Comparative Effectiveness of Ledipasvir/Sofosbuvir ± Ribavirinvs. Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir ± Ribavirin in 6961 Genotype 1 Patients Treated in Routine Medical Practice

L. I. Backus; P. S. Belperio; ; T. A. Shahoumian; T. P. Loomis; L. A. Mole


Aliment Pharmacol Ther. 2016;44(4):400-410. 

In This Article

Materials and Methods

This was an observational intent-to-treat cohort analysis of HCV-infected veterans receiving LDV/SOF ± RBV or OPrD ± RBV from VA. Data for this study were obtained from the VA's national Clinical Case Registry for HCV, an extract of the VA electronic medical record that contains demographics, laboratory results, pharmacy information and International Classification of Diseases diagnosis codes from inpatient hospitalisations, outpatient visits and problem lists of HCV-infected veterans seen at all VA medical facilities.[18]

Eligible subjects included all genotype 1 HCV-infected veterans from any VA facility nationwide who initiated 8 or 12 weeks of VA-prescribed LDV/SOF ± RBV or 12 weeks of OPrD ± RBV by 31 March 2015 with an end of treatment (EOT) by 14 July 2015 and a days supply less than or equal to 91 days. For patients who received multiple courses of therapy, only the first course was included. The choice of regimen and timing of follow-up visits and laboratory testing was at the discretion of the provider as patients were treated in routine practice. The present cohort includes 4356 treatment naïve patients treated with LDV/SOF ± RBV who were reported on previously.[19] Patients were excluded if they changed regimens without a treatment interruption (n = 64), had a baseline HCV RNA ≤1000 IU/mL (n = 218), had a liver transplant (n = 141), or had genotype subtype 1a and received OPrD without RBV (n = 16).

Treatment Outcome

Patients were considered to have SVR if they had HCV RNA results below the limit of quantification on all HCV RNA tests after the EOT including at least one test 10 weeks or more after the EOT. The 10 week time point was chosen to account for variability of clinic visits and of laboratory testing draws in clinical practice. Patients were categorised as not achieving SVR if they had a HCV RNA above the limit of quantification after the EOT, had no HCV RNA testing after the EOT and a HCV RNA above the limit of quantification on their last HCV RNA test while on treatment or died while on treatment or within 10 weeks of the EOT. Patients with HCV RNA below the limit of quantification on their last HCV viral load test, either on treatment or after the EOT, but no test 10 weeks of more after the EOT were excluded from the SVR analysis. The EOT was calculated as the last day covered by prescriptions of LDV/SOF or OPrD using the dates the medication was dispensed and the days' supply. HCV RNA was categorised as above or below the lower limit of quantification based on the locally reported HCV RNA result of which 98% utilised assays with a lower limit of quantification of 15 U/mL or less. Patients were followed from the initiation of LDV/SOF ± RBV or OPrD ± RBV through 29 February 2016, allowing for more than 32 weeks of follow-up after the EOT for all patients in the cohort.

Control Variables

Demographic and other baseline variables were determined at the time of treatment initiation and included age, gender, race/ethnicity, diabetes, HIV coinfection, history of decompensated liver disease (defined by oesophageal variceal haemorrhage, hepatic coma, hepatorenal syndrome or spontaneous bacterial peritonitis), prescribed proton pump inhibitor use, prior HCV antiviral treatment experience and HCV genotype 1 subtype. Subtype 1a included patients with reported results of 1a, mixed 1a/1b or 1 with subtype unspecified. Prior virological response was based on the most recent VA course of HCV antiviral treatment and categorised as relapse, partial response, null response and not defined. Baseline values for height and weight used to calculate body mass index (BMI) and the laboratory tests for alanine aminotransferase, aspartate aminotransferase, platelets and baseline HCV RNA were defined as the value within 1 year before and closest to the treatment start date. A FIB-4 score >3.25 at the start of treatment using baseline laboratory values was used as a marker of advanced liver disease.[20,21] Patients with FIB-4 ≤ 3.25 were considered to be 'noncirrhotic'.

In VA, HCV antiviral prescriptions are frequently filled for quantities less than 28 days. Patients were considered to have completed 8 weeks of LDV/SOF if they had received between 49 and 63 days' worth of medication and 12 weeks LDV/SOF ± RBV or OPrD ± RBV if they received between 77 and 91 days' worth of medication.

Statistical Analysis

Univariate comparisons used the Pearson chi-squared test with Yates' continuity correction for categorical variables. Multivariate logistic regression models were constructed to model SVR. Models included age, gender, race/ethnicity, diabetes, history of decompensated liver disease, treatment experience, BMI, FIB-4, genotype 1 subtype, and regimen. In a sensitivity analysis proton pump inhibitor use was included in the model. A set of models with the above baseline variables was constructed with all patients and with only patients who completed 12 weeks of treatment.

For all comparisons, a P < 0.01 was considered statistically significant. All analyses were performed using R version 3.1 (R Foundation for Statistical Computing, Vienna, Austria).

The protocol was approved by the Stanford University Institutional Review Board and the VA Palo Alto Health Care System Research and Development Committee.