Social Science (spss version 13.0; SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean ± SD or median (range) as appropriate and categorical variables were expressed as percentage. Sequential e-GFRs were compared using Kendall W test. All statistical tests were 2-tailed, and results were statistically significant with a P value was less than .05.

Comments

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