Impact of Hepatitis C Virus Therapy on Central Nervous System Outcomes

Chronic HCV infection frequently causes neurocognitive (NC) and mood disorders but whether
these disorders are caused by HCV or by the concomitant substance use and liver disease is
unclear. Response to treatment has been obscured by the neurotoxicity of interferon-based HCV
therapies. Newer DAAs are not neurotoxic and are expected to treat HCV-induced brain injury.
However, clinical trials have yet to be performed to determine their CNS benefits. This
presents a critical barrier to progress in the field that the proposed clinical trial will
directly address. The specific aims will be to:

AIM 1: To determine whether curing HCV, as indexed by 12-week sustained virologic response,
results in improvement in NC performance, neuroimaging, and measures of daily functioning;

AIM 2: To determine the viral, host, and pharmacologic correlates of neurocognitive and
neuroimaging outcomes; and

AIM 3: To explore how HIV alters the relationships observed in Aims 1 and 2.

The proposed, innovative clinical trial will improve scientific knowledge by determining the
biological and imaging correlates of the CNS and systemic effects of DAAs as well as the
distribution of these drugs into the CNS. The investigators' findings will also inform
clinical guidelines and practice about the safety and benefits of treating HCV in substance
using populations. In people who have HIV-associated NC disorder and HCV infection, treatment
with DAAs may prove to be a critical adjunct to antiretroviral for improving cognition and
returning patients to more functional lives.

Inclusion Criteria:

1. Adult (≥ 18 years old) subjects with chronic genotype 1 HCV and NCI with a GDS greater
than or equal to 0.5 (n=60).

2. Presence of chronic HCV infection based on chart review will be defined as positive
for anti-HCV antibody or HCV RNA at least 6 months before screening.

3. For the HIV/HCV co-infected group only, subjects must have HIV. HIV status will be
obtained through self report. Self report will be confirmed at screening using a HIV-1
point of care test. In the event that point of care test and self-report are
discordant, then HIV status will be confirmed by a licensed Western blot or a second
antibody test.

4. HIV/HCV co-infected subjects (n=12) must also have a HIV RNA measurement <50 copies/mL
at the pre-treatment visit.

5. Laboratory values:

- Platelets >150,000

- Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) <10x upper limit
of normal

- Creatinine clearance >30 milliliters/minute/1.73 centimeter squared

Exclusion Criteria:

1. Ledipasvir (LDV)/Sofosbuvir (SOF) is known to have drug interactions if
co-administered with the following drugs:

- Amiodarone

- P-glycoprotein (P-gp) inducers (e.g., rifampin, St. John's wort)

2. Cirrhosis or bridging fibrosis (Modified hepatic activity index (mHAI) stages 4-6 or
its equivalent).

- Liver biopsy at any time showing mHAI stage 4 or higher fibrosis OR

- FibroScan within 12 months demonstrating liver stiffness of ≥9.5 kilo Pascal or

- AST to platelet ratio index (APRI) ≥2.0 and Fibrosis-4 (FIB-4) ≥3.25

- NOTE: If APRI and FIB-4 are discordant one of the other forms of fibrosis staging
must be used.

3. Known allergy/sensitivity or any hypersensitivity to components of study drugs or
their formulation.

4. Any cause of liver disease other than chronic HCV infection, including but not limited
to the following:

- Hemochromatosis

- Alpha-1 antitrypsin deficiency

- Wilson's disease

- Autoimmune hepatitis

- Alcoholic liver disease

- Drug-related liver disease

5. Severe NC confounding conditions (stroke, head injury, or developmental learning
disability).

6. Regular use of anti-inflammatory drugs.

7. Current or recent treatment with pegylated interferon (PEG-IFN).

8. Other active inflammatory process (major infection, malignancy, rheumatoid
arthritis/autoimmune disorder) within the prior 28 days.

9. Contraindications to magnetic resonance imaging (MRI).

10. Bleeding diathesis, thrombocytopenia, or use of anticoagulants that would
contraindicate lumbar puncture.

11. Uncontrolled or active depression or other psychiatric disorder that in the opinion of
the site investigator might preclude adherence to study requirements or impact NC
functioning and assessments.

12. Active drug or alcohol use or dependence that, in the opinion of the site
investigator, would interfere with adherence to study requirements.

13. Presence of active or acute AIDS-defining opportunistic infections within 12 weeks
prior to study entry.