Perşembe Eylül 15th, 2016
L. I. Backus; P. S. Belperio; ; T. A. Shahoumian; T. P. Loomis; L. A. Mole
Aliment Pharmacol Ther. 2016;44(4):400-410.
http://www.medscape.com/viewarticle/866290?nlid=109253_804&src=WNL_mdplsfeat_160913_mscpedit_infd&uac=177387BK&spon=3&impID=1196211&faf=1
Abstract and Introduction
Abstract
Background Real-world data are needed to inform hepatitis C virus (HCV) treatment decisions.
Aim To assess the comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin (LDV/SOF ± RBV) vs. ombitasvir/paritaprevir/ritonavir + dasabuvir (OPrD) ± RBV in genotype 1 HCV patients treated in routine medical practice.
Methods Observational intent-to-treat cohort of genotype 1 patients initiating 8 or 12 weeks of LDV/SOF ± RBV or 12 weeks of OPrD ± RBV. Sustained virological response (SVR) required RNA below the limit of quantification at least 10 weeks after end of treatment.
Results 6961 patients initiated LDV/SOF (N = 4478), LDV/SOF + RBV (N = 1269), OPrD (N = 297), and OPrD + RBV (N = 917) at 126 facilities. Intention-to-treat SVR rates were 91.4% (3813/4170) for LDV/SOF, 90.0% (1098/1220) for LDV/SOF + RBV, 95.1% (269/283) for OPrD and 85.8% (746/869) for OPrD + RBV. SVR rates in those completing 8 weeks of LDV/SOF were 91.7% (1223/1333) and 12 weeks of LDV/SOF 94.6% (2475/2615), LDV/SOF + RBV 92.2% (1033/1120), OPrD 98.0% (248/253) and OPrD + RBV 95.5% (705/738). Significant predictors of SVR were African American race (OR 0.71, 95%CI 0.59–0.86, P < 0.001), body mass index (BMI) > 30 kg/m2 (OR 0.73, 95% CI 0.60–0.89, P = 0.002), FIB4 > 3.25 (OR 0.60, 95% CI 0.49–0.72, P < 0.001), OPrD + RBV compared to LDV/SOF (OR 0.60, 95% CI 0.48–0.76, P < 0.001) and subtype 1b (OR 1.38, 95% CI 1.11–1.71, P = 0.003). For those completing 12 weeks, FIB-4 > 3.25 and high BMI remained significant predictors.
Conclusions In this robust real-world cohort, SVR rates were similar to clinical trials. FIB-4 > 3.25 and high BMI were significant negative predictors of SVR. Reduced odds of SVR in African Americans and with OPrD + RBV likely arose from excess early discontinuation as these factors were no longer significant, when limited to patients completing a 12-week course.
Introduction
The landscape of antiviral therapy for chronic hepatitis C virus (HCV) infection continues to advance as all-oral options expand. Sustained virological response (SVR) rates reported in clinical trials with all-oral regimens are consistently above 90% for most HCV-infected patient populations and have become the expected norm. Because of the rapidity with which HCV therapies are progressing and the absence of comparative clinical trials, providers are left to extrapolate information to make clinical decisions about medication selection. Emerging real-world data of individual therapies have demonstrated results comparable to registration trials, however, comparative effectiveness evaluations are needed to determine whether clinical differences exist between regimens.[1–6] Comparative effectiveness analyses will become increasingly important as patients, providers, healthcare systems and managed care organisations consider additional nuances of convenience, drug interactions, treatment duration and ultimately cost effectiveness.
Ledipasvir/sofosbuvir (LDV/SOF) and ombitasvir/paritaprevir/ritonavir plus dasabuvir (OPrD) have been extensively evaluated individually in clinical trials of HCV-infected adults. The SVR rates in LDV/SOF trials of genotype 1 patients with and without cirrhosis ranged from 94% to 99% and in OPrD trials SVR rates ranged from 89% to 99%.[7–14] While these outcomes appear similar, differences in study design and patient populations prevent direct cross-study comparison of results.
Hepatitis C virus disproportionally affects the veteran population and the Department of Veterans Affairs (VA) is the largest US provider of healthcare to HCV-infected individuals caring for nearly 5% of all individuals in the US with HCV infection.[15,16] Thus, ongoing evaluation of the effectiveness of HCV antiviral regimens remains a priority for VA.[17] With the rapid uptake of all-oral HCV regimens across the VA system and the diverse HCV-infected veteran population receiving these regimens, we examined SVR rates and comparative effectiveness of LDV/SOF ± ribavirin (RBV) vs. OPrD ± RBV in genotype 1 HCV-infected veterans treated in routine medical practice
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
