Transmission of Chronic Hepatitis C in Pregnancy

The treatment of chronic hepatitis C virus infection has dramatically advanced in recent
years, with the availability of multiple interferon-free treatment regimens that result in
cure in over 95% of treatment naïve individuals with 8 -12 weeks of therapy. Despite these
advances, however, the natural history and treatment of HCV remains undefined in several
populations, including pregnancy. In particular, rates of vertical (mother to child)
transmission, perinatal and neonatal morbidity, assessment of disease severity (fibrosis) in
pregnancy and timing of treatment are not well understood.

At least 2.3 million people in the United States and 185 million people worldwide are
believed to have chronic HCV infection, although as it is frequently asymptomatic until the
development of end-stage liver disease (ESLD), this may be a significant underestimate.
Between 2012 and 2014 the HCV detection rate among women of childbearing age increased by 22%
nationally and over 200% in Kentucky, while the proportion of children born to HCV infected
women increased 68% nationally and 128% in Kentucky.

Currently, in the United States, the overall rate of children born to HCV infected women is
3.4 per 1,000 live births, with the highest rate in West Virginia, with 22.4 per 1,000 live
births occurring to HCV-infected women. Overall, the number of HCV infected reproductive age
women has doubled from 2006 to 2014, with an estimated 29,000 HCV infected women giving birth
and 1,700 infants vertically infected each year, according to previous estimates of vertical
transmission.The true incidence of vertical transmission of HCV is unknown, although the most
commonly cited meta-analysis reported a mean transmission rate of 5.8% in HIV-negative women
and 10.8% in HIV-positive women.

The timing of vertical transmission is also not well characterized. There is limited data
regarding the course of chronic hepatitis C during pregnancy, HCV viral loads appear to peak
during third trimester. Both utero and peripartum transmission appear possible, while
breastfeeding does not appear to be a risk factor. It appears that between 80 and 90% of
children who acquire hepatitis C via vertical transmission will develop chronic infection.
However, as sequelae of infection are not commonly observed in childhood, and appropriate
testing of exposed children is poor, this may not be a true reflection of actual prevalence.

The current AASLD/IDSA HCV Guidelines recommend all children born to HCV infected women be
tested, but they do not specify when or in what manner.

Maternal HCV infection has been shown to contribute to worsened perinatal and neonatal
outcomes in the absence of vertical transmission. It is associated with increased rates of
intrauterine fetal death, preterm delivery, low birth rate, increased risk for adverse
neonatal neurological outcomes, increased infant feeding difficulties and subsequent maternal
infertility.

Although there is sufficient time between the end of the first trimester and delivery to
provide curative therapy during pregnancy, no safety studies in pregnancy have been done.
Therefore, this study will offer curative DAA therapy to HCV infected Moms with the fixed
dose combination of sofosbuvir/velpatasvir (SOF/VEL) after the cessation of breastfeeding.
This combination of sofosbuvir, a nucleotide inhibitor of the NS5B RNA-dependent RNA
polymerase, and velpatasvir, an inhibitor of the NS5A transcriptional activator, is approved
for the treatment of chronic HCV infection due to genotypes 1 through 6.

Given the gaps in the investigator's understanding of HCV vertical transmission rates,
HCV-associated perinatal complications, and marked increases in both the number of women with
chronic HCV infection giving birth and the number of children under two years old testing
positive for HCV, this study will help to both better characterize the natural history of HCV
in pregnancy and ultimately, to facilitate its elimination when women are screened for
chronic HCV as part of routine gynecologic care and are offered curative therapy prior to
conception (or as part of prenatal care and when dosing during pregnancy can be safely
undertaken).

All participants will be offered curative therapy with sofosbuvir/velpatasvir (Epclusa ®)
after delivery and the cessation of breastfeeding. Subjects may be enrolled at any time after
conception up through 36 weeks gestation. The management of subjects in pregnancy will be in
accordance with ACOG guidelines and individual clinical judgment, however testing will
include, but not be limited to, testing for HCV infection, HIV infection, HBV infection, HSV
infection, group B Streptococcal colonization, HCV genotype, HCV viral load, as well as
assessment of hepatic and renal function. Staging of hepatic fibrosis must be performed
within 12 months prior to initiation of SOF/VEL. Acceptable methods of staging include
transient elastography or liver biopsy. If elastography is performed, it must be performed
either prior to pregnancy or at least 12 weeks following delivery, due to pregnancy-related
changes in hepatic stiffness. Subjects will be followed on a schedule that is determined by
their obstetric care providers throughout their pregnancy. Data from clinical and laboratory
records regarding the participants pregnancy and delivery, and their infant's medical record
from the infant's pediatrician from birth to 12 months of age will be collected. Following
delivery, infants will be evaluated at 12, 24 and 48 weeks of age, with testing for HCV RNA
to be obtained at each evaluation. Vertical transmission is defined as two positive HCV RNA
PCR tests, at least one before the 48 week visit, and again at the 12-month follow-up infant
visit.At 24 weeks following delivery, participants will begin therapy with
sofosbuvir/velpatasvir (SOF/VEL) once daily for 12 weeks. Therapy will not be initiated until
cessation of breastfeeding. Participants will be evaluated at the initiation of SOF/VEL
therapy, at 4 and 8 weeks after starting therapy, as well as 12 weeks following completion of
therapy for determination of SVR-12. Quantitative measurement of HCV RNA will be obtained at
each visit, as well as evaluation of renal and hepatic function.

Inclusion Criteria:

- Age 18 or older

- Chronic HCV infection, as defined by positive HCV antibody with confirmation of
positive HCV RNA PCR at least 6 months apart, per 2017 AASLD/IDSA criteria. Infection
with any genotype (including mixed genotypes) is permitted.

- If the diagnosis of chronic HCV is not established by two positive viral load
(RNA PCR) tests 6 months apart, subjects may be enrolled and followed until the
6-month test is performed. If the follow-up viral load test is negative (i.e. the
woman had acute infection that has cleared), the participant will be excluded
from further study participation. All participants excluded for this reason will
be replaced.

- Singleton pregnancy, up to and including 36 weeks' gestation, as documented by fetal
ultrasound at any time during the pregnancy.

- Willing and able to understand and sign the informed consent form

- Willing and able to sign release of Information forms for their own medical and
obstetric care and for their infant's neonatal and pediatric care for one year
following delivery, or when the last study viral load test is performed, whichever
comes later.

Exclusion Criteria:

- Co-infection with chronic hepatitis B.

- Active injection drug use, defined as the parenteral use of any substance for
non-medicinal purposes in the previous 60 days. Potential subjects who have a history
of active injection drug use will be referred to both syringe services programs to
prevent the acquisition of HIV and HBV and to substance abuse treatment. Potential
subjects who have injected within the last 60 days may be re-screened if they
participate in a drug treatment program, subject to the discretion of the
investigator.

- Decompensated cirrhosis, as determined by clinical history or examination

- Any major medical comorbidity that may confound assessment, such as cardiomyopathy,
pulmonary hypertension, type 1 diabetes mellitus or similar serious medical conditions
at the discretion of the investigator. Gestational diabetes mellitus or co-infection
with HIV are not criteria for exclusion.