12 Weeks of Ledipasvir (LDV)/Sofosbuvir (SOF) With Weight-based Ribavirin vs. 24 Weeks of LDV/SOF
12 Weeks of Ledipasvir (LDV)/Sofosbuvir (SOF) With Weight-based Ribavirin vs. 24 Weeks of LDV/SOF
People who are infected with Hepatitis C Virus (HCV) have a great chance of being cured of
 the infection when they are treated with sofosbuvir. However, in some instances, treatment
 with sofosbuvir-containing therapy does not work. It is not known if people respond to
 retreatment with sofosbuvir, after it did not work the first time. There is an important need
 to understand retreatment options in those instances. This clinical trial was done to study
 the response to two different regimens, ledipasvir/sofosbuvir and ledipasvir/sofosbuvir with
 ribavirin, and to see if they are safe and well-tolerated in HCV-infected persons whose
 previous treatment with sofosbuvir had failed.
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