Evaluating the Safety and Effectiveness of Interferon-Free Treatment of Hepatitis C Virus Infection in HIV-Coinfected Adults on Antiretroviral Therapy

Study Overview
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Brief Summary
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HIV and hepatitis C virus (HCV) infection are diseases that share the same risk factors and routes of transmission. For this reason, many people infected with HIV are also infected with HCV. Interferon (IFN) is a drug used to treat HCV; however, in people coinfected with HIV and HCV, IFN treatment often does not work well and can cause unwanted side effects. The purpose of this study was to evaluate the safety, tolerability, and effectiveness of IFN-free HCV treatment in HIV/HCV coinfected adults who were taking antiretroviral (ARV) therapy.

Detailed Description
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This study evaluated the safety, tolerability, and effectiveness of a combination of drugs to treat HCV in adults who were coinfected with HIV and HCV. The three drugs were paritaprevir/ritonavir/ombitasvir (PTV/r/OBT), dasabuvir (DSV), and ribavirin (RBV). In version 1 of the study, RBV was given to all participants. After revision in version 2, RBV was given only to participants with HCV genotype 1a; participants with HCV genotype 1b did not receive RBV. This study enrolled HCV genotype 1a or 1b and HIV-1 coinfected participants (HCV treatment-naïve or HCV treatment-experienced) who were on a concurrent integrase inhibitor (INI)-based (raltegravir [RAL] or dolutegravir [DTG]) or protease inhibitor (PI)-based (darunavir [DRV] or atazanavir [ATV]) ART regimen. (The ART regimens were not provided by the study.) The participants were assigned to one of four cohorts (Cohorts A, B, C, and D). Participants in Cohorts A and B were on INI-based ART; participants in Cohorts C and D, on PI-based ART. For each group, the study proceeded in two steps: Step 1: on-HCV treatment and Step 2: post-HCV treatment follow-up. Participants in Cohorts A and C received the HCV drugs for 24 weeks; participants in Cohorts B and D, for 12 weeks. The target sample size goal was a total of 100 participants, with 25 participants per cohort. Total study duration was up to 48 weeks. During Step 1 (on-HCV treatment), all participants had study visits at Weeks 2, 4, 6, 8, 10, and 12. Participants in Cohorts A and C had additional Step 1 study visits at Weeks 16, 20, and 24. All participants had Step 2 (post-treatment follow-up) study visits 4, 12, and 24 weeks after registration to Step 2. Participants in Cohorts B and D had an additional Step 2 visit 36 weeks after registration to Step 2. All study visits included a brief physical exam and blood collection. Select study visits included pregnancy testing for participants able to become pregnant, an electrocardiogram (EKG), an IFN gamma-induced protein 10 (IP-10) test, and collection of plasma samples. Participants were able to coenroll in one of two optional substudies. In one substudy, participants attended two study visits at entry/Day 0 and Week 4 for 12-hour intensive pharmacokinetic (PK) sampling. In another substudy, participants underwent liver biopsies at two time points and PK sampling. Study accrual was terminated early and participants who enrolled continued on study until completion.

Official Title
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Interferon-Free Therapy for Chronic Hepatitis C Virus Genotype 1 Infection in Participants With HIV-1 Coinfection Receiving Concurrent Antiretroviral Therapy (C_ASCENT)

Conditions
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HIV Infections, Hepatitis C

Intervention / Treatment
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* Drug: Paritaprevir/ritonavir/ombitasvir (PTV/r/OBT)
* Drug: Dasabuvir (DSV)
* Drug: Ribavirin (RBV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women age greater than or equal to 18 to less than or equal to 70 years at study entry. Body mass index (BMI) from greater than or equal to 18 to less than 38 kg/m^2 within 42 days of study entry. BMI was calculated as weight measured in kilograms (kg) divided by the square of height measured in meters (m). HIV-1 infection CD4+ cell count greater than or equal to 200 cells/uL and CD4+ cell percentage greater than or equal to 14% within 42 days of study entry. On a stable, qualifying ART regimen for at least 8 weeks prior to entry. HIV-1 RNA less than 50 copies/mL for at least 6 months prior to study entry. Presence of chronic HCV infection defined as positive for anti-HCV antibody or HCV RNA at least 6 months before screening, and positive for HCV RNA at the time of screening; OR positive for HCV RNA at the time of screening with a liver biopsy consistent with chronic HCV infection any time prior to study entry. HCV treatment-naïve or unsuccessful treatment with pegylated or standard IFN alfa with or without RBV. NOTE: No prior exposure to HCV NS3/4A PI (including but not limited to TVR, BOC, simeprevir), NS5A inhibitors (including but not limited to daclatasvir or ledipasvir), NS5B NNI or NI inhibitors (including but not limited to sofosbuvir) was allowed. HCV genotype 1a or 1b infection Serum HCV RNA greater than 10,000 IU/mL obtained within 42 days prior to study entry. The following laboratory values obtained within 42 days prior to study entry. Absolute neutrophil count (ANC) greater than or equal to 750/mm^3 Hemoglobin greater than or equal to 12 g/dL for men and greater than or equal to 11 g/dL for women Platelet count greater than or equal to 90,000/mm^3 International normalized ratio (INR) less than or equal to 1.5 Participants with known inherited bleeding disorder and INR greater than or equal to 1.5 could be enrolled. Calculated creatinine clearance (CrCl) using Cockcroft-Gault method greater than or equal to 60 mL/min Alanine aminotransferase (ALT) less than or equal to 7 times the upper limit of the normal range (ULN) Aspartate aminotransferase (AST) less than or equal to 7 times the ULN range Total bilirubin less than 3 mg/dL for participants not on ATV and less than 6 mg/dL for participants on ATV Direct bilirubin less than or equal to 1.5 times the ULN Albumin greater than or equal to 3.5 g/dL Serum alfa-fetoprotein (AFP) less than or equal to 100 ng/mL Classification of liver disease as cirrhotic or non-cirrhotic with no evidence of hepatocellular carcinoma according to specified criteria. For females of reproductive potential, a negative serum or urine pregnancy test with a sensitivity of less than or equal to 25 mIU/mL within 42 days prior to study entry. All participants must have agreed not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). If participating in sexual activity that could lead to pregnancy, the participant (men and women) had to agree to use two reliable methods of contraception simultaneously. Participants who were not of reproductive potential were eligible without requiring the use of contraceptives. Ability and willingness of the participant to provide written informed consent. Exclusion Criteria: Breastfeeding Pregnant sexual partner for male participants with HCV genotype 1a infection who would receive RBV. This criterion did not apply to male participants with HCV genotype 1b infection who would not receive RBV. Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation. Acute or serious illness requiring systemic treatment and/or hospitalization within 42 days prior to study entry. Active hepatitis B infection (positive hepatitis B surface antigen [HBsAg]) within 42 days prior to study entry. History of decompensated liver disease (including but not limited to encephalopathy, variceal bleeding, or ascites) prior to study entry. Any cause of liver disease other than chronic HCV infection, including but not limited to the following: hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's disease, autoimmune hepatitis, alcoholic liver disease, or drug-related liver disease. Uncontrolled or active depression or other psychiatric disorder within 24 weeks prior to study entry that in the opinion of the site investigator might preclude adherence to study requirements. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Serious illness including uncontrolled seizure disorders, active coronary artery disease within 24 weeks prior to study entry, or other chronic medical conditions that in the opinion of the site investigator might preclude completion of the protocol. Presence of active or acute AIDS-defining opportunistic infections within 12 weeks prior to study entry. Active or history of malignancy within 5 years prior to study entry other than basal cell carcinoma of the skin and/or cutaneous Kaposi's sarcoma (KS) and/or cervical or anal dysplasia or carcinoma in situ. Clinically significant abnormal EKG, or EKG with QT interval corrected for heart rate (QTc) using Fridericia's correction formula (QTcF) greater than 450 msec within 42 days of study entry. Use of colony stimulating factors, such as granulocyte colony stimulating factor (GCSF) or erythropoietin within 42 days of study entry. Infection with any HCV genotype other than genotype 1, or mixed genotype infection any time prior to study entry. History of major organ transplantation with an existing functional graft any time prior to study entry. History of hemoglobinopathy (e.g., thalassemia) or any other cause of or tendency to hemolysis any time prior to study entry. Anticoagulants such as Coumadin (Warfarin), Dicumarol, Plavix (Clopidrogel), low-molecular weight Heparin, Lovenox (Enoxaparin), or Dabigatran (Pradaxa), aspirin, and Non-steroidal Anti-Inflammatory Drugs (NSAIDs) within 2 weeks prior to entry.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A [INI-based ART + PTV/r/OBT + DSV +/- RBV 24 Weeks]<br>Participants took an INI-based (RAL or DTG) ART regimen for HIV-1 and received the following medications for 24 weeks: paritaprevir/ritonavir/ombitasvir (PTV/r/OBT), dasabuvir (DSV), and ribavirin (RBV) (RBV for all participants (version 1) and only for participants with HCV genotype 1a (version 2)). | Drug: Paritaprevir/ritonavir/ombitasvir (PTV/r/OBT)<br>* PTV/r/OBT: 150/100/25 mg (two 75/50/12.5 mg fixed-dose combination tablets) orally once a day<br>Drug: Dasabuvir (DSV)<br>* DSV: 250 mg orally twice a day<br>Drug: Ribavirin (RBV)<br>* RBV: 1,000 or 1,200 mg (weight-based) dosed in two divided doses orally twice a day (all participants (version 1); only participants with HCV genotype 1a (version2))<br>|
| Experimental: Cohort B [INI-based ART + PTV/r/OBT + DSV +/- RBV 12 Weeks]<br>Participants took an INI-based (RAL or DTG) ART regimen for HIV-1 and received the following medications for 12 weeks: paritaprevir/ritonavir/ombitasvir (PTV/r/OBT), dasabuvir (DSV), and ribavirin (RBV) (RBV for all participants (version 1) and only for participants with HCV genotype 1a (version 2)). | Drug: Paritaprevir/ritonavir/ombitasvir (PTV/r/OBT)<br>* PTV/r/OBT: 150/100/25 mg (two 75/50/12.5 mg fixed-dose combination tablets) orally once a day<br>Drug: Dasabuvir (DSV)<br>* DSV: 250 mg orally twice a day<br>Drug: Ribavirin (RBV)<br>* RBV: 1,000 or 1,200 mg (weight-based) dosed in two divided doses orally twice a day (all participants (version 1); only participants with HCV genotype 1a (version2))<br>|
| Experimental: Cohort C [PI-based ART + PTV/r/OBT + DSV +/- RBV 24 Weeks]<br>Participants took a PI-based (DRV or ATV) ART regimen for HIV-1 and received the following medications for 24 weeks: paritaprevir/ritonavir/ombitasvir (PTV/r/OBT), dasabuvir (DSV), and ribavirin (RBV) (RBV for all participants (version 1) and only for participants with HCV genotype 1a (version 2)). | Drug: Paritaprevir/ritonavir/ombitasvir (PTV/r/OBT)<br>* PTV/r/OBT: 150/100/25 mg (two 75/50/12.5 mg fixed-dose combination tablets) orally once a day<br>Drug: Dasabuvir (DSV)<br>* DSV: 250 mg orally twice a day<br>Drug: Ribavirin (RBV)<br>* RBV: 1,000 or 1,200 mg (weight-based) dosed in two divided doses orally twice a day (all participants (version 1); only participants with HCV genotype 1a (version2))<br>|
| Experimental: Cohort D [PI-based ART + PTV/r/OBT + DSV +/- RBV 12 Weeks]<br>Participants took a PI-based (DRV or ATV) ART regimen for HIV-1 and received the following medications for 12 weeks: paritaprevir/ritonavir/ombitasvir (PTV/r/OBT), dasabuvir (DSV), and ribavirin (RBV) (RBV for all participants (version 1) and only for participants with HCV genotype 1a (version 2)). | Drug: Paritaprevir/ritonavir/ombitasvir (PTV/r/OBT)<br>* PTV/r/OBT: 150/100/25 mg (two 75/50/12.5 mg fixed-dose combination tablets) orally once a day<br>Drug: Dasabuvir (DSV)<br>* DSV: 250 mg orally twice a day<br>Drug: Ribavirin (RBV)<br>* RBV: 1,000 or 1,200 mg (weight-based) dosed in two divided doses orally twice a day (all participants (version 1); only participants with HCV genotype 1a (version2))<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Virologic Response at 12 Weeks After HCV Treatment Discontinuation (SVR12) | SVR12 was defined as HCV RNA less than the assay LLOQ (<15 IU/mL) at 12 weeks post HCV treatment discontinuation. A two-sided 90% confidence interval was calculated for the percentage of participants with SVR12 response using Clopper-Pearson method. For those whose HCV early responses prior to SVR12 evaluation met the guidelines for HCV Virologic Failure (VF), their SVR12 outcome was defined as non-response. Those missing a HCV RNA result from the week 12 post HCV treatment discontinuation visit (and missing all subsequent evaluations) were considered non-responders. However, if HCV RNA evaluations subsequent to week 12 post treatment discontinuation were non-missing, then the first HCV RNA subsequent to week 12 post treatment discontinuation was instead used to define the primary outcome. | At 12 weeks after last dose of HCV study treatment. The duration for study treatment for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. | 
| Number of Participants With an Occurrence of Serious Adverse Events (SAEs) as Defined by International Conference on Harmonisation (ICH) Criteria | Participants who experienced at least one observed SAEs as defined by ICH after initiating HCV study treatment through 30 days post date of last dose of HCV study treatment. | From treatment initiation to 30 days post date of last dose of HCV study treatment (whether planned or premature discontinuation). The duration for HCV study treatment for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. | 
| Number of Participants Who Prematurely Discontinued HCV Study Treatment for Any Reason Other Than HCV Virologic Failure (VF) | HCV VF was defined as follows: confirmed increase from nadir in HCV RNA (defined as two consecutive HCV RNA measurements of >1 log10 IU/mL above nadir) at any time point; failure to achieve HCV RNA <LLOQ (<15 IU/mL) by week 6; confirmed HCV RNA ≥LLOQ (defined as two consecutive HCV RNA measurements ≥LLOQ (≥15 IU/mL)) at any point after HCV RNA <LLOQ during HCV treatment | From treatment initiation to either 24 weeks (for Cohort A and C) or 12 weeks (for Cohort B and D). The duration for HCV study treatment for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. | 
| Number of Participants With an Occurrence of Signs/Symptoms Grade 3 or Higher | Participants with signs/symptoms of grade 3 or higher post treatment initiation. Participants with grade 3 sign/symptom prior to treatment initiation must have had one grade higher than pre-treatment to meet this outcome. Severity grading was based on DAIDS AE Grading Table, Version 1.0. | From treatment initiation to 30 days post date of last dose of HCV study treatment (whether planned or premature discontinuation). The duration for HCV study treatment for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. | 
| Number of Participants With an Occurrence of Diagnoses Leading to Premature HCV Study Treatment or HIV-1 Antiretroviral (ARV) Discontinuation. | Participants who had diagnoses leading to premature HCV study treatment or HIV-1 ARV discontinuation post treatment initiation. | From treatment initiation to end of study follow-up at 48 weeks.The duration for HCV study treatment for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. The duration for ARV treatment for all cohorts was 48 weeks. | 
| Number of Participants With an Occurrence of Laboratory Abnormality Grade 3 or Higher. | Participants with an observed laboratory abnormalities grade 3 or higher post treatment initiation. If entry (pre-treatment) lab result was grade 3, then a grade 4 result was required to meet this outcome. Severity grading was based on DAIDS AE Grading Table, Version 1.0. | From treatment initiation to 30 days post date of last dose of HCV study treatment (whether planned or premature discontinuation). The duration for HCV study treatment for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced HIV-1 Virologic Failure (VF) | HIV-1 VF was defined as two consecutive HIV-1 RNA results ≥ 200 copies/mL. | From treatment initiation to 4 weeks after last dose of HCV study treatment. HIV-1 RNA was measured at weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 28. The durations for HCV study treatment for Cohorts A/C and Cohorts B/D were 24 and 12 weeks, respectively. | 
| Number of Participants With Selected HIV-1 Resistance Mutations Among Participants Who Experience HIV-1 Virologic Failure (VF) | Participants with one or more genotype mutations in protease conferring major resistance to any HIV-1 Protease Inhibitors (PI) antiretroviral drug, from a plasma sample drawn following confirmed HIV-1 VF outcome. | At confirmation of HIV-1 virologic failure. | 
| Levels of Soluble CD14 (sCD14) | Levels of sCD14. Baseline was defined as the date of first treatment dose. | At baseline, end of HCV treatment (EOT), and 12 weeks post EOT. The EOT for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. | 
| Change in Soluble CD14 (sCD14) | Absolute change from baseline in sCD14 levels in plasma calculated as value at the later time point minus baseline value. Baseline was defined as the date of first treatment dose. | At baseline, end of HCV treatment (EOT), and 12 weeks post EOT. The EOT for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. | 
| Levels of IP-10 Concentration. | Levels of IP-10 (Interferon gamma-induced protein 10) concentration in plasma. Baseline was defined as the date of first treatment dose. | At baseline, end of HCV treatment (EOT), and 12 weeks post EOT. The EOT for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. | 
| Change in IP-10 Concentration. | Absolute change from baseline in IP-10 (Interferon gamma-induced protein 10) concentration in plasma, calculated as value at the later time point minus baseline value. Baseline was defined as the date of first treatment dose. | At baseline, end of HCV treatment (EOT), and 12 weeks post EOT. The EOT for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. | 
| Number of Participants With HCV Mutations Conferring Resistance to Any Component of the HCV Treatment Regimen | Study team decided to remove this secondary outcome measure due to reduced interest in study treatment as a result of development and approval of newer DAA's. | From treatment initiation to 12 weeks post date of last dose of HCV study treatment. The duration for HCV study treatment for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. | 
| Percentage of Participants With Sustained Virologic Response at 24 Weeks After HCV Treatment Discontinuation (SVR24) | SVR24 was defined as HCV RNA less than the assay LLOQ (<15 IU/mL) at 24 weeks post treatment discontinuation. A two-sided 90% confidence interval was calculated for the percentage of SVR24 response using method of Clopper-Pearson. For those whose HCV early responses prior to SVR24 evaluation met the guidelines for HCV VF, their SVR24 outcome was defined as non-response. Those missing a HCV RNA result from the week 24 post HCV treatment discontinuation visit (and missing all subsequent evaluations) were considered non-responders. However, if HCV RNA evaluations subsequent to week 24 post treatment discontinuation were non-missing, then the first HCV RNA subsequent to week 24 post treatment discontinuation was instead used to define the primary outcome. | At 24 weeks after the date of last dose of HCV study treatment. The duration for study treatment for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. |