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

NCT ID: NCT02194998

Last Updated: 2021-11-04

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-16
• Study Completion Date: 2018-11-13

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.

Conditions

HIV Infections; Hepatitis C

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort A [INI-based ART + PTV/r/OBT + DSV +/- RBV 24 Weeks]

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)).

Group Type: EXPERIMENTAL

Paritaprevir/ritonavir/ombitasvir (PTV/r/OBT)

Intervention Type: DRUG

PTV/r/OBT: 150/100/25 mg (two 75/50/12.5 mg fixed-dose combination tablets) orally once a day

Dasabuvir (DSV)

Intervention Type: DRUG

DSV: 250 mg orally twice a day

Ribavirin (RBV)

Intervention Type: DRUG

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))

Cohort B [INI-based ART + PTV/r/OBT + DSV +/- RBV 12 Weeks]

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)).

Group Type: EXPERIMENTAL

Paritaprevir/ritonavir/ombitasvir (PTV/r/OBT)

Intervention Type: DRUG

PTV/r/OBT: 150/100/25 mg (two 75/50/12.5 mg fixed-dose combination tablets) orally once a day

Dasabuvir (DSV)

Intervention Type: DRUG

DSV: 250 mg orally twice a day

Ribavirin (RBV)

Intervention Type: DRUG

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))

Cohort C [PI-based ART + PTV/r/OBT + DSV +/- RBV 24 Weeks]

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)).

Group Type: EXPERIMENTAL

Paritaprevir/ritonavir/ombitasvir (PTV/r/OBT)

Intervention Type: DRUG

PTV/r/OBT: 150/100/25 mg (two 75/50/12.5 mg fixed-dose combination tablets) orally once a day

Dasabuvir (DSV)

Intervention Type: DRUG

DSV: 250 mg orally twice a day

Ribavirin (RBV)

Intervention Type: DRUG

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))

Cohort D [PI-based ART + PTV/r/OBT + DSV +/- RBV 12 Weeks]

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)).

Group Type: EXPERIMENTAL

Paritaprevir/ritonavir/ombitasvir (PTV/r/OBT)

Intervention Type: DRUG

PTV/r/OBT: 150/100/25 mg (two 75/50/12.5 mg fixed-dose combination tablets) orally once a day

Dasabuvir (DSV)

Intervention Type: DRUG

DSV: 250 mg orally twice a day

Ribavirin (RBV)

Intervention Type: DRUG

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))

Interventions

Paritaprevir/ritonavir/ombitasvir (PTV/r/OBT)

PTV/r/OBT: 150/100/25 mg (two 75/50/12.5 mg fixed-dose combination tablets) orally once a day

Intervention Type: DRUG

Dasabuvir (DSV)

DSV: 250 mg orally twice a day

Intervention Type: DRUG

Ribavirin (RBV)

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))

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mark S. Sulkowski, MD

Role: STUDY_CHAIR

Johns Hopkins University

Locations

Alabama CRS

Birmingham, Alabama, United States

UCLA CARE Center CRS

Los Angeles, California, United States

University of Colorado Hospital CRS

Aurora, Colorado, United States

Whitman-Walker Health CRS

Washington D.C., District of Columbia, United States

Rush University CRS

Chicago, Illinois, United States

Johns Hopkins University CRS

Baltimore, Maryland, United States

New Jersey Medical School Clinical Research Center CRS

Newark, New Jersey, United States

Weill Cornell Chelsea CRS

New York, New York, United States

Cincinnati Clinical Research Site

Cincinnati, Ohio, United States

Penn Therapeutics, CRS

Philadelphia, Pennsylvania, United States

University of Pittsburgh CRS

Pittsburgh, Pennsylvania, United States

The Miriam Hospital Clinical Research Site (TMH CRS) CRS

Providence, Rhode Island, United States

Trinity Health and Wellness Center CRS

Dallas, Texas, United States

Houston AIDS Research Team CRS

Houston, Texas, United States

University of Washington AIDS CRS

Seattle, Washington, United States

Puerto Rico AIDS Clinical Trials Unit CRS

San Juan, , Puerto Rico

Countries

United States; Puerto Rico

References

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.

Reference Type: DERIVED

PMID: 32406487 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://rsc.niaid.nih.gov/sites/default/files/table-for-grading-severity-of-adult-pediatric-adverse-events.pdf

DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009).

http://rsc.niaid.nih.gov/sites/default/files/manual-exped-aes-v2_0.pdf

Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010.

Other Identifiers

11935

Identifier Type: REGISTRY

Identifier Source: secondary_id

A5329

Identifier Type: -

Identifier Source: org_study_id