Safety, Tolerability, and Efficacy of Asunaprevir and Daclatasvir in Subjects Coinfected With HIV-HCV
Safety, Tolerability, and Efficacy of Asunaprevir and Daclatasvir in Subjects Coinfected With HIV-HCV
Chronic hepatitis C virus (HCV) infection is a major public health problem with an estimated
 180 million people infected worldwide. In the United States an estimated 4.1 million people
 are infected and HCV is the principal cause of death from liver disease and leading
 indication for liver transplantation. Within HIV/HCV co-infected patients, liver disease due
 to Hepatitis C progresses even more rapidly. While combination of ribavirin (RBV) and
 pegylated interferon (PEG) in combination with boceprevir/telaprevir is the currently
 recommended therapy for chronic HCV infection and has superior cure rates compared to PEG+RBV
 alone in HCV monoinfected patients, treatment is still associated with a high incidence of
 adverse events (AEs), discontinuations and poor cure rates in several populations. Within the
 HIV/HCV co-infected population treatment for HCV remains complicated given drug interactions
 between anti-retrovirals and HCV protease inhibitors, in addition to the extensive
 side-effects due to PEG +RBV alone. Recent studies have demonstrated that the use of a
 combination of anti-virals which target HCV without interferon (IFN) can cure HCV, without
 additional toxicities. These novel therapies that do not rely on an IFN backbone may
 additionally enhance cure rates in HIV/HCV co-infected, a population which has historically
 been difficult to cure.

 The findings from this study will aid in the understanding of antiviral and host responses
 and determinants of response to an IFN free regimen in HIV/HCV co-infected patients.
Chronic hepatitis C virus (HCV) infection is a major public health problem with an estimated
 180 million people infected worldwide. In the United States an estimated 4.1 million people
 are infected and HCV is the principal cause of death from liver disease and leading
 indication for liver transplantation. Within HIV/HCV co-infected patients, liver disease due
 to Hepatitis C progresses even more rapidly. While combination of ribavirin (RBV) and
 pegylated interferon (PEG) in combination with boceprevir/telaprevir is the currently
 recommended therapy for chronic HCV infection and has superior cure rates compared to PEG+RBV
 alone in HCV monoinfected patients, treatment is still associated with a high incidence of
 adverse events (AEs), discontinuations and poor cure rates in several populations. Within the
 HIV/HCV co-infected population treatment for HCV remains complicated given drug interactions
 between anti-retrovirals and HCV protease inhibitors, in addition to the extensive
 side-effects due to PEG +RBV alone. Recent studies have demonstrated that the use of a
 combination of anti-virals which target HCV without interferon (IFN) can cure HCV, without
 additional toxicities. These novel therapies that do not rely on an IFN backbone may
 additionally enhance cure rates in HIV/HCV co-infected, a population which has historically
 been difficult to cure.

 This is an open label study to assess the safety, tolerability and efficacy of two regimens
 for the treatment of HCV, asunaprevir (ASV) 100 mg BID and daclatasvir (DCV) 60 mg daily
 (selective HCV NS3 and NS5A inhibitors respectively) in 10 HIV/HCV genotype 1b co-infected
 treatment-naive and treatment experienced individuals and DCV + ASV + BMS-791325 administered
 as a fixed dose combination (FDC) pill in 20 HIV/HCV GT 1a or 1b coinfected treatment-naive
 and treatment experienced individuals.

 The findings from this study will aid in the understanding of antiviral and host responses
 and determinants of response to an IFN free regimen in HIV/HCV co-infected patients.
-  INCLUSION CRITERIA

 Subjects who meet the following criteria are eligible to enter the study:

 1. Eighteen years of age or older at screening

 2. Naive to treatment for hepatitis C or treatment experienced on previous IFN-containing
 treatment for chronic HCV infection. Patients who have been re-infected with HCV are
 excluded.

 3. Women are allowed to participate if they agree to always use at least two forms of
 birth control. One form must be barrier protection (i.e., condom or female condom) and
 the other is to meet one of the criteria below:

 1. Non-childbearing potential status (i.e., physiologically incapable of becoming
 pregnant)

 - Has had a hysterectomy or

 - Has had a bilateral oophorectomy or

 - Is post-menopausal (age greater than or equal to 50 and a demonstration of a
 total cessation of menses for greater than or equal to 1 year) or

 - Has had a bilateral tubal ligation or fallopian tube inserts

 2. Childbearing potential status women must have a negative serum pregnancy test at
 screening and agree to use an acceptable form of birth control, such as any of
 the following:

 - Complete abstinence from sexual intercourse 2 weeks prior to administration of
 the study drug until completion of the follow-up procedures and at least 5 weeks
 (women) after the last dose of the study drugs.

 - Vasectomized partner in reliably monogamous relationship.

 -  An intrauterine device (IUD) 2 weeks prior to administration of the study
 drugs continuously until completion of the follow-up procedures and at least
 5 weeks after the last dose of the study drugs.

 -  Double contraceptive method (condom or occlusive cap [diaphragm or
 cervical/vault caps]; spermicidal foam/gel/film/cream/suppository).

 -  Oral, implantable, transdermal, or injectable or any other form of hormonal
 contraceptives are NOT an acceptable form of contraception for females on
 this study.

 4. Men are allowed to participate if they agree to use at least 2 forms of birth control.
 One form must be barrier protection (i.e., condom or female condom) and the other is
 to meet one of the criteria below:

 1. Are sterile or

 2. Agree to use at least one of the following approved methods of contraception 2
 weeks prior to administration of the study drug until the completion of the
 followup procedures and at least 14 weeks after the last dose of the study drugs:

 -  A male condom with spermicide.

 -  A sterile sexual partner.

 -  A female sexual partner who has an IUD.

 -  A female sexual partner using a female condom with spermicide, intravaginal
 system (e.g., NuvaRing[registered]), diaphragm with spermicide, cervical cap
 with spermicide, or oral, implantable, transdermal, or injectable
 contraceptives.

 5. Chronic GT1b (2DAA arm) or Chronic GT 1 (1a or 1b) (3DAA arm) infection as documented
 by one or more measurements of serum HCV RNA greater than or equal to 2,000 IU/mL
 during screening and at least one of the following:

 1. A positive anti-HCV antibody, HCV RNA, or HCV genotype test result greater than
 or equal to 12 months prior to the baseline (Day 0) visit together with current
 positive HCV RNA or anti-HCV antibody test results.

 Or

 b. Positive HCV RNA test and anti-HCV antibody test results together with a liver biopsy
 consistent with chronic HCV infection or a liver biopsy performed before Day 0 with
 evidence of chronic hepatitis C infection disease, such as the presence of fibrosis.

 6. HIV treatment status:

 1. Documented HIV infection (defined by positive Western blot result or detectable HIV
 viral load), ARV untreated for >8 weeks preceding dosing and having either:

 1. A CD4 T-cell count greater than or equal to 500 cells/mm3 within 8 weeks of Day 0
 or

 2. An HIV viral load less than 500 copies/mL with a stable CD4 count for at least 3
 months

 2. Documented HIV-1 (defined by positive western blot result or detectable HIV viral
 load) infection on a stable protocol-approved, ARV regimen for greater than or equal
 to 4 weeks prior to dosing and is expected to continue the current ARV regimen through
 the end of study with all of the following

 1. a CD4 T-cell count > 100 cells/mm3

 2. a documented plasma HIV-1 RNA level less than the level of detection measured at
 least twice in the 4 weeks preceding dosing. If the lower limit of detection of
 the local HIV-1 RNA result is >50 copies/mL (e.g., <70 copies/mL, the screening
 plasma HIV-1 RNA level cannot exceed 50 copies/mL).

 3. HIV ARV agents including only:

 a. Raltegrativir plus one of the following

 b. Tenofovir and emtricitabine or abacavir and lamivudine

 7. Documentation of hepatitis C genotype 1b (2DAA arm) or GT 1 (1a or 1b) (3DAA arm) alone
 infection within 6 months prior to Day 0. HCV genotype/subtypes performed outside the NIH
 will be accepted for eligibility if performed using the Siemens LiPA v2.0 assay or an assay
 with equivalent performance in identifying the HCV genetype 1b (e.g., Abbott RealTime HCV
 Genotype II assay).

 8. Liver biopsy obtained within 36 calendar months prior to the baseline (Day 0) visit to
 verify the presence or absence of cirrhosis, except as indicated below. If no recent (<36
 months) liver biopsy is available, a liver biopsy may be performed prior to the baseline
 visit.

 1. Cirrhosis is defined as any one of the following:

 1. Any biopsy showing cirrhosis (at any time, not restricted to the 36 calendar
 months prior to baseline visit).

 2. A FibroSUR[trademark] score, of >0.75 and an aspartate aminotransferase (AST)
 platelet ratio index (APRI) of >2 within the last year.

 2. Absence of cirrhosis is defined as any one of the following:

 1. A liver biopsy performed within 36 calendar months of screening showing absence
 of cirrhosis.

 2. A FibroSUR[trademark] score, within the last year, of <0.48 and an APRI of <1.

 In the absence of a definitive diagnosis of presence or absence of cirrhosis by
 the criteria detailed above, a liver biopsy is required. The
 FibroSURE[trademark]test can be performed and the results can be used to
 determine the inclusion and exclusion criteria. Patients with Child Pugh B or C
 cirrhotics are excluded

 9. Ability to communicate effectively with the study investigator and other key
 personnel.

 10. Willingness to comply with the study restrictions and requirements.

 11. Opioid-dependent individuals must be participating in a supervised treatment
 program.

 12. Subjects must have an external primary care doctor (outside of the Clinical Center
 and the NIH) for their medical management.

 13. Willingness to have blood or tissue samples stored for future use to study liver
 disease and immune function.

 14. Willingness to undergo HLA typing.

 15. Otherwise healthy status as determined by medical history, physical examination,
 electrocardiogram (ECG), and clinical laboratory measurements performed at screening.

 Contraception

 The effects of ASV and DCV on the developing human fetus are unknown. For this reason, men
 and women of childbearing potential must agree to use adequate contraception as outlined in
 the inclusion and exclusion criteria prior to study entry and until 5 weeks (women ) and 14
 weeks (men) after last dose of study medication. Hormonal contraception is NOT considered
 an effective form of birth control for female subjects on this study. Oral contraceptives
 are not as effective in women taking ASV and DCV so women cannot rely on this form of birth
 control to prevent pregnancy. Females of childbearing-age must have a negative pregnancy
 test result prior to receiving ASV and DCV. If a woman becomes pregnant or suspects of
 being pregnant during the course of the study, she should inform the study staff and her
 primary care physician immediately.

 EXCLUSION CRITERIA

 1. Current or prior history of any of the following:

 1. Clinically significant illness (other than HCV) or any other major medical
 disorder that may interfere with the subject treatment, assessment of compliance
 with the protocol; subjects currently under evaluation for a
 clinically-significant illness (other than HCV) are also excluded

 2. Gastrointestinal disorder with post-operative condition that could interfere with
 the absorption of the study drug

 3. Poor venous access interfering with required study blood collection

 4. Clinical hepatic decompensation (i.e.,-ascites, encephalopathy or variceal
 hemorrhage)

 5. Hepatic impairment (e.g., Child-Pugh class B [moderate] or Child-Pugh class C
 [severe])

 6. Solid organ transplantation

 7. Significant pulmonary disease, significant cardiac disease or porphyria.

 8. Unstable psychiatric disease (subjects with psychiatric illness that is well
 controlled on a stable treatment regimen or currently not requiring medication
 may be included)

 9. Any malignancy or its treatment that in the opinion of the PI may cause ongoing
 interference with host immunity; subjects under evaluation for malignancy are not
 eligible

 10. Significant drug allergy (such as anaphylaxis or hepatotoxicity)

 11. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson s
 disease, alfa-1 antitrypsin deficiency, cholangitis)

 2. Positive nucleotide sequence analyses of the NS5A gene for Y93H or L31M/V
 polymorphisms for the 2DAA arm only.

 3. Positive test results at screening for hepatitis B virus (HBV) surface antigen (HBsAg)
 or HBV RNA (completed only if necessary to rule out chronic HBV)

 4. Current use of non-protocol approved ARVs

 5. A new AIDS-defining condition diagnosed within 30 days prior to date screening consent
 is signed or active serious infection (other than HIV and HCV), requiring parenteral
 antibiotics, antivirals or antifungals within 30 days prior to Day 0

 6. Abnormal hematological and biochemical parameters at screening, unless the test has
 been repeated and at least one subsequent result is within the acceptable range prior
 to study drug administration, including:

 1. Neutrophil count <750 cells/mm3

 2. Hemoglobin level <9 g/dL

 3. Platelet count less than or equal to 50,000 cells/mm3

 4. Estimated glomerular filtration rate, calculated by the chronic kidney disease
 epidemiology collaboration formula: <50 mL/min/1.73 m^2

 5. ALT or AST level greater than or equal to10 times upper limit of normal (ULN)

 6. Serum lipase level greater than or equal to 1.5 times ULN at screening or during
 the screening period in a patient with symptoms of pancreatitis

 7. Total bilirubin level greater than or equal to 2.0 times ULN, except in subjects
 with Gilbert s syndrome

 8. Albumin level less than or equal to 3.0 g/dL

 7. Donation or loss of blood of >400 mL within 8 weeks prior to the first dose of the
 study drugs

 8. Poorly controlled diabetes as indicated by a screening glycosylated hemoglobin (HbA1c)
 >10

 9. Known hypersensitivity to ASV, DCV or formulation excipients

 10. Pregnant or breastfeeding

 11. Screening or baseline with clinically significant ECG findings, or personal/first
 degree relative history of Torsade de pointes

 12. Need for the use of the following medications from 21 days prior to the start of study
 drugs through the end of treatment:

 1. Hematologic stimulating agents, erythropoiesis stimulating agents (ESAs),
 granulocyte colony stimulating factor (GCSF), thrombopoeitin (TPO) mimetics

 2. Chronic systemic antineoplastic or immunomodulatory treatment including
 supraphysiologic doses of immunosuppressants such as corticosteroids (e.g.,
 prednisone equivalent >10 mg/day for >2 weeks), azathioprine or monoclonal
 antibodies (e.g., infliximab)

 3. Investigational agents or devices for any indication

 13. Previous treatment with an HCV protease inhibitor or any DAA

 14. Medications for disease conditions excluded from the protocol (e.g.,- active cancer,
 transplantation) are not listed under the Concomitant medication section, and are
 disallowed from the study

 15. Use of certain medications and herbal/natural supplements per PI discretion, expected
 to result in increases or decreases in exposure to study or non-study medications as
 listed in Section 5.5 while receving study medications and within five half-lives or
 14 days [whichever is longer] of the first dose of study medications.

 16. Co-enrollment Guidelines: Co-enrollment in other clinical trials is restricted, other
 than enrollment in observational studies or those evaluating the use of a licensed
 medication. Study staff should be notified of co-enrollment status, as it may require
 prior approval of the investigator