Efficacy and Safety of Therapy Against HCV Based on Direct-acting Antivirals in Real-life Conditions
Efficacy and Safety of Therapy Against HCV Based on Direct-acting Antivirals in Real-life Conditions
Objectives: 1) To evaluate la proportion of hepatitic C virus (HCV)-monoinfected patients who
 show sustained virologic response (SVR) to treatment including direct-acting antivirals
 (DAAs) in the clinical practice in clinical units that treat infectious diseases and 2) to
 determine the frequency of adverse events, including those that are severe and/or cause
 treatment interruption, in DAA-based therapy in this setting.

 Design: Multicentric, prospective post-authorised cohort study. Setting: Hospitals of the
 Hepatitis Study Group (GEHEP) of the Spanish Society of Infectious Diseases and Microbiology
 (SEIMC).

 Study population: HCV-monoinfected patients that initiate DAA-based treatment outside
 clinical trials.

 Variables: The primary efficacy outcome variable is the proportion of patients who reach
 undetectable HCV-RNA 12 weeks after the scheduled end of therapy (SVR12). The primary safety
 outcome variable is the percentage of subjects who discontinue therapy due to adverse events.

 Statistical analysis: A descriptive study will be performed, as well as a double sensibility
 analysis of the frequency of SVR12 using both an intention-to-treat and an on-treatment
 approach. Those variables that are associated with SVR12 with a p-value <0.2 will be included
 in a logistic regression analysis in which SVR12 will be the dependent variable.
The incidence of hepatic decompensations and mortality is reduced considerable in patients
 who achieve sustained virologic response (SVR) to therapy against hepatitis C virus (HCV)
 infection. With the arrival of direct-acting antivirals (AAD) against HCV, rates of SVR are
 significantly higher than what was achieved with pegylated interferon (peg-IFN) in
 combination with ribavirin (RBV). Therefore, AADs could have a high impact in this context.
 Therefore, triple therapy against HCV genotype 1 based on the first-generation protease
 inhibitors (PI) telaprevir (TVR) or boceprevir (BOC) plus peg-IFN/RBV became standard therapy
 in 2011 and SVR rates as high as 68%-75% were reached in treatment-naïve patients. In
 treatment-experienced subjects, retreatment with triple therapy resulted in higher SVR rates
 than what was observed with dual therapy alone, however, treatment success strongly depends
 on the previous response pattern. Unfortunately, combinations based on TVR or BOC are not
 well tolerated, treatments are complex, costs are high and pharmacological interactions are
 frequently observed.

 The next generation of DAAs offers increased response rates and, furthermore, a better safety
 pattern than TVR or BOC. Additionally, the dosing of the newer DAAs is easier and more
 convenient, and pharmacological interactions of the newer DAAs are easier to manage or even
 not relevant. The FDA has approved the second-generation PI simeprevir, the HCV
 non-structural (NS) protein NS 5B inhibitor sofosbuvir, as well as the inhibitors of NS 5A
 daclatasvir and ledipasvir. Apart from a better efficacy, safety and convenience, these new
 DAAs are active against HCV genotypes other than 1. Finally, some of the new DAAs can be
 administered in interferon-free regimens and therefore offer treatment options for
 interferon-intolerant individuals or for those with a contraindication for peg-IFN.
 Therefore, in the near future, the vast majority of HCV monoinfected patients will be treated
 with a combination including a DAA. Currently, the main problem is the high cost of the DAAs
 challenging the health systems.

 In spite of the positive prospect regarding response rates to DAAs, there are a number of
 questions to be answered as soon as possible. On the one hand, the information on efficacy
 and safety of the DAAs available to date is derived from clinical trials that do not reflect
 the circumstances of the clinical practice. In this context, clinical trials usually include
 a considerably low proportion of patients with certain characteristics, such as cirrhotics.
 Data from the French cohort CUPIC reveal that this subgroup shows a lower tolerability of TVR
 or BOC than that reported in pivotal clinical trials. In fact, data obtained from this cohort
 resulted in a change of treatment guidelines for HCV monoinfected patients published by the
 Spanish Agency of Medicines. On the contrary, there is evidence based on observations made
 within the expanded access program study HEP3002 that individuals with advanced fibrosis show
 a efficacy and safety profile when treated with triple therapy that is more similar to that
 observed in clinical trials than within the CUPIC cohort. Nevertheless, in this study,
 exclusion criteria and follow-up were comparable to what is applied in clinical trials.
 Therefore, the study population may not reflect exactly the patient profile seen in
 real-life.

 Currently, information on the distinct aspects of treatment against HCV including DAAs under
 real-life conditions in Spain is scarce. Clinicians at the Infectious Diseases Units treat a
 high number of HCV monoinfected patients. These physicians are confronted with a patient
 population in which a history of drug abuse is predominant, the majority of the individuals
 having consumed injecting drugs, who frequently suffer psychiatric pathology and who receive
 concomitant therapy that cause problems regarding drug-drug interactions and adherence. Also,
 the HCV genotype distribution is different to what is observed in Hepatology Units, being the
 genotype 1a predominant as compared to 1b, 3 and 4. Taken into account what was mentioned
 above, these factors could cause different rates of SVR to DAAs, interruptions and voluntary
 drop-outs as compared to what has been reported, especially in the difficult-to-treat
 population.
Inclusion Criteria:

 -  older than 18 years

 -  initiation of therapy including a direct-acting antiviral against HCV

 Exclusion Criteria:

 -  HIV-infection

 -  unable to provide written informed consent