12 Weeks of Ledipasvir (LDV)/Sofosbuvir (SOF) With Weight-based Ribavirin vs. 24 Weeks of LDV/SOF

There is a pressing need to understand appropriate retreatment options for HCV-infected
patients who fail direct acting antiviral (DAA)-based regimens. To date, over 100,000
prescriptions have been written for SOF. Recent data indicate that SOF-based treatment
defined as SOF/RBV, SOF/pegylated-interferon (PEG-IFN)/RBV or SOF/simeprevir (SIM) +/- RBV
have led to treatment response of 70-92% in HCV genotype (GT) 1 patients, depending on the
regimen used and presence of liver cirrhosis. Thus, there is a growing number of individuals
who have failed SOF-based regimens and are in need of a retreatment strategy, the majority of
which are anticipated to be HCV GT1, given the US distribution of genotypes. There are no
data to inform retreatment strategies for HIV-infected individuals with SOF failure, who have
traditionally represented a harder to treat group and are impacted by DAA-antiretroviral
(ARV) interactions.

This was a phase II retreatment study of HCV GT1 and HIV coinfected participants who had
previous HCV virologic failure on a SOF-based regimen. Participants were randomized to one of
two treatment arms: 12 weeks of LDV/SOF with weight-based RBV (Arm A) or 24 weeks of LDV/SOF
alone (Arm B). The targeted sample size was 40, 20 participants in each arm.

Post-entry, the study visits were scheduled at weeks 1, 2, 4, 8, 12, 16, 20 and 24 after
study entry (with week 16, 20, 24 visits limited to those on the 24-week regimen), and at 4,
12 and 24 weeks after treatment discontinuation. The total study duration was 36 weeks in Arm
A and 48 weeks in Arm B. At each visit, a physical examination and blood collection were
conducted. HCV RNA was tested at each visit. For female participants of reproductive
potential, pregnancy tests were done. At on-treatment visits, participants also completed an
HCV treatment adherence questionnaire. Urinalysis was conducted at all on-treatment visits
and at 4 weeks post treatment. At select visits, plasma, whole blood, urine and dried blood
spots were collected.

The study was randomized because there was clinical equipoise on the benefits and drawbacks
in the two study arms. The study was not designed to be powered for comparisons between the
randomized study arms, and no formal statistical comparisons were conducted. The primary
analysis was conducted as a single-arm analysis for each regimen.

The study experienced enrollment difficulties due to the small number of HCV treatment
failures from select SOF-based regimens who would be eligible for this study, and closed to
accrual prematurely. The participants enrolled remained on study until completion of
follow-up.

Inclusion Criteria:

- Willing and able to provide written informed consent

- Documentation of non-cirrhotic or cirrhotic status

- HIV-1 infection

- HIV antiretroviral treatment status (ART), CD4+ T-cell (CD4) count and HIV-1 RNA as
follows: (1) not on ART with CD4 count >500 cells/mm^3 within 42 days of study entry,
(2) elite controller not on ART with CD4 >200 cells/mm^3 within 42 days of study entry
and HIV-1 RNA <500 copies/mL on all measurements within 48 weeks prior to study entry,
(3) on a stable protocol-approved ART with CD4 count >200 cells/mm^3 and HIV-1 RNA <50
copies/mL within 42 days of study entry

- HCV GT-1 within 12 months prior to study entry

- Prior virologic treatment failure with SOF-containing regimen (SOF/RBV, SOF/PEG/RBV,
and SOF/SIM)

- Body mass index (BMI) ≥18 kg/m^2 within 42 days prior to study entry

- Certain laboratory values obtained within 42 days prior to study entry

- Hemoglobin ≥12.0 g/dL for male, ≥11.0 g/dL for female participants

- Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase (ALT) (SGOT) <10
x ULN

- For female participants of reproductive potential, a negative serum pregnancy test
with a sensitivity of at least 25 mIU/mL performed at screening and within 48 hours
prior to study entry

- Agreement to use at least two reliable forms of contraceptive simultaneously while
receiving study treatment and for 6 months afterward

- Intention to comply with the dosing instructions and study schedule of assessments

Exclusion Criteria:

- Receipt of any investigational drug or device within 60 days prior to study entry

- Prior exposure to a DAA other than SOF and SIM

- Chronic liver disease of a non-HCV etiology

- Presence of active or acute AIDS-defining opportunistic infections within 42 days
prior to study entry

- Active, serious infection (other than HIV-1 or HCV) requiring parenteral antibiotics,
antivirals, or antifungals within 42 days prior to study entry

- Hepatitis B virus (HBV) infection (defined as HBsAg positive) within 42 days prior to
study entry

- History of clinically significant hemoglobinopathy

- Chronic current use of systemically administered immunosuppressive agents

- History of solid organ transplantation

- Current or prior history of clinical hepatic decompensation

- History of a gastrointestinal disorder (or postoperative condition) that could
interfere with the absorption of the study drug

- History of significant or symptomatic pulmonary disease, cardiac disease, or porphyria
that in the opinion of the investigator would interfere with the study

- History of difficulty with blood collection and/or poor venous access for the purposes
of phlebotomy

- Active drug or alcohol use or dependence

- Use of any prohibited concomitant medications per the LDV/SOF product labeling, within
42 days prior to study entry

- Known hypersensitivity to RBV, SOF, LDV, their metabolites, or formulation excipients
or any other contraindication to the use of RBV, SOF or LDV

- Currently receiving zidovudine (ZDV), didanosine (ddI), stavudine (d4T) or tipranavir

- Acute HIV infection defined as the phase immediately following infection during which
anti-HIV antibodies are undetectable

- Known hepatocellular carcinoma

- Breastfeeding or pregnancy

- A male participant with a pregnant female partner

- Receipt of colony stimulating agents, including but not limited to erythropoietin,
within 42 days prior to study entry