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