Supporting Treatment Outcomes Among PWID

Study Overview
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Brief Summary
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The goal of this study is to improve HCV care continuum outcomes for people who inject drugs (PWID), reduce potential onward transmission to others and improve HIV outcomes among those who are HIV/HCV coinfected. The study will evaluate whether HCV treatment outcomes (sustained virologic response, treatment completion, adherence) and post treatment outcomes (HCV reinfection, HIV viral suppression) in HCV mono- and HIV/HCV co-infected PWID can be optimized by tailoring treatment support in 7 PWID-focused integrated HIV/HCV prevention and treatment centers in India.

Detailed Description
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The primary objective is to evaluate whether the intensity of treatment adherence support affects sustained virologic response rates in HCV mono- and HIV/HCV co-infected participants receiving HCV direct-acting antivirals (DAA) in PWID-focused centers. Secondary objectives are: 1. To evaluate whether the intensity of treatment adherence support affects HCV treatment completion rates. 2. To evaluate whether the intensity of treatment adherence support affects HCV treatment adherence. 3. To estimate the incidence and correlates of HCV reinfection among HCV mono- and HIV/HCV coinfected PWID who achieve HCV cure. 4. To evaluate the impact of HCV cure on HIV viral suppression among HIV/HCV coinfected PWID. Investigators will evaluate this via a 3-arm, individual-level randomized clinical trial, in which treatment assignment probabilities vary according to participants' estimated propensity for treatment failure at baseline (precision randomization). An estimated 3,000 persons will be enrolled and randomized at 7 community-based integrated care centers (ICCs) across India across a duration of 18 - 24 months. Data from these 7 ICCs on early HIV treatment refills/viral suppression (3-6 months after antiretroviral therapy (ART) initiation) will be used to develop and validate an algorithm to predict propensity for HCV treatment failure. Prior to treatment initiation, each participant will undergo a questionnaire to capture information on barriers/ facilitators to treatment adherence identified in the prediction model in order to determine the propensity for HCV treatment failure (minimal or elevated risk). Individuals will be preferentially randomized to the support level that matches their failure risk. Those at elevated risk for treatment failure will be randomized at an allocation ratio of 3:2:1 for Arm 3 (high intensity support), Arm 2 (medium intensity support) and Arm 1 (low intensity support), respectively. Conversely, those at minimal risk will be randomized at a ratio of 1:2:3 to Arm 3 (high intensity support), Arm 2 (medium intensity support) and Arm 1 (low intensity support), respectively. Participants and study staff will be blinded to the risk classification (minimal, elevated) but, because of the nature of the interventions, blinding to intervention assignment is not possible. Persons will be treated for HCV according to the standard of care in India. Minimal laboratory monitoring will be used except when clinically indicated. Participants with decompensated cirrhosis will be excluded from treatment. All HIV/HCV co-infected participants and those HCV monoinfected participants who achieve SVR will be followed post-treatment. These individuals will be followed every six months after the SVR assessment to assess HCV reinfection and HIV viral suppression (among HIV/HCV coinfected participants) for up to 30 months after SVR.

Official Title
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A Precision Randomized Trial to Evaluate the Impact of Tailored Hepatitis C Virus (HCV) Treatment Adherence Support on HCV Treatment Outcomes in HIV/HCV Co-infected and HCV Mono-infected People Who Inject Drugs (PWID) in India.

Conditions
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Hepatitis C, HIV Coinfection

Intervention / Treatment
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* Behavioral: Low intensity HCV treatment adherence support
* Behavioral: Medium intensity HCV treatment adherence support
* Behavioral: High intensity HCV treatment adherence support


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Registered for care at an Integrated Care Center (ICC) in one of the 7 field sites. Active HCV infection confirmed by a detectable HCV RNA by PCR (HCV RNA ≥ 30 copies/ml) within 90 days prior to study entry. Liver disease stage defined as non-cirrhotic or compensated cirrhotic (metric/diagnostic criteria used for fibrosis staging) within 90 days prior to study entry. i. Albumin >3.0 g/L. ii. Hemoglobin >8.0 g/dL for women; >9.0 g/dL for men. iii. Platelet count >50,000/mm3. iv. Calculated creatinine clearance (CrCl) using Cockcroft-Gault method >30 mL/min. v. Aspartate aminotransferase (AST/SGOT) <10 times the upper limit of the normal range (ULN). vi. Alanine aminotransferase (ALT/SGPT) <10 times the ULN. vii. Total bilirubin <1.5 times the ULN for participants not on atazanavir (ATV) and <3 times the ULN for participants on ATV. viii. International normalized ratio (INR) <1.5 times the ULN. Life expectancy greater than 1 year (as determined by study clinician) Willing to initiate HCV treatment Agree to be randomized to an adherence support strategy and willingness to be Ability and willingness to provide written informed consent Female participants of reproductive potential must not be pregnant All female participants of reproductive potential must agree not to participate in a conception process All female participants of reproductive potential must agree to use at least one reliable form of contraceptive while receiving protocol-specified medication, and for 6 weeks after stopping the medication. Exclusion Criteria: Psychologically unfit to provide written informed consent. Planning to migrate within the next six months. Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation. Acute or serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry. In HIV positive participants, presence of active or acute AIDS-defining opportunistic infections within 30 days prior to study entry. Use of prohibited medications within the past 14 days prior to study entry. Evidence of decompensated liver disease on clinical exam. Evidence of active tuberculosis. Evidence of chronic hepatitis B infection (HBsAg positive). Currently on HCV treatment. Prior history of DAA-based HCV treatment Confirmed active SARS CoV-2 infection or suspected active SARS CoV-2 infection at enrollment. Currently nursing (breastfeeding).

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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a 3-arm, individual-level randomized clinical trial, in which treatment assignment probabilities vary according to participants' estimated propensity for treatment failure at baseline (precision randomization). Minimal risk individuals have a higher likelihood of being allocated to lower intensity intervention and elevated risk individuals have higher likelihood of being allocated to higher intensity intervention.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1: Low Intensity Intervention<br>4 weeks dispensation + standard adherence counseling | Behavioral: Low intensity HCV treatment adherence support<br>* A 28-day supply of medication will be dispensed to participants at entry, 4 weeks, and 8 weeks. Participants will receive standard adherence counseling at entry and every refill pickup/home or field delivery. Participants will have access to all of the services available at the ICC including facilitated linkage to referrals as needed. Site staff will routinely track clients who miss refill appointments in real-time using standard tracking measurements<br>|
| Active Comparator: Arm 2: Medium Intensity Intervention<br>4 weeks dispensation + support from patient navigator | Behavioral: Medium intensity HCV treatment adherence support<br>* The medium intensity intervention will include standard of care dispensation of a 28-day supply of medication at entry, 4 weeks and 8 weeks. Participants will be assigned to a patient navigator (PN) and receive tailored patient navigation support for medication reminders, picking up medication refills (or home or field delivery of study medications), overcoming barriers as well as service linkage. Participant will be contacted by the PN at least once every two weeks.<br>|
| Active Comparator: Arm 3: High Intensity Intervention<br>Directly Observed Therapy with flexible dispensing and support from patient navigator | Behavioral: High intensity HCV treatment adherence support<br>* The high intensity intervention will involve patient-centered DOT with flexibility in terms of the frequency of pickup and the site of DOT (ICC, field-based) with a minimum of at least 1 observed dose per week. Participants in this arm will also receive PN support for overcoming barriers and service linkage similar to participants in Arm 2. The main differences between Arms 2 and 3 are: (i) medications will not be dispensed for more than one week at a time (to coincide with opioid agonist therapy (OAT) dosing, where applicable); and (ii) ≥1 dose/week will be observed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained virologic response (SVR) by intervention group stratified by defined risk for treatment failure (minimal vs elevated) | The percentage of participants who achieved SVR defined as HCV RNA < lower limit of quantification (LLOQ) | First available HCV RNA between 10 and 60 weeks after scheduled end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HCV treatment completion | The percentage of participants who self-report completing their treatment course without an interruption of >14 days. | Reported between 12-84 weeks after the entry visit. | 
| Self-reported adherence >90% | The percentage of participants who self-report completing >90% of doses during treatment. | Measured at 4 week intervals for 12 weeks for participants on 12 weeks of treatment and for 24 weeks for participants on 24 weeks of treatment. | 
| Self-reported adherence level | The percentage of doses taken during treatment as self-reported by the participant. | Measured at 4 week intervals for 12 weeks for participants on 12 weeks of treatment and for 24 weeks for participants on 24 weeks of treatment. | 
| HCV reinfection | The percentage of participants who test positive for HCV Core Antigen after achieving SVR. | Measured at 6 month intervals after confirmation of SVR for up to 36 months. | 
| HIV viral suppression among HIV/HCV coinfected participants | The percentage of HIV/HCV co-infected participants with HIV RNA less than LLOQ after achieving SVR. | Measured using chart reviews after confirmation of SVR for up to 36 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Patient Navigation, Treatment Adherence, People who inject drugs (PWID), Directly Observed Therapy (DOT), India