HIV-HCV
Conditions
Keywords
Coinfection, HCV Genotype 1b, Interferon Free therapy, Liver Biopsy, Virological Response
Brief summary
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.
Detailed description
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.
Interventions
DRUGAsunaprevir and Daclatasvir
Oral treatment with Asunaprevir 100mg (ASV), twice daily, and Daclatasvir 60mg (DCV), once daily, for 24 weeks in HIV/HCV genotype 1b patients
DRUGAsunaprevir and Daclatasvir with BMS-791325
Oral treatment with Asunaprevir 200mg (ASV), Daclatasvir 30 mg (DCV) and BMS-791325 75 mg in a fixed dose combination pill (FDC), twice daily, for 12 weeks in HIV/HCV genotype 1a or 1b patients
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Bristol-Myers Squibb
National Institutes of Health Clinical Center (CC)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Subjects Who Achieve Sustained Viral Response (SVR12) 12 Weeks After the Stop of Treatment Drugs | 12 weeks after stop of treatment | The primary outcome was the percentage of patients with sustained viral response measured 12 weeks after the stop of treatment. The viral response was assessed by serum HCV RNA concentrations lower than 43 IU/mL - the lower limit of quantification. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HIV/HCV GT-1a/1b, 12 Wks ASV/DCV With BMS-791325 Oral treatment with Asunaprevir 200mg (ASV), Daclatasvir 30 mg (DCV) and BMS-791325 75 mg in a fixed dose combination pill (FDC), twice daily, for 12 weeks in HIV/HCV genotype 1a or 1b patients | 20 |
| HIV/HCV GT-1b, 24 Wks ASV/DCV Oral treatment with Asunaprevir 100mg (ASV), twice daily, and Daclatasvir 60mg (DCV), once daily, for 24 weeks in HIV/HCV genotype 1b patients | 10 |
| Total | 30 |
Baseline characteristics
| Characteristic | HIV/HCV GT-1a/1b, 12 Wks ASV/DCV With BMS-791325 | HIV/HCV GT-1b, 24 Wks ASV/DCV | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 9 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 8 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 9 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 5 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Male | 12 Participants | 3 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 20 | 3 / 10 |
| serious Total, serious adverse events | 3 / 20 | 5 / 10 |
Outcome results
Primary
The Percentage of Subjects Who Achieve Sustained Viral Response (SVR12) 12 Weeks After the Stop of Treatment Drugs
The primary outcome was the percentage of patients with sustained viral response measured 12 weeks after the stop of treatment. The viral response was assessed by serum HCV RNA concentrations lower than 43 IU/mL - the lower limit of quantification.
Time frame: 12 weeks after stop of treatment
Population: Subjects who received treatment drugs per arm as listed in the Outcome Measure Description
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HIV/HCV GT-1a/1b, 12 Wks ASV/DCV With BMS-791325 | The Percentage of Subjects Who Achieve Sustained Viral Response (SVR12) 12 Weeks After the Stop of Treatment Drugs | 90 Percentage of subjects |
| HIV/HCV GT-1b, 24 Wks ASV/DCV | The Percentage of Subjects Who Achieve Sustained Viral Response (SVR12) 12 Weeks After the Stop of Treatment Drugs | 80 Percentage of subjects |