Clinical trial NCT02333292: Efficacy and Safety of Therapy Against HCV Based on Direct-acting Antivirals in Real-life Conditions
Official title: Efficacy and Safety of Treatment Against Hepatitis C Virus Infection Based on Direct-acting Antivirals in Real-life Conditions: The GEHEP Cohort
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Chronic Hepatitis C Infection
Lead sponsor: Valme University Hospital
Sponsor class: OTHER
Collaborators: name: Hospital del SAS de Jerez
name: Hospital General Universitario Elche
name: Hospital La Línea de la Concepción
name: Complexo Hospitalario Universitario de A Coruña
name: Hospital de Figueres
name: Hospital Universitario Puerto Real
name: Hospital Universitario Virgen de la Victoria
name: Hospital Universitario de Canarias
name: Hospital General Universitario de Alicante
name: Hospital Universitario Araba
name: Hospital Royo Vilanova
name: Hospital Universitario de Burgos
name: Complejo Hospitalario Universitario de Huelva
name: Hospital Universitario Reina Sofia de Cordoba
name: Hospital Universitario Virgen Macarena
name: Complejo Hospitalario Universitario de Vigo
name: Clinica Universidad de Navarra, Universidad de Navarra
name: Hospital Clinico Universitario San Cecilio
name: Hospital Universitario La Fe
name: Hospital General Universitario de Valencia
name: Hospital Universitario Infanta Leonor
name: Hospital Universitario de Gran Canaria
name: Hospital General Universitario Santa Lucía
name: Centro Penitenciario Alicante 1
name: Hospital Regional Universitario Carlos Haya
name: Hospital Virgen de la Luz
name: Hospital General Universitario de Castellón
name: Parc Taulí Hospital Universitari
First posted: 2015-01-07
Enrollment: 1128
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: HCV-infected patients who initiated treatment against HCV including a direct-acting antiviral

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of Patients with Sustained Virological Response
timeFrame: 48 weeks
measure: Number of Participants with Adverse Events
timeFrame: 48 weeks
Secondary outcomes:
measure: Identification of predictors of SVR
timeFrame: 48 weeks
measure: Analyze efficacy and safety in patients that receive methadone maintenance therapy
timeFrame: 48 weeks
measure: Analyze efficacy and safety according to previous treatment outcome
timeFrame: 48 weeks
measure: Analyze efficacy and safety in patients with cirrhosis
timeFrame: 48 weeks
measure: Evaluate impact of SVR on biological, elastographical and clinical parameters
timeFrame: 48 hours
Other outcomes:
Locations:
city: Seville
country: Spain
facility: Valme University Hospital
state: Andalusia
Study officials:
affiliation: Valme University Hospital
name: Karin I Neukam, Dr
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Macias J, Monge P, Mancebo M, Merchante N, Neukam K, Real LM, Pineda JA. High frequency of potential interactions between direct-acting antivirals and concomitant therapy in HIV/hepatitis C virus-coinfected patients in clinical practice. HIV Med. 2017 Aug;18(7):445-451. doi: 10.1111/hiv.12471. Epub 2016 Nov 24.
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