Study of Hepatitis C Treatment During Pregnancy

There are 3.2 million persons in the United States chronically infected with hepatitis C
virus (HCV) with a 1-2.4% prevalence during pregnancy. The recent October 2014 approval of
the fixed dose combination, containing the NS5B polymerase inhibitor sofosbuvir (SOF) 90 mg
and the NS5A inhibitor ledipasvir (LDV) 400mg, marked a new era of IFN and ribavirin free,
directly acting antiviral treatment for HCV. A 12 week treatment course of LDV/SOF resulted
in a 99% cure rate when given as a once-a-day oral pill. Based on the animal model data
submitted to the FDA, this drug combination was given a pregnancy category B designation,
even though there is currently no experience with LDV/SOF in pregnant women.

Pregnancy is a time when women are uniquely motivated to engage in activities which are
geared toward improvement of their own health and ensuring the health of their unborn child.
As such, pregnant women have frequent prenatal care visits; and health care interventions,
such as antiviral therapy and monitoring, can be easily integrated into the existing
healthcare infrastructure of prenatal care. The benefits of HCV treatment are numerous,
including prevention of severe liver disease, hepatocellular carcinoma, and liver
transplantation, as well as improvements physical, emotional and social health. The most
recent guidelines by the Infectious Disease Society of America recommend that all
HCV-infected persons receive treatment. The antenatal period represents an ideal window of
opportunity for treatment of HCV in pregnancy due to increased antenatal health care
utilization and prevention of perinatal transmission of HCV to the infant.

Safe administration of drugs in pregnancy may require dose adjustment due to the
pregnancy-induced physiologic alternations. Therefore, careful pharmacokinetic (PK)
evaluation is a critical first step to ensure safe administration of drugs to both the mother
and the developing fetus. This is a single-arm, single-center, open label Phase 1 evaluation
of the PK and safety of treating HCV with a 12 week course of LDV/SOF in 15 HCV-infected
pregnant women. Therapy will be initiated at approximately 24 weeks of gestation. In this
study we will determine: 1) if the PK of the LDV and SOF are similar in pregnancy as compared
to those in nonpregnant women, 2) if the viral response to LDV/SOF treatment in pregnancy is
similar to that observed in nonpregnant women, and 3) if there are any initial maternal or
neonatal safety concerns detected with antenatal LDV/SOF administration compared with
HCV-infected historical controls delivered at our institution. From the findings of this
study, future studies will seek to optimize the dose, gestational age timing and treatment
duration of LDV/SOF during pregnancy. Antenatal HCV treatment will improve maternal health,
prevent further HCV transmission in the community and perinatal HCV transmission to the
child, and thus enhance the long-term health of two generations.

Inclusion Criteria:

1. Age 18 through 39 years (inclusive) at Screening

2. Able and willing to provide written informed consent to be screened for and take part
in the study procedures

3. Able and willing to provide adequate locator information

4. Chronic HCV, genotype 1, 4, 5, 6 infection, defined as HCV antibody detected at least
6 months prior to Screening and detectable HCV RNA viral load at Screening

5. Desired pregnancy at 23 + 0 to 24 + 6 weeks' gestation at Enrollment with gestational
dating confirmed by ultrasound

6. Singleton gestation with no known fetal abnormalities

7. Documented negative Hepatitis B testing for current infection (negative HBsAg test) or
previous infection (negative anti-HB Core) performed at the screening visit

8. Negative HIV testing at the screening visit

9. Per participant report at Screening and Enrollment, agrees not to participate in other
research studies involving drugs or medical devices for the duration of study
participation

Exclusion Criteria:

1. Participant report of any of the following at Screening or Enrollment:

1. Previous treatment for Hepatitis C virus with an NS5A inhibitor or sofosbuvir

2. Use of any medications contraindicated with concurrent use of ledipasvir or
sofobuvir according to the most current HARVONI package insert

3. Plans to relocate away from the study site area in the next 1 year and 4 months

4. Current sexual partner is known to be infected with HIV or Hepatitis B virus

5. History of cirrhosis documented by previous liver biopsy or liver imaging tests

2. Reports participating in any other research study involving drugs or medical devices
within 60 days or less prior to Enrollment

3. Clinically significant and habitual non-therapeutic drug abuse, not including
marijuana, as determined by Protocol Chair

4. At Screening or Enrollment, as determined by the Protocol Chair, any significant
uncontrolled active or chronic cardiovascular, renal, liver (such as evidence of
decompensated cirrhosis by ascites, encephalopathy, or variceal hemorrhage),
hematologic, neurologic, gastrointestinal, psychiatric, endocrine, respiratory,
immunologic disorder or infectious disease (other than Hepatitis C)

5. Has a high risk of preterm birth defined as a history of spontaneous preterm birth at
less than 34 weeks of gestation or a shortened cervical length of less than 20
millimeters

6. Has any of the following laboratory abnormalities at Screening:

1. Aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than 10
times the upper limited of normal

2. Hemoglobin less than 9 g/dL

3. Platelet count less than 90,000 per mm3

4. International normalized ratio (INR) > 1.5

5. Creatinine greater than 1.4

6. Medical history of cirrhosis

7. Has any other condition that, in the opinion of the IoR/designee, would preclude
informed consent, make study participation unsafe, complicate interpretation of study
outcome data, or otherwise interfere with achieving study objectives.