Immunologic Effects of HCV Therapy With HARVONI in HCV Genotype 1 Chronically Mono-infected Active and Former IDUs
Study Details
Study Description
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 |
|---|---|---|
|
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.
Study Design
Arms and Interventions
| 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 Names:
|
| 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 Names:
|
| 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. |
Outcome Measures
Primary Outcome Measures
- sCD14 (ng/mL) [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
- Virologic Response to Therapy as Measured by HCV RNA [24 weeks]
HCV RNA levels in plasma (IU/mL)
- Gene Expression Profiles [24 weeks]
Gene expression profiles in PBMC will be determined using RNA Seq
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Ability to give written informed consent in English
-
Age≥18 and ≤55
-
HCV antibody positive
-
HCV RNA >1,000 copies/mL plasma
-
HCV treatment naive
-
HCV genotype 1a or 1b or mixed type 1
-
AST, ALT <10x ULN
-
Direct bilirubin <3.0
-
Platelet count >50,000
-
Creatinine clearance >30mL/min as estimated by Cockroft Gault
-
Hemoglobin >10 if female, >11 if male
-
Albumin > 2.8
-
INR<2.0
-
If Group A: urine dip for opiates + and active injection drug use of heroin defined as injecting at least 3 times per week.
-
If Group B then no IDU for at least 4 months and a negative urine for opiates at screening.
-
Venous access for phlebotomy
-
Willingness to agree to effective contraception during the course of the study.
-
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:
-
HIV infection
-
Chronic infection with Hepatitis B
-
Uncompensated cirrhosis
-
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)
-
Any medical condition that in the opinion of the investigator would interfere with study participation and medical adherence
-
Pregnancy/breast feeding
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Rockefeller University Hospital | New York | New York | United States | 10021 |
Sponsors and Collaborators
- Rockefeller University
- National Institute on Drug Abuse (NIDA)
Investigators
- Principal Investigator: Martin Markowitz, MD, ADARC/Rockefeller University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MMA-0874
- 5R01DA033777
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Active Injection Drug Use (IDU) | Former Injection Drug Use (Former IDU) | Healthy Volunteers |
|---|---|---|---|
| Arm/Group Description | In active IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill oral daily x 12 weeks. | In former IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill oral daily x 12 weeks. | 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 screening. |
| Period Title: Overall Study | |||
| STARTED | 10 | 12 | 12 |
| COMPLETED | 10 | 12 | 12 |
| NOT COMPLETED | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Active Injection Drug Use (IDU) | Former Injection Drug Use (Former IDU) | Healthy Volunteers | Total |
|---|---|---|---|---|
| Arm/Group Description | In active IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill oral daily x 12 weeks. | In former IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill oral daily x 12 weeks. | 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 screening. | Total of all reporting groups |
| Overall Participants | 10 | 12 | 12 | 34 |
| Age (Count of Participants) | ||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
10
100%
|
12
100%
|
12
100%
|
34
100%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
3
30%
|
4
33.3%
|
4
33.3%
|
11
32.4%
|
| Male |
7
70%
|
8
66.7%
|
8
66.7%
|
23
67.6%
|
| Region of Enrollment (Count of Participants) | ||||
| United States |
10
100%
|
12
100%
|
12
100%
|
34
100%
|
Outcome Measures
| Title | sCD14 (ng/mL) |
|---|---|
| Description | 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. |
| Time Frame | 24 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| 9/10 Active injectors, 11/12 former injectors and 12/12 healthy volunteers completed the study. |
| Arm/Group Title | Active Injection Drug Use (IDU) | Former Injection Drug Use (Former IDU) | Healthy Volunteers |
|---|---|---|---|
| Arm/Group Description | In active IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill orally daily x 12 weeks Harvoni (Fixed dose combination ledipasvir/sofosbuvir): Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill daily x 12 weeks | In former IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill orally daily x 12 weeks Harvoni (Fixed dose combination ledipasvir/sofosbuvir): Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill daily x 12 weeks | 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. |
| Measure Participants | 10 | 12 | 12 |
| baseline |
1986
(217)
|
1918
(208)
|
1542
(249)
|
| week 4 |
2060
(443)
|
1805
(183)
|
|
| week 12 |
2036
(339)
|
1782
(193)
|
|
| week 24 |
1973
(266)
|
1819
(193)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Active Injection Drug Use (IDU), Former Injection Drug Use (Former IDU), Healthy Volunteers |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Descriptive pilot study. Not relevant. | |
| Statistical Test of Hypothesis | p-Value | 0.07 |
| Comments | ||
| Method | Kruskal-Wallis | |
| Comments | ||
| Title | Virologic Response to Therapy as Measured by HCV RNA |
|---|---|
| Description | HCV RNA levels in plasma (IU/mL) |
| Time Frame | 24 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| 9/10 Active injectors, 11/12 former injectors and 12/12 healthy volunteers completed the study. Healthy volunteers are HCV uninfected therefore HCV RNA levels are not measured on this group of participants. |
| Arm/Group Title | Active Injection Drug Use (IDU) | Former Injection Drug Use (Former IDU) | Healthy Volunteers |
|---|---|---|---|
| Arm/Group Description | In active IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill oral daily x 12 weeks. | In former IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill oral daily x 12 weeks. | 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 screening. |
| Measure Participants | 10 | 12 | 0 |
| baseline |
7781148
(8662099)
|
2320026
(3994266)
|
|
| week 12 |
0
(0)
|
0
(0)
|
|
| week 24 |
0
(0)
|
0
(0)
|
| Title | Gene Expression Profiles |
|---|---|
| Description | Gene expression profiles in PBMC will be determined using RNA Seq |
| Time Frame | 24 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| 9/10 Active injectors, 11/12 former injectors and 12/12 healthy volunteers completed the study. Healthy volunteers were only studied at baseline. No data for weeks 4, 12, 24. |
| Arm/Group Title | Active Injection Drug Use (IDU) | Former Injection Drug Use (Former IDU) | Healthy Volunteers |
|---|---|---|---|
| Arm/Group Description | In active IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill oral daily x 12 weeks. | In former IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill oral daily x 12 weeks. | 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 screening. |
| Measure Participants | 9 | 11 | 12 |
| baseline |
9
|
11
|
12
|
| 4 weeks |
9
|
11
|
|
| 12 weeks |
9
|
11
|
|
| 24 weeks |
9
|
11
|
Adverse Events
| Time Frame | ||||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Active Injection Drug Use (IDU) | Former Injection Drug Use (Former IDU) | Healthy Volunteers | |||
| Arm/Group Description | In active IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill oral daily x 12 weeks. | In former IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill oral daily x 12 weeks. | 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 screening. | |||
All Cause Mortality |
||||||
| Active Injection Drug Use (IDU) | Former Injection Drug Use (Former IDU) | Healthy Volunteers | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/10 (0%) | 1/12 (8.3%) | 0/12 (0%) | |||
Serious Adverse Events |
||||||
| Active Injection Drug Use (IDU) | Former Injection Drug Use (Former IDU) | Healthy Volunteers | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/10 (0%) | 1/12 (8.3%) | 0/12 (0%) | |||
| General disorders | ||||||
| Drug overdose | 0/10 (0%) | 0 | 1/12 (8.3%) | 1 | 0/12 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| Active Injection Drug Use (IDU) | Former Injection Drug Use (Former IDU) | Healthy Volunteers | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/10 (0%) | 0/12 (0%) | 0/12 (0%) | |||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Martin Markowitz MD |
|---|---|
| Organization | Aaron Diamond AIDS Research Center |
| Phone | 212-448-5020 |
| mmarkowitz@adarc.org |
- MMA-0874
- 5R01DA033777