The investigator's hypothesis is that active injectors will show a partial reduction in markers of immune activation with HCV therapy whereas non-injectors will show a more significant reduction in these markers, and will exhibit levels of immune activation that approach that seen in similarly studied healthy volunteers.This is based on observations that this group of investigators have made. They have shown that individuals who inject drugs have high level of immune activation in blood and tissue. Immune activation or chronic inflammation has been associated with accelerated aging, cardiovascular, renal and liver disease as well as CNS dysfunction. It remains unclear whether increased levels of immune activation are due to non-sterile injection of drugs, chronic infection with Hepatitis C, chronic opiate use, or perhaps combinations of all 3. To understand the potential contribution of infection with Hepatitis C the investigators will compare levels of immune activation pre- and post treatment with an all oral, one pill once daily, interferon sparing treatment of HCV in 2 groups of chronically HCV infected patients- one actively injecting with drugs and the other free of injection for at least 4 months. Immune activation comparisons will also include non-injecting healthy volunteers.

This group of multidisciplinary investigators has discovered increased levels of immune activation among HIV-1-uninfected active injection drug users (IDUs) when compared to non-IDU controls . The vast majority (80%) are also infected with HCV.

Active injectors have high levels of immune activation as measured by sCD14, CD8 co-expression of CD38 and HLA-DR, as well as Type 1 cytokines.

Within months of ceasing injecting, there are observable decreases in some parameters however in general they remain elevated when compared to non-injecting healthy volunteers.

As approximately 80% of these subjects are HCV infected and viremic, these results are confounded as to the cause of the observed increased levels of markers of immune activation- active injection or chronic Hepatitis C. Until recently HCV treatment required the use of IFN which has immunomodulatory activity which would cause perturbations in the markers of immune activation. However the development of direct acting agents (DAA) to treat HCV has revolutionized therapy. In this trial the investigators will employ the once daily FDC formulation of sofosbuvir and ledipasvir to assess changes in markers of immune activation during therapy.

There have been multiple clinical trials of FDC LDV-SOF in patients with Genotype 1 HCV. When taken once daily for 12 weeks, sustained virologic response rates have been very high with response rates nearing 99% in most studies with a 12-week course of therapy.

Common adverse events associated with FDC LDV-SOF in ION-1 include fatigue (21%), headache (25%), nausea (11%), insomnia (8%), asthenia (7%), diarrhea (11%), rash (7%), irritibility (7%), cough (3%), and pruritis (5%).

Ledipasvir undergoes minimal metabolism and expectations are that this medication will have few clinically significant drug-drug interactions. In general, sofosbuvir is considered to have relatively few clinically significant drug-drug interactions, but coadministration of sofosbuvir with the following medications is not recommended because these medications may significantly lower sofosbuvir levels:

Anticonvulsants: carbamazepine, oxycarbazepine, phenobarbital, and phenytoin Antimycobacterials: rifabutin, rifampin, rifapentine Herbal Supplements: St. John's wort HIV Protease Inhibitors: tipranavir-ritonavir Antiarrhythmic Drugs : amiodarone (Cordarone®, Nexterone®, Pacerone®)

Participants will be provided with a 12-week course of FDC LDV-SOF which will provide a near 99% likelihood of a SVR in participants who are adherent to therapy with low likelihood of significant adverse events and drug-drug interactions.

In treating HCV effectively the investigators will measure changes in immune activation and gene expression that accompany HCV treatment.

Inclusion Criteria:

1. Ability to give written informed consent in English

2. Age≥18 and ≤55

3. HCV antibody positive

4. HCV RNA >1,000 copies/mL plasma

5. HCV treatment naive

6. HCV genotype 1a or 1b or mixed type 1

7. AST, ALT <10x ULN

8. Direct bilirubin <3.0

9. Platelet count >50,000

10. Creatinine clearance >30mL/min as estimated by Cockroft Gault

11. Hemoglobin >10 if female, >11 if male

12. Albumin > 2.8

13. INR<2.0

14. If Group A: urine dip for opiates + and active injection drug use of heroin defined as injecting at least 3 times per week.

15. If Group B then no IDU for at least 4 months and a negative urine for opiates at screening.

16. Venous access for phlebotomy

17. Willingness to agree to effective contraception during the course of the study.

18. If Group C: - negative urine for opiates at screening

    • no recreational drug use for at least 2 years (excluding marijuana)
    • HIV, HCV and HBV uninfected

Exclusion Criteria:

1. HIV infection

2. Chronic infection with Hepatitis B

3. Uncompensated cirrhosis

4. Required use of:

   Anticonvulsants: carbamazepine, oxycarbazepine, phenobarbital, and phenytoin

   Antimycobacterials: rifabutin, rifampin, rifapentine

   Herbal Supplements: St. John's wort

   HIV Protease Inhibitors: tipranavir-ritonavir

   Antiarrhythmic Drugs: amiodarone (Cordarone, Nexterone, Pacerone)

5. Any medical condition that in the opinion of the investigator would interfere with study participation and medical adherence

6. Pregnancy/breast feeding

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