Directly Observed Therapy for HCV in Chennai, India
Directly Observed Therapy for HCV in Chennai, India
The primary objective of this pilot trial is to evaluate the feasibility of 12 weeks vs. 24
 weeks of field-based directly observed therapy (DOT) for HCV therapy in a resource-limited
 setting. The investigators will compare treatment completion rates among 50 persons
 chronically infected with HCV who will be randomized to receive either 1) 12 weeks of
 sofosbuvir (SOF) + ribavirin (RBV) + pegylated interferon alfa-2a (PEG); or 2) 24 weeks of
 SOF + RBV. Treatment will be delivered daily by field workers at a location of a participants
 choosing. Secondary objectives are 1) To compare the efficacy of SOF+RBV with or without PEG
 as measured by the proportion of subjects with sustained viral response at 12 weeks after
 discontinuation of therapy (SVR12); 2) To evaluate the safety and tolerability of SOF+RBV
 with or without PEG; 3) To assess the impact of SVR12 on insulin resistance.
This will be a non-blinded randomized clinical trial with 50 participants randomized at a 1:1
 allocation ratio to one of two treatment arms.

 Arm 1: Sofosbuvir (400mg/daily) + Pegylated Interferon alfa-2a (180µg/weekly) + Ribavirin
 (800mg/daily) for 12 weeks

 Arm 2: Sofosbuvir (400mg/daily) + Ribavirin (800mg/daily) for 24 weeks

 Pegylated-interferon alfa-2a (PEG) will be delivered subcutaneously once weekly. Sofosbuvir
 (SOF) and ribavirin (RBV) will be taken orally once daily for the entire study period.

 The study will take place at the YR Gaitonde Centre for AIDS Research and Education
 (YRGCARE). YRG CARE is a non-profit medical and research institution in Chennai. YRGCARE
 Medical Centre provides medical care for more than 18,000 persons with HIV disease. Currently
 more than 8000 persons are receiving highly active antiretroviral therapy at the center.

 Participants will be recruited from the YR Gaitonde Centre for Substance Abuse Research
 (YRGCSAR), which is affiliated with YRGCARE. The investigators will primarily recruit
 subjects from a cohort study of current and former people who inject drugs (PWID) that is
 ongoing at the same center. Eligible participants will be randomized to one of the two
 treatment arms after providing written informed consent. Treatment will be delivered directly
 to participants daily by field workers at a location of the participants choosing.
 Participants will be asked to visit the study clinic every four weeks during treatment and 12
 weeks after completing treatment for additional study procedures. In addition, participants
 in Arm 1 will be asked to visit the clinic every week to receive their PEG injection.

 The primary outcome is treatment completion. Secondary outcomes include SVR12, safety and
 tolerability and insulin resistance.
Inclusion Criteria:

 1. Willing/able to provide consent

 2. Age ≥ 18

 3. Chronic HCV (HCV RNA positive)

 4. Resident of Chennai and can provide locator information

 5. If co-infected with HIV, must have CD4 (Cluster of Differentation 4) > 350 cells/mm3
 and either: 1) ART naïve or 2) if on ART be on a tenofovir-containing regimen. If a
 participant's CD4 drops below 350 cells/μl (threshold for treatment in India), will
 have to initiate a tenofovir-containing regimen (current standard of care).

 6. Participants must have the following at screening:

 1. Alanine Aminotransferase (ALT) ≤ 10 x the upper limit of normal (ULN)

 2. Aspartate Aminotransferase (AST) ≤ 10 x ULN

 3. Hemoglobin ≥ 12 g/dl for males and 11 g/dl for females

 4. International normalized ratio (INR) ≤ 1.5 x ULN unless subject has known
 hemophilia or is stable on an anticoagulant regimen affecting INR

 5. Albumin ≥ 3 g/dl

 6. Direct bilirubin ≤ 1.5 x ULN

 7. Creatinine clearance ≥ 60 ml/min (Cockgroft-Gault Equation)

 8. Alpha fetoprotein < 50 ng/ml

 9. Absolute neutrophil count (ANC) ≥ 1,500/μL

 10. Platelets ≥ 90,000/μL

 11. Thyroid stimulating hormone (TSH) ≤ ULN

 7. A female subject is eligible if it is confirmed that she is:

 1. Not pregnant or nursing

 2. Of non-childbearing potential (i.e., women who have had hysterectomy, have both
 ovaries removed or medically documented ovarian failure, or are postmenopausal
 women > 50 years of age with cessation (for ≥12 months) of previously occurring
 menses

 3. Of childbearing potential and negative urine pregnancy test prior to
 randomization and agree to one of the following from 3 weeks prior to
 Baseline/Day 1 until 6 months after the last dose of RBV.

 -  Complete abstinence from intercourse.

 Or

 • Consistent use of approved methods of birth control in addition to a male partner
 who correctly uses a condom from 3 weeks prior to Baseline/Day 1 until 6 months after
 the last dose of RBV.

 8. Male participants must agree to consistently and correctly use a condom. If their
 female partner is of childbearing potential, their partner must agree to use one of
 the study approved non-hormonal methods of birth control or a hormone-containing
 contraceptive, from the date of screening until 7 months after their last dose of RBV

 9. Male participants must agree to refrain from sperm donation for at least 7 months
 after the last dose of RBV.

 10. Of generally good health as determined by the investigator.

 11. Able to comply with the dosing instructions for study drug administration and willing
 to complete the study schedule of assessments.

 Exclusion Criteria:

 1. Pregnant/nursing female or male with pregnant/nursing female partner.

 2. Current or prior history of clinical hepatic decompensation (e.g., ascites,
 encephalopathy or variceal hemorrhage, MELD<12)

 3. Prior hepatitis C treatment

 4. Infection with hepatitis B virus

 5. Chronic use of systematically administered immunosuppressive agents (e.g., prednisone
 equivalent >10 mg/day)

 6. Use of any prohibited concomitant medications within 28 days of the Baseline/Day 1
 visit.

 7. Contraindications to RBV therapy or PEG/RBV

 8. Known hypersensitivity to RBV or PEG, the metabolites or formulation excipients

 9. Additional exclusion criteria related to Aim 1 regimen

 1. Pre-existing significant psychiatric condition(s) including severe depression,
 severe bipolar disorder and schizophrenia. Other psychiatric disorders are
 permitted if the condition is well controlled with a stable treatment regimen for
 ≥ 1 year from screening.

 2. Presence of autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid
 arthritis, sarcoidosis).

 3. History of clinical significant retinal disease.