DRug Use & Infections in ViEtnam - Hepatitis C (DRIVE-C)

Study Overview
=================
Brief Summary
-----------------
The study aims to assess the effectiveness of a model of hepatitis C screening and integrated care, targeting people who inject drugs (PWIDs) in Hai Phong, Vietnam. In a wider perspective, this model linked to mass screening through repeated Respondent Driven Sampling (RDS) surveys, to simplified treatment protocol, and to large community-based support to improve referral to care, retention in care, adherence to treatment and prevention of reinfection, may have the potential to eliminate HCV among PWIDs in this city.

Detailed Description
-----------------
Objectives : The primary objective of this study is to assess the effectiveness of a model of hepatitis C screening and integrated care targeting PWIDs in Hai Phong, Vietnam. This model will encompass all steps involved in achieving HCV cure among PWIDs: i) Mass detection of hepatitis C infection among PWIDs: in the community through a large community-based Respondent Driven Sampling survey (RDS); and in HIV out-patient clinics and methadone treatment centers where serological testing should have been made, but not HCV RNA to confirm hepatitis C infection. ii) a community-based support to improve referral to specific care for those with hepatitis C infection; iii) a HCV care system delivery integrated within the existing health system with a simplified treatment protocol taking into account PWIDs specificities such as frequent HIV co-infection and methadone treatment; iv) an optimized treatment adherence through a combination of health care therapeutic education and CBO support; v) an increase in harm reduction activities to encompass HCV risk transmission and to prevent HCV reinfection. Secondary objectives are: to assess all steps of the hepatitis C cascade of care (Hepatitis C infection diagnosis; HCV care enrolment; HCV treatment initiation; HCV treatment success); to assess the occurrence of adverse events (death, morbidity) and drug-related side-effects; to evaluate adherence to HCV treatment; to determine factors associated with treatment failure defined by a positive HCV RNA 12 weeks after the end of HCV treatment; to estimate the reinfection rate at the end of the study and to identify risk factors of HCV reinfection; to project the impact and cost-effectiveness of the implemented HCV treatment intervention. Study design : the effectiveness-implementation hybrid study type 1 design will simultaneously allow assessing the effectiveness of Direct-Acting Antivirals (DAA) care strategy among PWIDs in Vietnam, and the potential obstacles to widespread implementation. The strategy of care includes a large community-based mass screening, a simplified treatment protocol based on a combination of DAAs, taking into account co-morbidities (addiction, HIV), physician training and important support of Community Based Organizations (CBO's) for linkage to care after screening, treatment adherence and prevention of reinfection after cure. In addition, 2 others components are included in the study: A modeling exercise to assess the impact of the intervention at the population level, A cost-effectiveness analysis to further inform policy-makers. Patients will be followed for 48 weeks after initiating HCV treatment. The estimated enrolment is 1050 participants. Study population: people who currently inject drugs or who have recently started opioid substitution treatment. Implementation: The study is linked to the NIDA RO1 DA041978 / ANRS 12353 DRIVE project. Participant recruitment will take place through DRIVE RDS survey and DRIVE cohort follow-up visit in two community sites managed by peer-groups in Hai Phong. All participants with positive HCV serology will be screened for hepatitis C and positive HCV RNA will be proposed for DAA treatment in 3 hospital-based HCV clinics. All participants will attend 9 study visits, comprising of clinical examination, blood collection for side effects and viral load assessment, therapeutic education, questionnaires on alcohol use, on sexual, drug use and other behaviors focusing on HCV infection risks or HCV reinfection risks and on quality of life, and harm reduction activities with the support of CBOs.

Official Title
-----------------
Towards HCV Elimination: Evaluation of an Integrated Model of HCV Care Targeting People Who Inject Drugs in Hai Phong, Vietnam

Conditions
-----------------
Hepatitis C, Drug Use, Viral Hepatitis C

Intervention / Treatment
-----------------
* Drug: Sofosbuvir 400 mg and Daclatasvir 60 mg
* Drug: Sofosbuvir 400 mg and Daclatasvir 90 mg
* Drug: Ribavirin
* Drug: Sofosbuvir and Daclatasvir for 24 weeks


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA Participants of the ANRS 12353/NIDA ROI DA 041978 DRIVE study (age > 18 years; positive urine test for heroin an/o methamphetamine & skin marks of injection ) who either participated to the DRIVE RDS3 survey, or to the HIV-positive and HIV-negative DRIVE cohorts; Hepatitis C infection defined by a positive HCV RNA Signed informed consent form EXCLUSION CRITERIA Severe associated diseases requiring specific treatment (including all specific AIDS defining illnesses, any severe sepsis, severe decompensated cirrhosis, suspicion of hepatocellular carcinoma); Any condition which might, in the investigator's opinion, compromise the safety of the patient by participating in the study including very severe clinical condition; Previous history of DAA use; Contraindication for treatment with sofosbuvir or daclatasvir; For women of childbearing potential i.e. women of childbearing age who are not menopausal, or permanently sterilized or not refraining from sexual activity: Pregnancy and breastfeeding Refusal to use a contraceptive method Renal failure with creatinine clearance ≤ 30 milliliter per minute; Person deprived of freedom by a judicial or administrative decision; Person who plan to move out from Hai Phong in the next 12 months; Person unable to understand the study;

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: All patients with detectable HCV RNA, eligible for treatment, will receive Direct Acting Antiviral drugs.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: All patients<br>All patients will receive sofosbuvir 400-mg and daclatasvir 60-mg (1 tablet each per day) during 12 weeks. | Drug: Sofosbuvir 400 mg and Daclatasvir 60 mg<br>* All patients will receive sofosbuvir 400-mg and daclatasvir 60-mg (1 tablet each per day) during 12 weeks.<br>|
| Other: HIV/HCV co-infected patients<br>For HIV/HCV co-infected patients receiving efavirenz or nevirapine, daclatasvir dose will be increased to 90-mg per day (sofosbuvir 400 mg and daclatasvir 90 mg) | Drug: Sofosbuvir 400 mg and Daclatasvir 90 mg<br>* For HIV/HCV co-infected patients receiving efavirenz or nevirapine, daclatasvir dose will be increased to 90-mg per day.<br>|
| Other: Cirrhosis<br>In case of cirrhosis : ribavirin will be added to sofosbuvir / daclatasvir 12 weeks | Drug: Ribavirin<br>* In case of cirrhosis: Ribavirin will be added to sofosbuvir/daclatasvir during the 12 weeks of treatment. The dose will be adapted to the patient weight although the vast majority of patients (weight < 75 kg) will receive 500 mg x 2/day. In case of ribavirin contra-indication or side effects leading to ribavirin discontinuation, sofosbuvir/daclatasvir will be used 24 weeks.<br>|
| Other: Cirrhosis with ribavirin contra-indication<br>In case of cirrhosis with ribavirin contra-indication : sofosbuvir and daclatasvir for 24 weeks | Drug: Sofosbuvir and Daclatasvir for 24 weeks<br>* In case of cirrhose and of ribavirin contra-indication or side effects leading to ribavirin discontinuation, sofosbuvir/daclatasvir will be used 24 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of all patients in success of the model of care | Proportion of patients with HCV RNA < 15 IU/mL at the end of the study among patients who have signed the informed consent. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with detectable HCV RNA | Proportion of patients with HCV RNA > 15 IU/mL among those with positive HCV Ab | Screening pre-inclusion | 
| Proportion of patients enrolled in care | Proportion of patients with HCV RNA > 15 IU/mL who attended the pre inclusion visit at HCV clinic among those with hepatitis C infection; | Pre-inclusion visit | 
| Proportion of patients initiating DAA treatment | Proportion of patients who initiate the treatment among patients enrolled in care and eligible for treatment | Initiation treatment visit | 
| Proportion of patients cured | Number of patients with HCV RNA < 15 IU/mL among those initiating the treatment eligible | Week 24 | 
| Rate of reinfection | Number of patients with HCV RNA ≥ 15 IU/mL at the end of the study among cured patients | Week 48 | 
| Rate of mortality | Rate of deaths among all participants with hepatitis C infection | Week 48 | 
| Frequency, type and time to grade 3 or 4 adverse clinical or biological events. | All adverse events will be graded according to the ANRS adverse events grading table | Week 48 | 
| Frequency, type and time to drug-related clinical or biological adverse reactions | All drug-related clinical or biological adverse reactions of grade 3 or 4 or leading to treatment interruption | Week 48 | 
| Adherence assessment | Self-questionnaire on DAA drug intake and drug accountability for DAA | Week 12 | 
| Factors associated with HCV treatment failure | Socio-demographic, co-infection, virological, adherence, behavioral, psychiatric disorders, intervention contact, recent incarceration, homelessness factors | Week 24 | 
| Factors associated with HCV reinfection | Socio-demographic, co-infection, virological, adherence, behavioral, psychiatric disorders, intervention contact, recent incarceration, homelessness factors | Week 48 | 
| Effect of the HCV treatment intervention | Estimation of the impact of the intervention on HCV infections and DALYs averted, QALYs saved, HCV incidence and prevalence as projected by the model under various scenarios | Week 48 | 
| Incremental cost-effectiveness ratio (ICER) | Estimation of the mean ICER which will be compared against standard thresholds for intervention's being cost-effective in LMIC settings | Week 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
People who inject drugs, Hepatitis C, Direct Acting Antiviral, HCV Elimination, Vietnam, Viral hepatitis C