Clinical trial NCT02194998: Evaluating the Safety and Effectiveness of Interferon-Free Treatment of Hepatitis C Virus Infection in HIV-Coinfected Adults on Antiretroviral Therapy
Official title: Interferon-Free Therapy for Chronic Hepatitis C Virus Genotype 1 Infection in Participants With HIV-1 Coinfection Receiving Concurrent Antiretroviral Therapy (C_ASCENT)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: HIV Infections
Hepatitis C
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2014-07-21
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants With Sustained Virologic Response at 12 Weeks After HCV Treatment Discontinuation (SVR12)
timeFrame: 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.
measure: Number of Participants With an Occurrence of Serious Adverse Events (SAEs) as Defined by International Conference on Harmonisation (ICH) Criteria
timeFrame: 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.
measure: Number of Participants Who Prematurely Discontinued HCV Study Treatment for Any Reason Other Than HCV Virologic Failure (VF)
timeFrame: 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.
measure: Number of Participants With an Occurrence of Signs/Symptoms Grade 3 or Higher
timeFrame: 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.
measure: Number of Participants With an Occurrence of Diagnoses Leading to Premature HCV Study Treatment or HIV-1 Antiretroviral (ARV) Discontinuation.
timeFrame: 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.
measure: Number of Participants With an Occurrence of Laboratory Abnormality Grade 3 or Higher.
timeFrame: 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 outcomes:
measure: Number of Participants Who Experienced HIV-1 Virologic Failure (VF)
timeFrame: 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.
measure: Number of Participants With Selected HIV-1 Resistance Mutations Among Participants Who Experience HIV-1 Virologic Failure (VF)
timeFrame: At confirmation of HIV-1 virologic failure.
measure: Levels of Soluble CD14 (sCD14)
timeFrame: 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.
measure: Change in Soluble CD14 (sCD14)
timeFrame: 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.
measure: Levels of IP-10 Concentration.
timeFrame: 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.
measure: Change in IP-10 Concentration.
timeFrame: 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.
measure: Number of Participants With HCV Mutations Conferring Resistance to Any Component of the HCV Treatment Regimen
timeFrame: 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.
measure: Percentage of Participants With Sustained Virologic Response at 24 Weeks After HCV Treatment Discontinuation (SVR24)
timeFrame: 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.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama CRS
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Washington
country: United States
facility: Whitman-Walker Health CRS
state: District of Columbia
city: Chicago
country: United States
facility: Rush University CRS
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University CRS
state: Maryland
city: Newark
country: United States
facility: New Jersey Medical School Clinical Research Center CRS
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Chelsea CRS
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Clinical Research Site
state: Ohio
city: Philadelphia
country: United States
facility: Penn Therapeutics, CRS
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh CRS
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hospital Clinical Research Site (TMH CRS) CRS
state: Rhode Island
city: Dallas
country: United States
facility: Trinity Health and Wellness Center CRS
state: Texas
city: Houston
country: United States
facility: Houston AIDS Research Team CRS
state: Texas
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: San Juan
country: Puerto Rico
facility: Puerto Rico AIDS Clinical Trials Unit CRS
Study officials:
affiliation: Johns Hopkins University
name: Mark S. Sulkowski, MD
role: STUDY_CHAIR
References:
citation: Anthony DD, Sulkowski MS, Smeaton LM, Damjanovska S, Shive CL, Kowal CM, Cohen DE, Bhattacharya D, Alston-Smith BL, Balagopal A, Wyles DL. Hepatitis C Virus (HCV) Direct-Acting Antiviral Therapy in Persons With Human Immunodeficiency Virus-HCV Genotype 1 Coinfection Resulting in High Rate of Sustained Virologic Response and Variable in Normalization of Soluble Markers of Immune Activation. J Infect Dis. 2020 Sep 14;222(8):1334-1344. doi: 10.1093/infdis/jiaa254.