Impact of new DAA therapy on real clinical practice: a multicenter region-wide cohort study

Abstract

Background: Management of chronic hepatitis C (CHC) has significantly accelerated in the last few years. Currently, second generation direct acting antivirals (DAAs) promise clearance of infection in most of patients. Here we present the results of the first analysis carried out on data of Lazio clinical network for DAAs.

Methods: The study was designed as a multicenter cohort: a) to assess the evolution of treatment during the first 24 months of the activity of the Clinical Network; b) to report overall efficacy of treatments; c) to analyze potential factors associated with lack of virological response at 12 weeks after therapy (SVR12); d) to evaluate the variation of ALT at baseline and 12 weeks after therapy in those who achieved SVR12 in comparison to those who did not. Analyses of efficacy were carried out with multilevel mixed effect logistic regression model. ALT temporal variation was assessed by mixed effect model mixed models with random intercept at patient's level and random slope at the level of the time; i.e. either before or after therapy.

Results: Between 30 December 2014 and 31 December 2016 5279 patients started a DAA treatment; of those, 5127 (in 14 clinical centers) had completed the 12-week follow-up. Overall proportion of SVR12 was 93.41% (N = 4780) with no heterogeneity between the 14 clinical centers. Interruption as the consequence of severe side effect was very low (only 23 patients). Unadjusted analysis indicates that proportion of SVR12 significantly changes according to patient's baseline characteristics, however after adjusting for potential confounders only adherence to current guidelines, stage of liver diseases, gender, transplant and HIV status were independently associated with the response to therapy. Analysis of ALT temporal variation showed that ALT level normalized in most, but not, all patients who achieved SVR12.

Conclusion: Our study confirmed the extraordinary efficacy of DAAs outside clinical trials. The advantage of DAAs was particularly significant for those patients who were previously considered as difficult-to-treat and did not have treatment options before DAAs era. Intervention based on network of select centers and prioritization of patients according to diseases severity was successful. Further studies are needed to establish whether clearance of HCV after DAAs therapy can arrest or even revert liver fibrosis in non-cirrhotic patients and/or improve life quality and expectancy in those who achieve SVR12 with cirrhosis.

Keywords: Chronic hepatitis C; Clinical study; Direct acting antiviral; Hepatitis C virus; Liver cirrhosis; Liver damage; Mixed effect model; Multicenter cohort study; New therapy; Treatment efficacy.

Fig. 1

Flow charts to describe selection of population sample included in the different analyses. Blue boxes report the number of patients in each stage of selection; green boxes report excluded subjects with reason; orange boxes report the type of analysis carried out

Fig. 2

Distribution of the 5279 DAA naïve patients according to DAAs combination and month of start of therapy. SOF: sofosbuvir±ribavirin±Peg-Interferon; SIM: simeprevir+ribavirin+Peg-interferon. 2D/3D: ombitasvir+paritaprevir+ritonavir±dasabuvir±ribavirin; LED+SOF: ledipasvir+sofobuvir; DAC + SOF: daclatasvir+sofosbuvir. The frequency of each specific combination is reported in Table 1

Fig. 3

Proportion of the patients according quality of treatment and urgency of treatment. a Monthly proportion of the 5279 patients who received either sub-optimal, optimal or not recommend of treatment according to EASL 2016 guidelines. Group A, treatments currently considered as optimal in 2016 EASL guidelines; group B, treatments that is shorter than currently recommended and/or does not included all the recommended drugs/combinations and thus considered suboptimal in 2016 EASL guidelines; group C, treatments that contains all drugs as group A, but also included additional drug (e.g. ribavirin RBV) and/or it is longer than currently recommended. NA: not assessable (patients’ information to assess quality are missing). b Monthly proportion of the 5279 patients who had access to therapy by base line clinical features. Urgent:: patients with cirrhosis, candidate to liver transplant; recipients of organ transplant, patients with severe HCV associated extra-hepatic manifestation; Non cirrhotic: all other patients

Fig. 4

Kinetics of ALT level in 4 different groups of patients according to the stage of liver disease (i.e. with/without cirrhosis) and therapy outcome (i.e. fail or SVR12). a Box-plot describe the distribution of the 3179 patients according values of ALT level patients either before the start of therapy (blue boxes; T0) and eventually 12 weeks after therapy (red boxes; FUP12). Almost all patients had ALT value above upper normal limit (black dotted line; 40 U/L) before therapy. More than 75% of patients who achieve SVR12 normalized ALT at 12 weeks after the end of therapy. A normalization of ALT values was also reported in about 50% of those who did not achieve SVR at 12 weeks after the end of therapy. b Temporal variation of ALT levels before treatment and 12 weeks after the endo of therapy. Estimates, 95%CI and p-values were carried out according to a mixed effect model which take in account correlation of data at the level of each individual patients. A significant reduction of ALT is reported for all patients. However average reduction of ALT levels is about 2 time higher in those who achieved SVR12 than in those who did not