Antiviral Pharmacology and Adherence in Drug Users

Study Overview
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Brief Summary
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Approximately one half of all Americans living with Hepatitis C virus (HCV) are drug users, yet they are the least likely to receive HCV treatment. Drug users are presumed non-adherent and therefore denied potentially life-saving therapy. This assumption can only be confirmed or dispelled through prospective pharmacologic and adherence studies in this population. Such studies would be greatly enhanced by an objective, quantitative measure of adherence which does not currently exist in the HCV field. Through the work proposed in this application, sixty HIV/HCV co-infected drug users will be treated with direct acting antiviral agents (DAA) and randomized to receive directly observed DAA therapy (DOT) vs. no directly observed therapy (no-DOT). Patients randomized to no-DOT will have wirelessly observed therapy (WOT) which involves use of a portable medication dispenser that sends a signal to a server with the date and time when the dispenser is opened. In Aim 1, DAA concentrations will be compared in those randomized to DOT vs. no-DOT. DAA pharmacokinetics will also be defined accounting for clinical factors like degree of hepatic impairment and use of concomitant recreational and antiretroviral drugs. The goal is to quantify adherence in this population and the effect of variable adherence on drug concentrations. In Aim 2, DAA concentrations (plasma, cellular, hair) will be linked with adherence patterns identified using WOT and DOT. The goal is to identify a drug concentration biomarker that predicts adherence in this population. In Aim 3, the relationship between DAA adherence (as measured by WOT and DOT and drug concentrations) and rate of cure will be established. The goal is to define the degree of adherence needed for HCV cure.

Official Title
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Antiviral Pharmacology and Adherence in Drug Users

Conditions
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HEPATITIS C, Virus, Human Immunodeficiency

Intervention / Treatment
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* Behavioral: Directly Observed Therapy
* Behavioral: Wirelessly Observed Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to give informed consent HIV-infected men and women Chronic HCV infection as documented by quantifiable HCV RNA HCV genotype 1, 4, 5, 6 18-70 years of age Willingness and ability to comply with study procedures, including DOT, WOT, and biweekly clinic visits Considered an active drug user by HCV provider and self-reported drug use within the past month Exclusion Criteria: Glomerular filtration rate < 30 mL/min/1.73 m2 Receipt of prior HCV treatment and radiographic, histologic, or clinical evidence of cirrhosis Decompensated liver disease (i.e., ascites, history of esophageal variceal bleeding, hepatic encephalopathy) Medications not recommended per the SOF/LDV prescribing information (e.g., tipranavir and other P-gp inducers, tenofovir disoproxil fumarate plus cobicistat, rosuvastatin, amiodarone) Any medical condition that in the opinion of the investigators will make it challenging to adhere to the study protocol, such as unstable heart disease or cancer Chronic Hepatitis B virus Infection For females, active pregnancy or any intent to become pregnant For both sexes, an unwillingness to use contraception during the study period On parole or impending sentencing

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Sofosbuvir/Ledipasvir with Directly Observed Therapy (DOT)<br>Participants randomized to vDOT will be provided a smart phone with cellular service and will be pre-programmed with the mobile phone-based video application and contact information for study personnel. | Behavioral: Directly Observed Therapy<br> <br> * Other names: DOT;|
| Other: Sofosbuvir/Ledipasvir with Wirelessly Observed Therapy (WOT)<br>Participants on WOT will be provided the Wisepill portable medication dispenser. | Behavioral: Wirelessly Observed Therapy<br> <br> * Other names: WOT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare each individual's modeled estimate of ledipasvir and metabolites of sofosbuvir (GS-331007 and GS-331007-TP) steady state concentrations (Css) from non-linear mixed effects modeling to Css in subjects receiving DOT vs. WOT. |  | 12 weeks | 
| Quantify GS-331007-TP concentrations in dried blood spots as a function of adherence (doses taken/doses prescribed). |  | 12 weeks | 
| Estimate the probability of HCV cure as a function of adherence using logistic regression. |  | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Hepatitis C, Drug Abuse, Hepatitis C Virus, sofosbuvir, ledipasvir, pharmacology, pharmacokinetics