Real-life Security and Efficacy of DAA-based Therapy in HCV/HIV-Coinfected Patients

October 14, 2016 updated by: José A. Mira Escarti, Valme University Hospital

Security and Efficacy of Triple Therapy Including Direct-Acting Antivirals Against Chronic Hepatitis C Infection In HIV-Coinfected Patients In Real-Life Conditions: The Prospective HEPAVIR Cohort.

The purpose of this study is to evaluate the efficacy and tolerability of DAA-based regimens in the clinical practice in HIV/HCV-coinfected patients.

Hypothesis: The efficacy and tolerability of DAA-based regimens in the clinical practice is different to what is observed in clinical trials in HIV/HCV-coinfected patients.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Treatment strategies aimed to achieve sustained virologic response (SVR) are of highest priority in patients with chronic hepatitis C and HIV coinfection, since SVR leads to a dramatic reduction in the incidence of hepatic decompensations and mortality in this setting. Until recently, therapy against hepatitis C virus (HCV) was based on pegylated interferon (peg-IFN) plus ribavirin (RBV). This combination prompt SVR only in approximately 50% of the HCV genotype 1 (HCV-1)-infected patients. Furthermore, it is costly and associated with multiple and sometimes serious side effects. In the setting of HIV/HCV-1-coinfection, rates of SVR are even lower and do not exceed 25% in the clinical practice.

Considerable increases of SVR have been achieved recently with the arrival of direct acting antivirals (DAA) against HCV. Among the first of these new agents are the protease inhibitors telaprevir (TVR) and boceprevir (BOC), which are approved for HCV-1 infection. Data obtained from clinical trials have demonstrated that the combination of peg-IFN/RBV with TVR or BOC significantly augments SVR rates as compared to what is observed with peg-IFN plus RBV only. As a consequence, triple therapy including peg-IFN, RBV plus TVR or BOC has become the standard therapy for HCV-1-infected patients in our setting. In addition, a number of further DAAs are currently in the final phases of development, as it is the case for the protease inhibitors faldaprevir and simeprevir, the polymerase NS5B inhibitor sofosbuvir and the NS5A inhibitor daclatasvir.

Although the considerable improvement of therapy outcome with DAA-including regimens is giving a positive prospective, there are a number of questions that have to be solved as soon as possible. On the one hand, the information on response to DAA in the coinfected population is derived from clinical trials, which often do not reflect patient management in the clinical practice. Also, the populations included in clinical trials are highly selective and may lack the high proportion of difficult-to-treat individuals expected among the candidate population, i.e., those who failed previous treatment and who bear compensated cirrhosis. In fact, data derived from the French cohort CUPIC including HCV-monoinfected, cirrhotic patients, show that tolerability and efficacy of TVR and BOC-based treatment is lower than observed in pivotal trials. On the other hand, similar to dual therapy including Peg-IFN/RBV, it is possible that both response rates and safety profiles of DAAs are not comparable between HCV-monoinfected and HIV/HCV-coinfected patients. In this context, the coinfected population has singularities as the coadministration of antiretroviral therapy, that may cause drug-drug-interactions and decreased tolerability, thus resulting in diminished efficacy. Finally, it is of highest relevance to identify predictive factors for treatment response in the new DAA-based regimens in order to individualize treatment decision and duration of therapy.

Due to the above mentioned, studies on safety and efficacy of DAA-based therapy under real life conditions in HIV/HCV-coinfected patients are urgently needed.

Primary objectives:

  • To determine the efficacy of DAA-based therapy in the clinical in patients with chronic hepatitis C and HIV coinfection.
  • To determine the security of DAA-based therapy in the clinical in patients with chronic hepatitis C and HIV coinfection.

Secondary objectives:

  • Identification of predictive factors for response to DAA-based treatment in the studied population.
  • Compare security and efficacy of the different DAAs used.
  • Evaluate the on-treatment HCV kinetics for the different regimens.

Scheduled visits: 0, 1, 2, 4, 8, 12, 24, 36 and 48 weeks, as well as 12 and 24 weeks post-treatment.

Definition SVR: Undetectable HCV-RNA 24 weeks after scheduled end of treatment.

Definition of hepatic fibrosis:

  • advanced fibrosis: F3 as determined by liver biopsy or 11 kilopascals as determined by transient elastometry
  • cirrhosis: F4 as determined by liver biopsy or 14.6 kilopascals as determined by transient elastometry

Variables collected within in the cohort:

  • primary outcome variable: SVR (efficacy study) and % of patients who discontinued therapy due to adverse events (safety study)
  • epidemiological variable: age, sex, interleukin 28B rs12979860 genotype
  • variables related to hepatitis C virus-infection: infection route, genotype, grade of hepatic fibrosis and method used for its determination, baseline Child-Pough-Index, previous hepatic decompensations
  • treatment-related variables: previous response to treatment, doses and dose reductions/discontinuations of peg-IFN, RBV and the DAA(s), overall severe adverse events, adverse events that occur in more than 5% of the patients, hepatic decompensations, deaths, HCV viral load at baseline and at each visit
  • variables related to HIV-infection: Centers for Disease Control and Prevention (CDC) category, HIV viral load, cluster of differentiation 4 (CD4) cell count, antiretroviral regimen
  • analytical variables: aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelets, leucocytes, low-density lipoprotein cholesterol, bilirubin, gamma-glutamyltransferase (GGT), alkaline phosphatase,
  • clinical variables: alcohol intake Quality assurance and data checks: Data will be obtained from controlled databases at the participating centers. Databases will be monitored and controlled by queries every three months. Descriptive statistics will be be applied in order to detect transcription errors.

Source data verification: not planned.

All grade 3 or 4 adverse events, as well as all unexpected events, will be reported to the Andalusian Center for Pharmacovigilance (Centro Andaluz de Farmacovigilancia, www.cafv.es).

A sample size of 230 is planned for this study.

Statistical analysis: The outcome variables of this study will be the achievement of SVR, as well as the development of severe adverse events during follow-up. Descriptive statistical analysis will be performed in order to describe the cohort. Continuous variables will be expressed as median [interquartile range (IQR)] and categorical variables as number [percentage; 95% confidence interval (CI)]. The association of continuous variables with SVR or the frequency of patients who discontinue therapy will be analyzed using the Student's t-test for normal distribution and the Mann-Whitney U-test otherwise whereas the relationship with categorical variables will be determined applying the χ2-test or the Fisher's test, when applicable. Those factors that show an association in the univariate analysis with a p<0.2, as well as those with a biologically possible influence, will be entered logistic regression in order to identify independent predictors for SVR. The adjusted odds ratio (AOR) and the respective 95% CI will be calculated. All p values <0.05 will be considered statistically significant. Data will be analyzed using the SPSS statistical software package release 19.0 (SPSS Inc., Chicago, Illinois, USA) and STATA 9.0 (StataCorp, College Station, Texas, USA).

Sample size calculations: Estimating a SVR rate of 55%, with a confidence interval of 95% and a lost-to-follow-up rate of 5%, a minimum of 230 patients should be included in order to obtain a precision of 5%.

Study Type

Observational

Enrollment (Anticipated)

1000

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

All patients who consecutively attend the Unit of Infectious Diseases of the Study Group for Viral Hepatitis (HEPAVIR) of the Andalusian Society of Infectious Diseases (Sociedad Andaluza de Enfermedades Infecciosas, SAEI), Spain, will be considered for this study.

Description

Inclusion Criteria:

  • Older than 18 years
  • HIV infection determined by enzymeimmunoassay and confirmed by Western Blot
  • Naïve to treatment including a DAA
  • Initiation of triple therapy including a DAA
  • Written informed consent to participate in the study and to undergo genetic determinations

Exclusion Criteria:

  • Pregnancy
  • Any contraindication for the administration of peg-IFN, RBV or the respective DAA
  • Patients who are not able to provide informed consent to participate in the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
DAA-based therapy against HCV
HIV/HCV-coinfected patients who start therapy against HCV including one or more DAA
Drug: DAA against HCV
Other Names:
  • simeprevir
  • sofosbuvir
  • ledipasvir
  • dasabuvir
  • ombitasvir
  • daclatasvir
  • paritaprevir
  • velpatasvir
  • elbasvir
  • grazoprevir
  • telaprevir
  • boceprevir

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients who achieve SVR to DAA-based therapy as measure of efficacy
Time Frame: 18 months
Achievement of SVR to DAA-based therapy in the clinical practice in patients with chronic hepatitis C and HIV coinfection.
18 months
Number of patients who develop severe adverse events as measure of safety
Time Frame: 18 months
Development of severe adverse events related to DAA-based therapy in the clinical practice in patients with chronic hepatitis C and HIV coinfection.
18 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients who achieve SVR to a BOC-based regimen as compared to numbers of patients who achieve SVR to a TVR-based regimen.
Time Frame: 18 months
In order to compare TVR- and BOC-based therapy, the numbers of patients who achieve SVR to DAA-based therapy will be analyzed.
18 months
Number of patients who reach undetectable HCV-RNA at week 4 of PI-based therapy as a measure of on-treatment response to therapy.
Time Frame: 18 months
18 months
Number of patients who develop adverse events during a BOC-based regimen as compared to numbers of patients who develop adverse events during a TVR-based regimen.
Time Frame: 18 months
In order to compare TVR- and BOC-based therapy, the numbers of patients who develop adverse events during either treatment will be analyzed.
18 months
Number of patients who achieve SVR to an interferon-free regimen.
Time Frame: 36 weeks
The numbers of patients who achieve SVR to DAA-based therapy in absence of interferon will be analyzed.
36 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Valme University Hospital

Collaborators

Hospital Universitario de Canarias
Hospital Universitario Virgen Macarena
Hospital Universitario Virgen de la Arrixaca
Hospital Universitario Reina Sofia de Cordoba
Fundación de Investigación Biomédica - Hospital Universitario de La Princesa
Hospital Regional de Malaga
Hospital Universitario Central de Asturias
Hospital Universitario Virgen de la Victoria
Hospital Universitario Puerta del Mar
Hospital Universitario Puerto Real
Hospital Álvaro Cunqueiro
Complejo Hospitalario Universitario de Huelva
Hospital Universitario de Gran Canaria
Complejo Hospitalario de Jaen
Hospital Torrecárdenas
Hospital Poniente
Hospital La Línea

Investigators

  • Principal Investigator: Karin Neukam, PhD, Valme University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2012

Primary Completion (Anticipated)

December 1, 2020

Study Completion (Anticipated)

December 1, 2020

Study Registration Dates

First Submitted

January 6, 2014

First Submitted That Met QC Criteria

February 5, 2014

First Posted (Estimate)

February 6, 2014

Study Record Updates

Last Update Posted (Estimate)

October 17, 2016

Last Update Submitted That Met QC Criteria

October 14, 2016

Last Verified

October 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HEPAVIR-DAA

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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