HCV Treatment Immune Response With Grazoprevir/Elbasvir Before or After Renal Transplant

Host Mechanisms Involved in Achieving SVR Using Grazoprevir and Elbasvir in Treatment of Chronic Hepatitis C in Patients With CKD Before and After Renal Transplantation

The purpose of this study is to determine whether patients treated for chronic hepatitis C (HCV) with zepatier (grazoprevir/elbasvir) prior to kidney transplant will have a stronger immune response compared to patients treated after kidney transplant. 25 patients with chronic kidney disease (CKD) and HCV will be treated with zepatier and 25 kidney transplant recipients with chronic kidney disease will be treated with zepatier. Blood markers of immune function will be monitored in both groups to determine their response to therapy.

Study Overview

• Status: Completed
• Conditions: Renal Insufficiency, Chronic; Hepatitis C; Disorder of Transplanted Kidney
• Intervention / Treatment: Drug: Post-transplant Grazoprevir and Elbasvir

Detailed Description

The study will be a pilot, prospective, single-center, open-label, non-randomized, non-controlled, parallel clinical trial. 25 HCV genotype 1 infected patients post transplant will be enrolled in the study. Recruitment will be conducted through the renal transplant and nephrology outpatient clinics at the University of Maryland.

The post-transplant cohort will include renal transplant recipients of both living donor and deceased donor organs infected with HCV prior to their transplantation with GFRs <50 with active HCV viremia. These patients will be recruited from the University of Maryland's multidisciplinary transplant nephrology clinic or infectious disease clinic.

Screening All patients will be screened at the Institute of Human Virology (IHV) Clinical Research Unit. At this visit, all patients will have screening labs drawn and a history and physical examination performed. Additional requirements will be genotype testing prior to enrollment, but after transplant and disease staging within 12 months of enrollment by liver biopsy, elastography, or biochemical testing. For those who do not have a genotype or disease staging within the specified time frame, genotyping and elastography will be repeated as part of the study screening work up. Eligibility will be determined based upon these results within 6 weeks of starting the study drugs.

Given the reduced efficacy of this regimen in patients with genotype 1a with the presence of baseline NS5A resistance-associated variants (RAVs), the investigators will screen patients for RAVs in patients with HCV genotype 1a at the time of enrollment. Any patient with genotype 1a HCV found to have NS5A RAVs will undergo 16 weeks of therapy according to current treatment guidelines.

Starting therapy Study drugs will be administered starting on day 0 after a history and physical examination is performed and safety labs are checked. All patients will sign an informed consent as approved by our Institutional Review Board (IRB) prior to administration of study drugs.

Study visits during treatment Patients will be followed every 4 weeks while they are receiving study drugs. HCV viral load (VL), safety labs and hepatic panel will be performed at each of these visits. Patients will also be advised about study adherence and monitored for adverse events.

Safety and adverse event monitoring At each study visit, research nurses will inquire about adverse events that may or may not be related to study drugs. Any unfavorable medical occurrences will be recorded, whether or not considered related to the patient's participation in the research, temporally associated with the patient's participation in the research. Adverse events (AEs) classified as grade 3 or higher will be reported to the IRB and principal investigator. Any grade 3 or 4 AEs and all serious adverse events (SAEs) will be reviewed as they occur by the study team.

Safety labs will also be drawn at these visits. Levels of immunosuppressive agents will also be determined at these visits as appropriate. The need for dose modification of the patient's immunosuppression in the time between visits will be recorded.

End of treatment visit Patients will be seen 12 weeks after starting study drugs (or 16 weeks in the case of genotype 1a patients with baseline NS5A RAVs) for an end of study visit. HCV VL, safety labs and hepatic panel will be performed at this visit. Patients will also be counseled about study adherence and the investigators will inquire about adverse events.

Post treatment follow up visits Patients will be followed every 4 weeks for 12 weeks after they complete treatment. HCV VL, safety labs and a hepatic panel will be performed at these visits.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• At least 18 years of age at the time of screening
• Have stable renal function for one month (30 days) prior to enrollment
• Have Chronic HCV infection prior to transplantation with documented HCV viremia ≥ 1,000 IU/ml at screening and either documented HCV Ab positivity or HCV viremia ≥ 1,000 IU/ml at least 6 months prior to enrollment.
• Documented genotype 1 HCV infection prior to enrollment and after their transplant in the post-transplantation cohort
• HCV disease staging within 12 months prior to enrollment by liver biopsy, transient elastography, or biochemical testing
• Be able to give informed consent and comply with study guidelines
• Women of childbearing age will be required to have a negative pregnancy test at enrollment and use birth control throughout the duration of treatment.

Inclusion Criteria Specific to the Pre-transplant Arm

Patients will either be:

• On the transplant waiting list followed by the University of Maryland's nephrology clinic or the Baltimore VA's nephrology clinic
• On chronic hemodialysis not yet on the transplant list and followed in the University's hemodialysis center or in the University's nephrology clinic
• Have chronic kidney disease with GFR <50

Inclusion Criteria Specific to the Post-transplant Arm

• Patients will have undergone renal transplantation no greater than five years prior to enrollment and will be followed in our University's nephrology and infectious disease clinic. They will all have stable renal function at the time of enrollment.

Exclusion Criteria:

• Documented positive hepatitis B (HBV) surface antigen, and/or HBV DNA prior to enrollment
• Any prior exposure to HCV protease inhibitor therapy
• HIV co-infection if on a protease inhibitor based regimen
• Increase in creatinine of 15% or greater within one month (30 days) of the screening visit
• Evidence of hepatocellular carcinoma at the time of enrollment
• Liver disease caused by an etiology other than HCV
• F4 or decompensated cirrhotic patients
• Child Pugh class B or C
• AST or ALT >350 within 6 months prior to enrollment
• Albumin < 3g/dL at the time of enrollment
• Platelet count < 75 at the time of enrollment
• History of clinically significant allergy or adverse event with protease inhibitors
• Evidence of the acquisition of HCV at the time of or after transplantation
• Pregnant or breastfeeding women
• Cyclosporine; St. John's Wort; Efavirenz; Phenytoin; Carbamazepine; Bosentan; HIV protease inhibitors; modafinil; ketoconazole; or rifampin use within 7 days of enrollment
• Coadministration of more than 20 mg atorvastatin; 10 mg rosuvastatin; 20 mg of fluvastatin, lovastatin or simvastatin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Post-transplant; This arm will evaluate the treatment of patients with HCV and chronic kidney disease (GFR <50) who have had a kidney transplant using grazoprevir and elbasvir.	Drug: Post-transplant Grazoprevir and Elbasvir; Treatment will be started in the post-transplant patients on day 0 with the combination pill zepatier, containing grazoprevir 100mg/elbasvir 50mg by mouth once daily. The medications will be continued for a total of 12 weeks (16 weeks if resistance mutations, RAVs, are detected); Other Names: Zepatier

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SVR 12	Sustained virologic response (SVR) will be assessed by measuring the quantitative HCV viral load 12 weeks after completing treatment. This will be a measure of circulating HCV virus in participants off therapy, 12 weeks after finishing treatment, to determine the durability of the response to the treatment.	This will be measured at post-treatment week 12 (study week 24 or week 28 for those with resistance mutations)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety as Assessed by Adverse Event Monitoring, Including Routine Lab Work	Safety will be assessed by adverse event monitoring, including routine lab work	This will be measured at day 0, weeks 2, 4, 8, 12 (and 16 if resistance mutations are present)
Kidney Function	Clinical review using labs and the patient's chart will be performed for change in kidney graft function by change in eGFR or creatinine	This will be measured at day 0, treatment week 2, treatment week 4, treatment week 8, treatment week 12, ( treatment week 16, if applicable), post-treatment week 4 (week 16/20), and post-treatment week 12 (week 24/28)
Change in T Cell Response	The study will involve measuring the change in T cell response by analyzing the frequency of exhaustion markers PD-1 and activation markers ICOS, CD38, CD69 at day 0, week 4, and week 12.	This will be collected at day 0, week 4, and week 12
Change in T Cell Immunophenotypes	The study will involve measuring the change in T cell immunophenotypes	This will be collected at day 0, week 4, and week 12
Quantification of Antiviral Cytokines	The study will involve measuring interferon gamma and TNF alpha levels	This will be collected at day 0 and week 4
Kidney Allograft Rejection	Clinical review using labs and the patient's chart will be performed for documented episodes of kidney rejection	This will be measured at post-treatment week 12

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Investigators: Principal Investigator: Jennifer S Husson, MD, University of Maryland School of Medicine, Institute of Human Virology

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2017
• Primary Completion (Actual): September 1, 2021
• Study Completion (Actual): June 8, 2022

Study Registration Dates

• First Submitted: August 19, 2016
• First Submitted That Met QC Criteria: September 14, 2016
• First Posted (Estimated): September 15, 2016

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Kidney Diseases; Urologic Diseases; Disease Attributes; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Renal Insufficiency, Chronic; Hepatitis; Hepatitis C; Renal Insufficiency; Anti-Infective Agents; Antiviral Agents; Grazoprevir
• Other Study ID Numbers: HP-00071069

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported, after deidentification will be shared.
• IPD Sharing Time Frame: Data will be available immediately upon publication for a duration of 5 years following publication.
• IPD Sharing Access Criteria: Investigators who provide a methodologically sound proposal to achieve the aims in the approved proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No