Sofosbuvir-Containing Regimens Without Interferon For Treatment of Acute Hepatitis C Virus (HCV) Infection
Sofosbuvir-Containing Regimens Without Interferon For Treatment of Acute Hepatitis C Virus (HCV) Infection
Early identification of acute HCV infection is essential to prevent chronic infections and
 the long-term liver disease complications that may occur. Early identification and treatment
 of HCV during the acute phase can result in significantly higher response rates with shorter
 durations of therapy.

 Pegylated-interferon alfa (PEG-IFN) was the typical treatment for HCV infection. Participants
 subcutaneously inject PEG-IFN where the average duration of treatment was approximately 20
 weeks. With the advancement of direct-acting antivirals (DAAs), it was possible to see if a
 new DAA might be non-inferior compared to (PEG-IFN).

 The study was designed to see if a fixed-dose combination tablet can replace the old HCV
 treatments by being more effective, safer and better tolerated in HIV-infected participants
 with new HCV infection. The study was a Phase I, open-label, two cohort clinical trial, in
 which 44 acutely HCV-infected HIV-1 positive participants were enrolled. Participants in each
 cohort were evaluated in two steps: on treatment (Step 1) and follow-up after discontinuing
 study treatment (Step 2). The cohorts were enrolled sequentially. Participants in Cohort 1
 were enrolled and administered oral Sofosbuvir (SOF) in combination with weight-based
 ribavirin (RBV). Participants in Cohort 2 were enrolled and administered an oral fixed dose
 combination of Ledipasvir/Sofosbuvir (LDV/SOF).
The first cohort opened with SOF/RBV treatment for 12 weeks and accrued 17 participants. All
 participants under Cohort 1 were to visit the clinical site at weeks 0, 1, 2, 4, 8, and 12
 when on treatment (Step 1), then visit the clinical site again at 2, 4, 8, 12 and 24 weeks
 during follow-up after discontinuing study treatment (Step 2).

 The second cohort opened for an 8-week treatment of LDV/SOF and included at least 27
 subjects. All participants under Cohort 2 were to visit the clinical site at weeks 0, 1, 2,
 4, and 8 when on treatment (Step 1), then visit the clinical site again at 2, 4, 8, 12 and 24
 weeks during follow-up after discontinuing study treatment (Step 2).

 Both cohorts were monitored for safety and HCV viral load response while the participants
 were on treatment.

 The primary objective did not compare the cohorts together; instead, each study cohort was
 formally assessed for efficacy with sustained virologic response 12 weeks after treatment
 based on non-inferiority criteria compared to a historical SVR rate of 60% separately.
A5327 Eligibility Criteria (Cohort 1 and Cohort 2)

 Step 1 inclusion criteria for both cohorts (Cohort 1 and Cohort 2)

 -  HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or
 chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and
 confirmed by a licensed Western blot or a second antibody test by a method other than
 the initial rapid HIV and/or E/CIA, or by HIV-1 p24 antigen, or plasma HIV-1 RNA viral
 load. [NOTE: The term "licensed" refers to a FDA-approved kit, which is required for
 all IND studies.] WHO (World Health Organization) and CDC (Centers for Disease Control
 and Prevention) guidelines mandate that confirmation of the initial test result must
 use a test that is different from the one used for the initial assessment. A reactive
 initial rapid test should be confirmed by either another type of rapid assay or an
 E/CIA that is based on a different antigen preparation and/or different test principle
 (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral
 load.

 -  A documented confirmation of acute HCV infection within 6 months prior to A5327 entry
 or HCV reinfection as described below:

 1. Acute HCV infection was defined as meeting one of the following criteria and
 exclusion of other causes of acute hepatitis:

 -  New (<24 weeks prior to initial A5327 entry) ALT elevation to ≥5X upper
 limit of normal (ULN) OR >250 U/L in patients with documented normal ALT in
 the preceding 12 months or ≥10X ULN OR >500 U/L in patients with abnormal or
 no measured ALT baseline in the preceding 12 months with detectable HCV RNA
 excluding those with any prior positive anti-HCV. OR

 -  Detectable HCV RNA with prior negative anti-HCV Ab or undetectable HCV RNA
 within the preceding 6 months.

 2. Acute HCV reinfection was defined by documentation of clearance of prior
 infection (as evidenced by positive anti-HCV Ab) either spontaneously or after
 treatment with two negative HCV RNA a minimum of 6 months apart AND meeting one
 of the following criteria in addition to exclusion of other causes of acute
 hepatitis:

 -  New (<24 weeks prior to initial A5327 entry) ALT elevation to ≥5X ULN OR
 >250 U/L in patients with documented normal ALT in the preceding 12 months
 or ≥10X ULN OR >500 U/L in patients with abnormal or no measured ALT
 baseline in the preceding 12 months with detectable HCV RNA. OR

 -  Positive HCV RNA with prior negative HCV RNA within the preceding 6 months.

 -  HCV RNA confirmed to be detectable >12 weeks after first laboratory evidence of acute
 HCV and still within the <24 week from first laboratory evidence of acute HCV
 infection window. First laboratory evidence of infection was defined as date of first
 elevated liver enzymes or date of first serologic evidence of HCV seroconversion
 and/or viremia (whichever occurs first). [NOTE: If the screening visit occurred less
 than 12 weeks from the first laboratory evidence of infection, then the participant
 was required a pre-entry study visit to confirm detectable HCV RNA at least 12 weeks
 from the first laboratory evidence of infection had passed. It was optimal for this
 pre-entry visit to occur as close as possible to 12 weeks from first laboratory
 evidence to ensure timely treatment. Potential participants who entered screening but
 who had an undetectable HCV RNA (<LLOQ TND) at the pre-entry visit (when required)
 exhibited evidence of possible spontaneous clearance and will not meet the entry
 criteria.]

 -  Body mass index (BMI) ≥ 18 kg/m^2

 -  Screening electrocardiogram (ECG) without clinically significant abnormalities as
 determined by the investigator.

 -  Willing and able to provide written informed consent.

 -  Men and women age ≥ 18 years.

 -  All participants agreed not to participate in a conception process (eg, active attempt
 to become pregnant or to impregnate, sperm donation, in vitro fertilization). [NOTE:
 Female candidates who were pregnant or breastfeeding were not eligible. A male
 candidate who had a pregnant female partner was not eligible for the study.]

 -  When participating in sexual activity that could lead to pregnancy, all participants
 must agree to use at least two reliable forms of contraceptive simultaneously while
 receiving protocol-specified medications, and for 6 months after stopping the
 medications. Such methods included:

 -  Condoms (male or female) with or without a spermicidal agent

 -  Diaphragm or cervical cap with spermicide

 -  Intrauterine device (IUD)

 -  Tubal ligation

 -  Hormone-based contraceptive (except those containing drospirenone)

 [NOTE: Providers and participants were advised that not all contraceptive choices listed
 above can prevent HIV transmission and that some may actually increase the risk of HIV
 acquisition. Study participants who were sexually active with HIV-1 negative or unknown
 HIV-1 serostatus partners were advised that they needed to consider effective strategies
 for reducing the risk of HIV transmission, as well as meeting the requirement for effective
 contraception during their participation in the study. Study participants discussed
 contraceptive choices and HIV risk reduction methods with their health care provider.]

 -  Participants who were not of reproductive potential (women who had been
 post-menopausal for at least 24 consecutive months or had undergone hysterectomy
 and/or bilateral oophorectomy or salpingectomy or men who had documented azoospermia
 or undergone vasectomy) were eligible without requiring the use of contraceptives.
 Acceptable documentation of sterilization and menopause was specified below.

 -  Written or oral documentation communicated by clinician or clinician's staff of
 one of the following:

 -  Physician report/letter

 -  Operative report or other source documentation in the patient record (a
 laboratory report of azoospermia was required to document successful vasectomy)

 -  Discharge summary

 -  Follicle stimulating hormone-release factor (FSH) measurement elevated into the
 menopausal range as established by the reporting laboratory.

 -  Intention to comply with the dosing instructions for study drug administration and
 able to complete the study schedule of assessments.

 Step 1 inclusion criteria for Cohort 1 only

 -  HIV-1 ARV therapy fell into one of the following criteria:

 1. ARV untreated, for example due to (1) lack of indication per provider (CD4 T-cell
 count >500 cells/mm3) or (2) decision by provider and participant to defer ARV
 therapy during the study drug dosing period (8 or 12 weeks), or (3) elite
 controller (CD4+ >200 cells/mm3). OR

 2. On a stable, protocol-approved (didanosine (ddI), stavudine (d4T), zidovudine
 (ZDV) excluded), ARV regimen for >8 weeks prior to screening with a CD4 T-cell
 count >200 cells/mm3 and a documented plasma HIV-1 RNA level <50 copies/mL or <
 lower limit of quantification (LLOQ) of local assay if LLOQ is >50 copies/mL by
 any laboratory that has a Clinical Laboratory Improvement Amendments (CLIA)
 certification or its equivalent ≥ 8 weeks preceding the A5327 screening visit.
 HIV-1 RNA levels should be within 1 year of the screening visit. Screening HIV-1
 RNA must be < 50 copies/mL as measured by any local laboratory using an
 FDA-approved assay.

 -  Candidates must have had the following laboratory parameters within 10-42 days prior
 to study entry:

 1. Hemoglobin ≥ 12 g/dL for male, ≥11 g/dL for female participants

 2. International normalized ratio (INR) ≤1.5 x ULN unless participant was known
 hemophilia or was stable on an anticoagulant regimen affecting INR

 3. Albumin ≥ 3 g/dL

 4. Creatinine clearance (CrCl) ≥ 60 mL/min, as calculated by the Cockcroft-Gault
 equation (refer to section 6.3.5 for calculator utility link)

 -  Female participants of reproductive potential (defined as women who have not been
 post-menopausal for at least 24 consecutive months, ie, who have had menses within the
 preceding 24 months, or women who had not undergone surgical sterilization,
 specifically hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy)
 must had a negative serum pregnancy test with a sensitivity of at least 25 mIU/mL
 performed during screening, within 48 hours prior to study entry.

 Step 1 inclusion criteria for Cohort 2 only

 -  HCV genotype 1a, 1b, or 4 infection with source documentation from a CLIA-approved
 laboratory (or its equivalent). [NOTE: Those with mixed 1a/b genotype were classified
 as 1a.]

 -  HIV-1 ARV therapy fell into one of the following criteria:

 1. ARV untreated, for example due to (1) lack of indication per provider (CD4 T-cell
 count >500 cells/mm3) or (2) decision by provider and participant to defer ARV
 therapy during the study drug dosing period (8 or 12 weeks), or (3) elite
 controller (CD4+ >200 cells/mm3). OR

 2. On a stable, protocol-approved ARV regimen (the following ARVs are not allowed:
 ddI, d4T, and TPV/r) for >8 weeks prior to screening with a CD4 T-cell count >200
 cells/mm3 and a documented plasma HIV-1 RNA level <50 copies/mL or <LLOQ of local
 assay if LLOQ is >50 copies/mL by any laboratory that had a Clinical Laboratory
 Improvement Amendments (CLIA) certification or its equivalent ≥ 8 weeks preceding
 the A5327 screening visit. HIV-1 RNA levels should be within 1 year of the
 screening visit. Screening HIV-1 RNA must be <50 copies/mL as measured by any
 local laboratory using an FDA-approved assay.

 -  Candidates must have had the following laboratory parameters within 10-42 days prior
 to study entry:

 1. Hemoglobin ≥9 g/dL for male and female participants

 2. International normalized ratio (INR) ≤1.5 x ULN unless participant had known
 hemophilia or wass stable on an anticoagulant regimen affecting INR

 3. Albumin ≥3 g/dL

 4. Creatinine clearance (CrCl) ≥60 mL/min, as calculated by the Cockcroft-Gault
 equation (refer to section 6.3.5 for calculator utility link)

 -  Female participants of reproductive potential (defined as women who had not been
 post-menopausal for at least 24 consecutive months, ie, who had menses within the
 preceding 24 months, or women who had not undergone surgical sterilization,
 specifically hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy)
 must had a negative serum or urine pregnancy test within 48 hours prior to study entry
 by any laboratory or clinic that had a CLIA certificate or its equivalent, or was
 using a point-of-care (POC)/CLIA-waived test. The serum, urine or POC pregnancy test
 must had a sensitivity of at least 25 mIU/mL.

 Step 1 exclusion criteria for both cohorts (Cohort 1 and Cohort 2)

 -  Received investigational drug or device within 60 days prior to study entry.

 -  Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson's disease, α1
 antitrypsin deficiency, primary sclerosing cholangitis).

 -  Presence of active or acute AIDS-defining opportunistic infections within 30 days
 prior to study entry. [NOTE: A list of AIDS-defining opportunistic infections as
 defined by the CDC, can be found in Appendix B of the following document:
 http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm]

 -  Active, serious infection (other than HIV-1 or HCV) requiring parenteral antibiotics,
 antivirals, or antifungals within 30 days prior to study entry.

 -  Infection with hepatitis B virus (HBV) defined as HBsAg positive.

 -  Evidence of acute hepatitis A infection defined as HAV IGM positive.

 -  Chronic use of systemically administered immunosuppressive agents (eg, prednisone
 equivalent > 10 mg/day).

 -  History of solid organ transplantation.

 -  Current or prior history of clinical hepatic decompensation (eg, ascites,
 encephalopathy or variceal hemorrhage).

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

 -  History of significant or symptomatic pulmonary disease, cardiac disease, or
 porphyria.

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

 -  History of clinically significant illness or any other major medical disorder that may
 interfere with participant treatment, assessment, or compliance with study
 requirements, which may included active drug or alcohol use or dependence.

 -  Use of any prohibited concomitant medications within 30 days prior to study entry.

 -  Acute HIV infection defined as the phase immediately following infection during which
 anti-HIV antibodies are undetectable. [NOTE: Participants with early infection,
 defined as within the first 6 months of infection and with a positive HIV antibody,
 should be discussed with the A5327 protocol core team. These participants may be
 considered for inclusion in the study on a case by case basis with the specific
 documented approval of the protocol chairs.]

 Step 1 exclusion criteria for Cohort 1 only

 -  Prior exposure to a direct-acting antiviral (DAA) targeting the HCV NS5B polymerase.
 [NOTE: DAAs include but are not limited to: mericitabine, ABT-333, ABT-072, BI-207127,
 BMS-791325, VX-222, tegobuvir, IDX719, setrobuvir, GS-9669, VX-135.]

 -  History of clinically significant hemoglobinopathy (eg, sickle cell disease,
 thalassemia).

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

 -  Currently receiving ZDV, ddI, or d4T.

 Step 1 Exclusion criteria for Cohort 2 only

 -  Any preceding attempt at HCV treatment during this acute HCV infection episode, ie, 24
 weeks prior to entry.

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

 -  Currently receiving TPV/r, ddI, d4T or amiodarone.

 -  Pregnancy or Breastfeeding.