Efficacy and Safety of Therapy Against HCV Based on Direct-acting Antivirals in Real-life Conditions

Study Overview
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Brief Summary
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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
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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.

Official Title
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Efficacy and Safety of Treatment Against Hepatitis C Virus Infection Based on Direct-acting Antivirals in Real-life Conditions: The GEHEP Cohort

Conditions
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Chronic Hepatitis C Infection

Intervention / Treatment
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* Drug: Telaprevir
* Drug: Boceprevir
* Drug: Sofosbuvir
* Drug: Simeprevir
* Drug: Daclatasvir
* Drug: Ledipasvir
* Drug: ritonavir-boosted Paritaprevir/ Ombitasvir
* Drug: Dasabuvir
* Drug: Velpatasvir
* Drug: Elbasvir
* Drug: Grazoprevir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| IFN<br>HCV-infected patients, pre-treated or treatment-naïve, who start a regimen containing pegylated interferon in combination with any DAA | Drug: Telaprevir<br>* Initiation of a regimen containing TVR<br>* Other names: TVR;Drug: Boceprevir<br>* Initiation of a regimen containing BOC<br>* Other names: BOC;Drug: Sofosbuvir<br>* Initiation of a regimen containing SOF<br>* Other names: SOF;Drug: Simeprevir<br>* Initiation of a regimen containing SMV<br>* Other names: SMV;|
| IFN-free<br>HCV-infected patients, pre-treated or treatment-naïve, who start a regimen containing one or more DAA | Drug: Sofosbuvir<br>* Initiation of a regimen containing SOF<br>* Other names: SOF;Drug: Simeprevir<br>* Initiation of a regimen containing SMV<br>* Other names: SMV;Drug: Daclatasvir<br>* Initiation of a regimen containing DCV<br>* Other names: DCV;Drug: Ledipasvir<br>* Initiation of a regimen containing LDV<br>* Other names: LDV;Drug: ritonavir-boosted Paritaprevir/ Ombitasvir<br>* Initiation of a drug combination of PTV/OTV<br>* Other names: PTV/OTV;Drug: Dasabuvir<br>* Initiation of a regimen containing DBV<br>* Other names: DBV;Drug: Velpatasvir<br>* Initiation of a regimen containing VPV<br>* Other names: VPV;Drug: Elbasvir<br>* Initiation of a regimen containing EBV<br>* Other names: EBV;Drug: Grazoprevir<br>* Initiation of a regimen containing GZR<br>* Other names: GZR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients with Sustained Virological Response | Efficacy of treatment against hepatitis C virus infection based on direct-acting antivirals in real-life conditions as reflected in proportion of patients who achieve sustained virological response 12 weeks after end of therapy. | 48 weeks | 
| Number of Participants with Adverse Events | Safety of treatment against hepatitis C virus infection based on direct-acting antivirals in real-life conditions as reflected in the number of patients with adverse events. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification of predictors of SVR |  | 48 weeks | 
| Analyze efficacy and safety in patients that receive methadone maintenance therapy |  | 48 weeks | 
| Analyze efficacy and safety according to previous treatment outcome |  | 48 weeks | 
| Analyze efficacy and safety in patients with cirrhosis |  | 48 weeks | 
| Evaluate impact of SVR on biological, elastographical and clinical parameters |  | 48 hours |