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Immunologic Effects of HCV Therapy With HARVONI in HCV Genotype 1 Chronically Mono-infected Active and Former IDUs

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ClinicalTrials.gov Identifier: NCT02347345
Recruitment Status : Completed
First Posted : January 27, 2015
Results First Posted : August 13, 2019
Last Update Posted : August 13, 2019
Sponsor:
Collaborator:
National Institute on Drug Abuse (NIDA)
Information provided by (Responsible Party):
Martin Markowitz, Rockefeller University

Brief Summary:
The investigator's hypothesis is that active injectors will show a partial reduction in markers of immune activation with HCV therapy whereas non-injectors will show a more significant reduction in these markers, and will exhibit levels of immune activation that approach that seen in similarly studied healthy volunteers.This is based on observations that this group of investigators have made. They have shown that individuals who inject drugs have high level of immune activation in blood and tissue. Immune activation or chronic inflammation has been associated with accelerated aging, cardiovascular, renal and liver disease as well as CNS dysfunction. It remains unclear whether increased levels of immune activation are due to non-sterile injection of drugs, chronic infection with Hepatitis C, chronic opiate use, or perhaps combinations of all 3. To understand the potential contribution of infection with Hepatitis C the investigators will compare levels of immune activation pre- and post treatment with an all oral, one pill once daily, interferon sparing treatment of HCV in 2 groups of chronically HCV infected patients- one actively injecting with drugs and the other free of injection for at least 4 months. Immune activation comparisons will also include non-injecting healthy volunteers.

Condition or disease Intervention/treatment Phase
Hepatitis C Drug: Harvoni (Fixed dose combination ledipasvir/sofosbuvir) Phase 4

Detailed Description:

This group of multidisciplinary investigators has discovered increased levels of immune activation among HIV-1-uninfected active injection drug users (IDUs) when compared to non-IDU controls . The vast majority (80%) are also infected with HCV.

Active injectors have high levels of immune activation as measured by sCD14, CD8 co-expression of CD38 and HLA-DR, as well as Type 1 cytokines.

Within months of ceasing injecting, there are observable decreases in some parameters however in general they remain elevated when compared to non-injecting healthy volunteers.

As approximately 80% of these subjects are HCV infected and viremic, these results are confounded as to the cause of the observed increased levels of markers of immune activation- active injection or chronic Hepatitis C. Until recently HCV treatment required the use of IFN which has immunomodulatory activity which would cause perturbations in the markers of immune activation. However the development of direct acting agents (DAA) to treat HCV has revolutionized therapy. In this trial the investigators will employ the once daily FDC formulation of sofosbuvir and ledipasvir to assess changes in markers of immune activation during therapy.

There have been multiple clinical trials of FDC LDV-SOF in patients with Genotype 1 HCV. When taken once daily for 12 weeks, sustained virologic response rates have been very high with response rates nearing 99% in most studies with a 12-week course of therapy.

Common adverse events associated with FDC LDV-SOF in ION-1 include fatigue (21%), headache (25%), nausea (11%), insomnia (8%), asthenia (7%), diarrhea (11%), rash (7%), irritibility (7%), cough (3%), and pruritis (5%).

Ledipasvir undergoes minimal metabolism and expectations are that this medication will have few clinically significant drug-drug interactions. In general, sofosbuvir is considered to have relatively few clinically significant drug-drug interactions, but coadministration of sofosbuvir with the following medications is not recommended because these medications may significantly lower sofosbuvir levels:

Anticonvulsants: carbamazepine, oxycarbazepine, phenobarbital, and phenytoin Antimycobacterials: rifabutin, rifampin, rifapentine Herbal Supplements: St. John's wort HIV Protease Inhibitors: tipranavir-ritonavir Antiarrhythmic Drugs : amiodarone (Cordarone®, Nexterone®, Pacerone®)

Participants will be provided with a 12-week course of FDC LDV-SOF which will provide a near 99% likelihood of a SVR in participants who are adherent to therapy with low likelihood of significant adverse events and drug-drug interactions.

In treating HCV effectively the investigators will measure changes in immune activation and gene expression that accompany HCV treatment.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Immunologic Effects of HCV Therapy With Fixed Dose Combination Ledipasvir/Sofosbuvir (HARVONI) in HCV Genotype 1 Chronically Mono-infected Active and Former IDUs.
Actual Study Start Date : November 15, 2016
Actual Primary Completion Date : November 15, 2016
Actual Study Completion Date : November 15, 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Sofosbuvir

Arm Intervention/treatment
Active Comparator: Active injection drug use (IDU)
In active IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill orally daily x 12 weeks
Drug: Harvoni (Fixed dose combination ledipasvir/sofosbuvir)
Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill daily x 12 weeks
Other Name: Fixed dose combination ledipasvir/sofosbuvir

Active Comparator: Former injection drug use (former IDU)
In former IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill orally daily x 12 weeks
Drug: Harvoni (Fixed dose combination ledipasvir/sofosbuvir)
Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill daily x 12 weeks
Other Name: Fixed dose combination ledipasvir/sofosbuvir

No Intervention: Healthy volunteers
HIV, HCV and HBV negative, never injected drugs, no recreational drugs for at least 2 years (does not include marijuana) and negative urine screen for opiates at the screening visit.



Primary Outcome Measures :
  1. sCD14 (ng/mL) [ Time Frame: 24 weeks ]
    Marker of immune activation as measured by levels of soluble CD14. Note that the levels of sCD14 were only measured at baseline in the Healthy Volunteers group and therefore there are no data for weeks 4, 12, or 24 entered.


Secondary Outcome Measures :
  1. Virologic Response to Therapy as Measured by HCV RNA [ Time Frame: 24 weeks ]
    HCV RNA levels in plasma (IU/mL)

  2. Gene Expression Profiles [ Time Frame: 24 weeks ]
    Gene expression profiles in PBMC will be determined using RNA Seq



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Ability to give written informed consent in English
  2. Age≥18 and ≤55
  3. HCV antibody positive
  4. HCV RNA >1,000 copies/mL plasma
  5. HCV treatment naive
  6. HCV genotype 1a or 1b or mixed type 1
  7. AST, ALT <10x ULN
  8. Direct bilirubin <3.0
  9. Platelet count >50,000
  10. Creatinine clearance >30mL/min as estimated by Cockroft Gault
  11. Hemoglobin >10 if female, >11 if male
  12. Albumin > 2.8
  13. INR<2.0
  14. If Group A: urine dip for opiates + and active injection drug use of heroin defined as injecting at least 3 times per week.
  15. If Group B then no IDU for at least 4 months and a negative urine for opiates at screening.
  16. Venous access for phlebotomy
  17. Willingness to agree to effective contraception during the course of the study.
  18. If Group C: - negative urine for opiates at screening

    • no recreational drug use for at least 2 years (excluding marijuana)
    • HIV, HCV and HBV uninfected

Exclusion Criteria:

  1. HIV infection
  2. Chronic infection with Hepatitis B
  3. Uncompensated cirrhosis
  4. Required use of:

    Anticonvulsants: carbamazepine, oxycarbazepine, phenobarbital, and phenytoin

    Antimycobacterials: rifabutin, rifampin, rifapentine

    Herbal Supplements: St. John's wort

    HIV Protease Inhibitors: tipranavir-ritonavir

    Antiarrhythmic Drugs: amiodarone (Cordarone, Nexterone, Pacerone)

  5. Any medical condition that in the opinion of the investigator would interfere with study participation and medical adherence
  6. Pregnancy/breast feeding

    -


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02347345


Locations
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United States, New York
Rockefeller University Hospital
New York, New York, United States, 10021
Sponsors and Collaborators
Rockefeller University
National Institute on Drug Abuse (NIDA)
Investigators
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Principal Investigator: Martin Markowitz, MD ADARC/Rockefeller University

Publications of Results:
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Responsible Party: Martin Markowitz, Aaron Diamond Professor/Clinical Director, Rockefeller University
ClinicalTrials.gov Identifier: NCT02347345     History of Changes
Other Study ID Numbers: MMA-0874
5R01DA033777 ( U.S. NIH Grant/Contract )
First Posted: January 27, 2015    Key Record Dates
Results First Posted: August 13, 2019
Last Update Posted: August 13, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Martin Markowitz, Rockefeller University:
HCV, injection drug use
Additional relevant MeSH terms:
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Hepatitis C
Hepatitis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Flaviviridae Infections
RNA Virus Infections
Sofosbuvir
Ledipasvir
Ledipasvir, sofosbuvir drug combination
Antiviral Agents
Anti-Infective Agents